Fetopathy due to Renin-Angiotensin System Inhibitors

Fetal renin-angiotensin system blockade syndrome and renal tubular dysgenesis, in the pharmacological and the genetic forms

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

Fetopathy due to renin-angiotensin system inhibitors is the set of fetal and neonatal lesions resulting from pharmacological blockade of the maternal-fetal renin-angiotensin system (RAS) during gestation, particularly from the second half of pregnancy onwards. The picture combines fetal anuria, oligohydramnios or anhydramnios, neonatal renal failure, arterial hypotension resistant to vasopressors, pulmonary hypoplasia, an ossification defect of the cranial vault and growth restriction, and carries high perinatal mortality [9, 12]. The renal lesion that serves as its histological substrate is renal tubular dysgenesis, characterised by the absence or paucity of differentiated proximal tubules, with glomeruli and distal tubules relatively preserved [14, 16].

The interest of this picture for medical genetics is twofold. On the one hand, it is a drug-induced embryofetopathy that constitutes a mandatory differential diagnosis of the dysmorphic syndromes with oligohydramnios sequence, and whose identification depends on a dated drug history, because no morphological or histological finding distinguishes it from the genetic forms [5, 27]. On the other hand, the same phenotype may result from biallelic variants in four genes of the renin-angiotensin system itself, in an autosomal recessive Mendelian disease whose recurrence risk is 25% per pregnancy, in contrast with the risk of the pharmacological form, which is determined by continuation or withdrawal of the drug [3, 8]. The distinction conditions reproductive counselling, prenatal diagnosis and the decision on continuation of the pregnancy.

The clinical history of the problem begins in the first years of inadvertent obstetric use of ACE inhibitors. In 1984, Boutroy and colleagues described that the administration of captopril in pregnancy reduced fetal angiotensin-converting enzyme activity and compromised neonatal adaptation [28]. In 1991, Barr and Cohen proposed the link between the renal lesion and hypoplasia of the cranial vault, the “kidney-skull connection”, interpreting hypocalvaria as a consequence of prolonged fetal hypotension on the membranous bone of the skull, highly vascularised and dependent on high oxygen tension to ossify, unlike bones of endochondral origin, which are not affected [3]. In 1993, Pryde, Sedman, Nugent and Barr described three infants with intrauterine exposure and an adverse outcome and consolidated the designation ACE inhibitor fetopathy, defined by fetal hypotension, anuria with oligohydramnios, growth restriction, pulmonary hypoplasia, renal tubular dysplasia and hypocalvaria [29]. In 1994, Barr published the teratogen update that fixed the clinical pattern and the proposed mechanism: the consistency of the association between the class and the combination of oligohydramnios-anuria, neonatal hypotension, renal dysplasia and hypocalvaria justified restricting use before formal epidemiological proof was available, and mammalian models showed dose-dependent fetotoxicity [30]. The author added that, the underlying mechanism being fetal hypotension, the fetopathy might not be exclusive to this class, although ACE inhibitors were particularly prone to produce the renal effects and their consequences [30].

The extension of the problem to angiotensin II AT1 receptor antagonists was reported in 2001 by Martinovic and colleagues, in a letter on fetal toxic effects of these drugs [31], and confirmed by subsequent series that showed a risk higher than that of ACE inhibitors [12, 17]. In 2012, Bullo and colleagues assembled seventy-two published reports, with 118 documented cases of exposure to ACE inhibitors and 68 of exposure to ARBs, and proposed the unified designation fetal renin-angiotensin system blockade syndrome, since the picture depends on the common mechanism and not on the drug class [1]. The current nomenclature reflects this unification: Orphanet classifies renal tubular dysgenesis (ORPHA:3033) and distinguishes three aetiological subtypes, the form of genetic origin (ORPHA:97369), the drug-induced form (ORPHA:97368) and the form due to twin-to-twin transfusion (ORPHA:97367), recognising that the same lesion results from fetal renal hypoperfusion of any cause [2, 4, 11, 32].

The genetic side of the story followed an independent course until 2005. Renal tubular dysgenesis was described as a familial pathological entity by Allanson, Pantzar and MacLeod in 1983, in two stillborn sisters of a non-consanguineous couple, with Potter sequence and absent convoluted proximal tubules, all tubules having a primitive appearance and resembling collecting ducts [3]. Subsequent series extended the description: Swinford and colleagues in 1986 in a second non-consanguineous family, MacMahon and colleagues in 1990 with a review of twelve cases in five families, and Allanson and colleagues in 1992 with nine additional cases from a single paediatric centre, work that noted that amniotic fluid volume may be normal before 22 weeks and that oligohydramnios in the late second trimester with structurally normal kidneys should raise suspicion and prompt detailed pathological examination [3]. In 1995, Ariel and colleagues demonstrated, by nephron microdissection in an infant of consanguineous Palestinian parents, marked hypoplasia of every segment of the nephron, from the glomerulus to the collecting duct, and suggested that hypoplasia of the distal portions, and not only of the convoluted proximal tubule, is characteristic of the disease [3]. In 1997, McFadden and colleagues gathered the cranial anomalies scattered across the published cases, noted that six of Allanson's twenty-four cases had microcephaly, underdeveloped cranial bones or very wide fontanelles, and concluded that skull anomalies are a common component of the hereditary form, as they were already known to be of the form acquired through maternal ACE inhibitor use [3]. The aetiological convergence was thus foreshadowed by pathology before it was demonstrated by genetics.

The founding paper of the Mendelian form is by Gribouval and colleagues, published in Nature Genetics in 2005: in eleven individuals from nine families with renal tubular dysgenesis, the authors identified homozygous or compound heterozygous variants in the genes for renin, angiotensinogen, angiotensin-converting enzyme and angiotensin II type 1 receptor, and proposed that the renal lesions and the early anuria result from the chronically low perfusion pressure of the fetal kidney, a consequence of inactivity of the renin-angiotensin system [10]. It was the first Mendelian renal disease attributed to genetic defects of this system. The same work explicitly framed the acquired form: fetal renal hypoperfusion had been proposed as the mechanism from the findings in twin-to-twin transfusion of monochorionic pregnancies, in which the donor fetus may develop renal tubular dysgenesis, in major cardiac malformations and in severe liver diseases, and dysgenesis with wide fontanelles had been observed in fetuses exposed in utero to ACE inhibitors or to angiotensin II receptor antagonists [3, 10]. In 2006, Lacoste and colleagues characterised the expression of the renin-angiotensin system in twenty-nine fetuses or newborns from eighteen families and established the correlation between the severity of the tubular lesion and loss of immunostaining for angiotensinogen and the converting enzyme in the proximal tubule [16]. In 2012, the review by Gribouval and colleagues assembled fifty-four distinct variants in forty-eight unrelated families and showed that the clinical course is similar whichever gene is mutated, which underlines that the disease results from defects of the common pathway and not of one particular gene [3, 14].

The two histories converged at one point of prognosis. Until 2008 it was considered that all patients with the hereditary form died in utero or in the first days of life; Zingg-Schenk and colleagues then reported the first patients to survive the neonatal period and remain alive, and noted that the clinical diagnosis is easily missed after birth without renal biopsy or information on affected relatives [33]. The past decade has accumulated survivors in both forms, with chronic kidney disease of variable stage, and has shifted the clinical question from the recognition of lethality to the decision on the intensity of neonatal support and to long-term follow-up [13, 21, 34, 35].

For the purposes of this article, fetopathy due to renin-angiotensin system inhibitors is defined as the set of fetal and neonatal manifestations attributable to intrauterine exposure to ACE inhibitors, to ARBs, to direct renin inhibitors or to combinations containing one of these agents, and autosomal recessive renal tubular dysgenesis as the Mendelian disease caused by biallelic variants in ACE, REN, AGT or AGTR1. Renal tubular dysgenesis due to twin-to-twin transfusion and the forms secondary to other causes of fetal renal hypoperfusion are addressed under the differential diagnosis. Congenital anomalies of the kidney and urinary tract in general, REN-associated autosomal dominant tubulointerstitial kidney disease and the polycystic kidney diseases are referred to here only as differential diagnoses.

2. Molecular Genetics and Pathophysiology

2.1 The renin-angiotensin cascade and the points of pharmacological blockade

The renin-angiotensin system is a proteolytic cascade of four main components, each of which corresponds simultaneously to a gene of the Mendelian form and to a target of a class of antihypertensive drugs. The gene AGT (1q42.2; MIM 106150) encodes angiotensinogen, the hepatic precursor of the system, which renin cleaves into angiotensin I [36, 37]. The gene REN (1q32.1; MIM 179820) encodes renin, an aspartic protease produced by the juxtaglomerular cells and secreted after cleavage of a signal peptide and a prosegment; angiotensinogen is its only known substrate, and its cleavage is the rate-limiting step of the whole cascade [7, 38]. The gene ACE (17q23.3; MIM 106180) encodes angiotensin-converting enzyme, a two-domain dipeptidyl carboxypeptidase that converts angiotensin I into angiotensin II and inactivates bradykinin, besides degrading enkephalins, substance P and neurotensin; it exists in a membrane-bound form and in a soluble circulating form [5, 39]. The gene AGTR1 (3q24; MIM 106165) encodes the angiotensin II type 1 receptor, a Gq protein-coupled receptor that signals through phospholipase C and elevation of cytosolic calcium and mediates vasoconstriction, aldosterone release and renal sodium retention [6, 40].

Angiotensin-converting enzyme inhibitors block the step catalysed by ACE, angiotensin II type 1 receptor antagonists block the receptor encoded by AGTR1, and direct renin inhibitors, of which aliskiren is the only marketed representative, block the enzyme encoded by REN [5, 6, 41]. The sacubitril/valsartan combination contains an AT1 antagonist and shares, through that component, the fetal toxicity of the class [42]. The mechanistic consequence is direct: a fetus exposed to any of these drugs is, functionally, in the same state of pathway inactivity as a fetus with biallelic loss-of-function variants in one of the four genes. It is this equivalence that explains the histological indistinguishability of the two situations [5, 14].

2.2 Mechanism of the renal and skeletal damage

The fetal renin-angiotensin system regulates blood pressure and fluid and electrolyte balance, takes part in vessel growth and is necessary for pulmonary and renal development [41]. The dominant mechanistic hypothesis, formulated in the founding work and maintained in the subsequent literature, is that of hypoperfusion: inactivity of the pathway chronically reduces the perfusion pressure of the fetal kidney, and that hypoperfusion prevents the normal development and differentiation of the proximal tubules [10, 14]. The absence of fetal urine output produces oligohydramnios or anhydramnios, and from there the sequence is mechanical: fetal compression, pulmonary hypoplasia, Potter facies, joint contractures and positional limb defects [8, 11].

Two chronological aspects govern severity. The first is the timing of the transition in the origin of the amniotic fluid. Until about fourteen weeks, amniotic fluid is mainly a transudate, predominantly from the fetal skin and partly across the placental membranes; from fourteen weeks the fetal skin keratinises, production by transudation declines and is replaced by fetal urine production, so that volume comes to depend on the balance between fetal swallowing and urine output [27]. A fetus whose urine output ceases before that transition retains amniotic fluid, but a fetus whose urine output ceases after it loses it. The second aspect is the critical window of lung development: the canalicular phase, between sixteen and twenty-four weeks, is the period in which reduced amniotic volume produces the most severe pulmonary hypoplasia, and the earlier the oligohydramnios the more severe the effect on the lung [27].

From the combination of these factors arises the window of pharmacological risk. Recent sources place the compromise of fetal renal function and urine production from about the twentieth week of gestation [13], and the prospective series from six teratology services found that all pregnancies with evidence of fetopathy had exposure after twenty weeks and zero days [12]. The Oxford Desk Reference describes the fetal renin-angiotensin system as functional from about twenty-six weeks, attributing the effects to the direct action of ACE inhibitors on that system [9]; the divergence between twenty and twenty-six weeks is relevant in practice, because surveillance should begin at the earliest limit documented in the clinical cohorts.

Hypocalvaria has an explanation of its own within the same mechanism. Persistent fetal arterial hypotension affects the membranous bone of the skull, which is highly vascularised and requires high oxygen tension to grow and ossify normally, unlike bones of endochondral origin, which are not affected in renal tubular dysgenesis, whether primary or secondary [3]. Wide fontanelles were described in several of the genetic cases of the founding series, and skull ossification defects are today one of the signs that raise diagnostic suspicion [3, 14].

2.3 Histopathology and tissue expression of the system

The histopathological hallmark is the absence or paucity of differentiated proximal tubules, with glomeruli and distal tubules relatively preserved [5, 10]. The systematic study of twenty-nine fetuses and newborns from eighteen families documented severe proximal tubule defects in every fetus from eighteen weeks of gestation, with lesions also involving other tubular segments, associated with thickening of the renal arterial vasculature, from the arcuate artery to the afferent arteriole [16]. Immunohistochemistry of the system in that series showed a pattern that helps to localise the defect: renal renin expression was markedly increased in nineteen of the twenty-four patients studied, belonging to thirteen families, and renal renin was undetectable in four patients from three families, whereas angiotensinogen and the converting enzyme were absent or present in small amounts in the proximal tubule, in correlation with the severity of the tubular changes; no specific changes in angiotensin II receptor expression were detected [16]. The reading is mechanistic: when the defect lies downstream of renin, renal renin rises compensatorily, with hyperplasia of the cells that produce it; when the defect is renin itself, immunostaining is negative [6, 16].

In the pharmacological form, the lesional spectrum is broader than isolated tubular dysgenesis. The study of fourteen fetuses and newborns who died shortly after exposure found, besides the usual dysgenesis, thickening of the muscular wall of the arterioles and interlobular arteries, glomerular cysts and interstitial fibrosis, lesions that develop early in fetal life [43]. The authors proposed that these lesions, once established before birth, persist after withdrawal of the drug and normalisation of perfusion pressure, and that this persistence explains the unfavourable late renal course of some survivors, even when the oligohydramnios had been reversible [13, 43].

2.4 Recent experimental contributions to the mechanism

Two recent studies have refined the hypoperfusion hypothesis. In kidney organoids derived from induced pluripotent stem cells, with inactivation of ACE or of AGTR1 and also from patient cells, the proximal tubules formed in vitro indistinguishably from controls, in normoxia and in hypoxia; fully differentiated AGTR1-null organoids engrafted and matured normally under the renal capsule of immunodeficient mice, but AGTR1-null organoids at the renal vesicle stage did not engraft, because of insufficient expression of vascular endothelial growth factor A, and both growth in hypoxia and ectopic expression of that factor rescued engraftment [44]. The authors propose that proximal tubule dysgenesis is, first and foremost, a non-cell-autonomous consequence of delayed angiogenesis, which deprives the proximal tubules at a critical moment of their development [44]. The implication is that the mechanism is not exhausted by systemic perfusion pressure, although the final result is the same.

The second contribution comes from functional study of the mutants. In the converting enzyme, the critical parameter is not circulating enzymatic activity but insertion into the plasma membrane: a truncated mutant that was enzymatically active but only secreted and never inserted into the membrane was associated with neonatal death, whereas a mutant whose product reached the plasma membrane and was rapidly secreted was compatible with life after transient neonatal renal failure; two missense mutants and two further truncating mutants were neither inserted nor secreted, and molecular modelling suggested relevant structural changes, such as the disruption of salt bridges [45]. The practical conclusion is that the complete absence of ACE expression at the cell surface is incompatible with life, and that measurement of plasma ACE activity does not serve as a diagnostic test, because a lethal variant may produce active secreted enzyme [5, 45]. In renin, three point variants, among them a duplication of a tyrosine residue in the region homologous to position 9 of other aspartic proteases and two substitutions in the catalytic domain and adjacent to the “flap” that covers the substrate-binding site, produced misfolded, enzymatically inactive prorenin with abnormal intracellular trafficking, in cell models with and without the capacity to process prorenin into renin [46].

2.5 Spectrum of variants and gene-by-gene distinction

The largest series of variants assembled fifty-four distinct variants in forty-eight unrelated families, most of them novel at the time [14]. The gene ACE is the most frequently implicated; the abstract of the series itself gives 64.6% of families and the OMIM text gives 64.4%, a rounding divergence without clinical consequence [3, 14]. OMIM details the remaining distribution: REN variants in 20% of families, AGT variants in only four families and AGTR1 variants in three (8.3%) [3]. There is no genotype-phenotype correlation between genes: clinical severity is similar whichever gene is mutated, which confirms that the disease arises from the defect of the common pathway [3, 14].

Within the ACE gene, however, there is a correlation with the type of variant. A review of sixty-one genetically confirmed cases of ACE-related renal tubular dysgenesis found overall survival of 24.6%, significantly lower in patients with biallelic truncating variants (8.6%) than in those with at least one non-truncating allele; the location of the variant within the gene did not consistently predict prognosis, although there was clustering of reported variants at the 3' end and a tendency to greater severity with variants at the 5' end [34]. This correlation is consistent with the functional finding that what determines lethality is the complete absence of ACE at the cell surface [45].

The following table assembles the variants mentioned in this article, with the MANE transcript and the conversion confirmed in VariantValidator or in ClinVar. The historical nomenclature of several of them, in the original papers, uses numbering without the signal peptide or one-letter abbreviations; the correspondence cannot be deduced by hand.

2.6 Common variants of the same genes that are not diagnostic

Three of the four genes carry a common-variant literature that must not contaminate the interpretation of a diagnostic result. The 287-base-pair Alu element insertion/deletion polymorphism in ACE is the most studied variant of the gene; the genotype correlates with the level of circulating enzyme and has been associated with a very wide range of common diseases, with response to ACE inhibitors and with athletic performance, but none of these associations has a gene validity assertion in ClinGen, and the genotype neither establishes nor excludes any individual diagnosis [5]. The coding polymorphism M235T of AGT (historical numbering, = NM_000029.4:c.803T>C p.(Met268Thr)) and linked promoter variants constitute one of the oldest and most voluminous common-variant literatures in essential hypertension and pre-eclampsia, with a small per-allele effect, and do not make AGT a Mendelian hypertension gene [36]. In AGTR1, common variation has been associated with essential hypertension as a multifactorial susceptibility factor, and the only GenCC submission for “genetic essential hypertension” is of no known relationship with the disease; ClinGen has no gene validity or actionability assertion for this gene [6]. The only gene-disease relationship curated by ClinGen for ACE is with renal tubular dysgenesis, classified as definitive, autosomal recessive, on 11 December 2024 [5].

2.7 Allelic disorders

The gene REN is the only one of the four with a second established Mendelian disease: heterozygous variants cause REN-associated autosomal dominant tubulointerstitial kidney disease (MIM 613092; ORPHA:217330), formerly termed familial juvenile hyperuricaemic nephropathy type 2, with hypoproliferative anaemia of childhood onset, hyperkalaemia, metabolic acidosis, hyperuricaemia and slowly progressive chronic kidney disease [7, 38]. The coexistence of the two diseases in the same gene illustrates gene dosage: biallelic loss abolishes the axis during fetal life and prevents proximal tubular development, whereas monoallelic loss, through variants of the signal peptide or of the prosegment that cause retention in the endoplasmic reticulum and reduced secretion, produces a relative insufficiency compatible with life and with postnatal expression [7]. The gene ACE has two further OMIM entries written in the notation reserved for susceptibilities and non-pathological traits, for microvascular complications of diabetes and for benign serum elevation of the enzyme [5]. The gene AGT is included in reproductive carrier screening panels, such as Mackenzie's Mission and Prepair 1000+ of PanelApp Australia [36].

2.8 Inheritance and recurrence

Mendelian renal tubular dysgenesis is autosomal recessive, with a recurrence risk of 25% in each subsequent pregnancy of the couple [3, 8]. The pharmacological form is not heritable: the recurrence risk depends on whether the woman continues the same drug in the next pregnancy, and is high if the medication is not reviewed [8, 9]. OMIM further includes, in the same entry, a distinct entity designated renal tubular dysgenesis with choanal atresia and athelia, described in three siblings with a lethal syndrome combining choanal atresia, absent nipples, preauricular pits and tags, branchial clefts, abnormal pulmonary lobation, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, thymus and parathyroid, accessory spleen, imperforate anus, clinodactyly and broad digits with small nails; in this family X-linked recessive inheritance was possible, but there were four healthy maternal uncles, and neither autosomal dominant inheritance with gonadal mosaicism nor a subtle chromosomal abnormality could be excluded [3]. A fourth patient, female, with choanal atresia, athelia, renal tubular dysfunction with renal magnesium wasting and a family history of cervical cysts, was described later and considered to share the same syndrome [3].

3. Clinical Spectrum and Manifestations by System

3.1 The fetal and neonatal phenotype of exposure

The classical picture of exposure to ACE inhibitors in the second and third trimesters combines renal tubular dysgenesis, prolonged renal failure, anuria and hypotension in the newborn, reduced cranial ossification, pulmonary hypoplasia, patent ductus arteriosus, intrauterine growth restriction of mild to severe degree and fetal or neonatal death; similar effects have been described for angiotensin II receptor antagonists [9]. The most systematic prospective description, assembling six European and Israeli teratology information services, defines the spectrum as a continuum running from transient oligohydramnios to neonatal anuria and permanent renal damage, through joint contractures, hypocalvaria, pulmonary hypoplasia and intrauterine or neonatal death [12]. The prescribing information approved by the United States agency describes the same sequence in condensed form: use of drugs acting on the renin-angiotensin system in the second and third trimesters reduces fetal renal function and increases fetal and neonatal morbidity and mortality, and the resulting oligohydramnios may be associated with pulmonary hypoplasia and skeletal deformations, with skull hypoplasia, anuria, hypotension, renal failure and death as possible neonatal effects [19].

The oligohydramnios sequence, common to all causes of fetal anuria, adds manifestations of compression. The main components are pulmonary hypoplasia, micrognathia and postural anomalies, among them talipes, and compression also produces large ears, present in more than 97% of cases in the oligohydramnios sequence series, flattened against the head, and redundant skin [8, 27]. The cause of death is respiratory failure, from failure of the late development of the alveolar sacs [8]. It is worth noting that, when the oligohydramnios results from chronic amniotic fluid loss and is accompanied by arthrogryposis, pulmonary hypoplasia occurs in only 50% of cases, with usually normal intrauterine growth, and the multiple contractures respond well to physiotherapy; this distinction helps to calibrate the prognosis when the aetiology of the oligohydramnios is not renal [8].

3.2 Risk conditional on exposure and differences between classes

The clinically decisive question is not the prevalence of the fetopathy in the population but the risk that an exposed fetus will develop it. Two large cohorts answer that question and agree in direction, though not in magnitude, because they measure different things.

In the prospective cohort of the teratology services, eighty-nine pregnancies with exposure to ACE inhibitors and one hundred and one with exposure to ARBs beyond the first trimester were identified; fifty-nine of the one hundred and ninety were classified as having evidence of fetopathy. Restricting the analysis to prospectively collected cases with exposure from twenty weeks and zero days, the rate of fetopathy was 3.2% with ACE inhibitors and 29.2% with ARBs [12]. In that cohort, isolated oligohydramnios during pregnancy counted as a manifestation of fetopathy even when there was no evidence of disease in the newborn, and there were five cases in which oligohydramnios was the only manifestation, at times reversible after withdrawal of the drug [13].

In the German cohort based on reimbursement data, which covers about 20% of the country's population and includes pregnancies beginning between 2006 and 2019 with exposure after day 140, two hundred and three live births exposed to renin-angiotensin-aldosterone system inhibitors were identified, sixty-one of them to ARBs, and twenty-nine thousand six hundred and seventy-four live births exposed to metoprolol or methyldopa as a comparison group. Diagnoses compatible with fetopathy occurred in eight of the two hundred and three exposed (3.9%), against three hundred and twenty-eight of the twenty-nine thousand six hundred and seventy-four (1.1%) in the comparison group; by class, in one of one hundred and forty-one exposed to ACE inhibitors (0.7%), seven of sixty-one exposed to ARBs (11.5%) and none of the single infant exposed to a renin inhibitor [13]. The difference in magnitude from the prospective cohort is explained by two reasons that the authors themselves make explicit: the German cohort included only live births, excluding intrauterine fetal deaths and terminations for fetal anomaly, and identified fetopathy by neonatal symptoms, not counting isolated oligohydramnios of pregnancy as fetopathy; if the cases of isolated oligohydramnios were removed from the prospective cohort, it would have zero cases of fetopathy among thirty-one exposed to ACE inhibitors and three among twenty-four exposed to ARBs [13].

The finding common to both cohorts, and to the systematic review of published cases, is that the risk is markedly greater with angiotensin II receptor antagonists than with ACE inhibitors [1, 12, 13]. The systematic review of seventy-two reports, with one hundred and eighteen documented cases of exposure to ACE inhibitors and sixty-eight of exposure to ARBs, found that 52% of newborns exposed to ACE inhibitors and only 13% of those exposed to ARBs had no complication at all, a difference with p below 0.0001 [1]. In the Berlin institute series, devoted to AT1 antagonists, oligohydramnios or anhydramnios occurred in five of twenty-nine prospective cases with exposure beyond the first trimester (17%), two of them with other signs of fetopathy, and the risk was estimated at more than 30% when treatment continued beyond the twentieth week [17].

The duration of exposure and the drug-free interval before delivery also matter. The probability of recovery of amniotic fluid volume was greater with withdrawal before thirty weeks and with a longer drug-free interval before delivery [12]. The Berlin series concluded, to the same effect, that the risk increases with the duration of treatment up to the end of pregnancy and that oligohydramnios and anhydramnios may be reversible after withdrawal of the AT1 antagonist [17].

3.3 Manifestations by system

Renal. This is the system primarily affected and the one that determines prognosis. The spectrum runs from transient oliguria, with complete recovery, to anuric renal failure requiring replacement therapy. In the German cohort, renal anomalies were coded in five of the two hundred and three exposed (2.5%), against eighty-four of twenty-nine thousand six hundred and seventy-four (0.3%) in the comparison group, including Potter syndrome and renal dysplasia in two (1.0%) against eighteen (0.1%), severe renal failure or chronic renal failure in four (2.0%) against thirty-one (0.1%) and cystic kidney disease in one (0.5%) against twenty-four (0.1%) [13]. In the series of the Midwest paediatric nephrology consortium, with twenty-four cases of fetopathy, exposure after the first trimester was associated with more severe renal manifestations: chronic dialysis or transplantation was required in eight of seventeen patients with exposure after the first trimester (47%) and in none of the seven with exposure limited to the first trimester, with p equal to 0.05 [53].

Respiratory. Pulmonary hypoplasia results from the oligohydramnios and is the main cause of neonatal death. In the German cohort, congenital pulmonary hypoplasia and dysplasia were coded in four of the two hundred and three exposed (2.0%), being four of the sixty-one exposed to ARBs (6.6%), against sixteen of twenty-nine thousand six hundred and seventy-four (0.1%) [13]. Pneumothorax and pneumomediastinum were described among the pulmonary complications of the Midwest series, including manifestations not previously noted in the literature [53].

Skeletal and craniofacial. Hypocalvaria, with very wide sutures and fontanelles, is the most characteristic extrarenal finding and has been part of the definition of the fetopathy since the first descriptions [29, 30]. A large fontanelle from exposure to ACE inhibitors appears in the differential diagnosis of enlarged fontanelles, alongside congenital infection and aminopterin exposure [54]. To these are added joint contractures and positional limb defects, arising from compression [11, 12].

Cardiovascular. Patent ductus arteriosus is part of the classical picture [9]. Arterial hypotension in the newborn is refractory to conventional support and constitutes, in the severe forms, the dominant haemodynamic problem [5, 21]. Thrombosis of the inferior vena cava, in the vicinity of the renal veins, was proposed as a new feature of AT1 antagonists from three cases among sixteen retrospective reports [17], and was coded in one of the two hundred and three exposed in the German cohort (0.5%), against ten of twenty-nine thousand six hundred and seventy-four [13].

Central nervous system. The Midwest series documented central nervous system anomalies in patients with fetopathy, including cystic encephalomalacia, cortical blindness, sensorineural deafness and arachnoid cysts, some of which had not previously been described in this entity [53]. The systematic review of published cases includes cerebral complications among the most frequent manifestations after exposure to ARBs [1].

Growth. Intrauterine growth restriction, of mild to severe degree, is part of the classical picture [1, 9]. In the observational cohort of first-trimester exposure to ARBs, higher rates of prematurity were found, with an adjusted odds ratio of 3.0 and a 95% confidence interval of 1.7 to 5.1, and reduced birth weight after adjustment for sex and gestational age [55].

3.4 Mortality and early course

In the German cohort, of the eight newborns with fetopathy six were born preterm and four died in the first week of life; three of these four had pulmonary hypoplasia or dysplasia and three had renal diagnoses of dysplasia, hypoplasia or congenital failure [13]. Similar lethality has been reported in case series: five of eleven live births with fetopathy in a French series and four of seven in another German series, whereas the teratology services cohort reported lower lethality, with seven neonatal deaths and three in the first year among fifty-four live births with fetopathy, combining prospective and retrospective cases [13]. In the Berlin institute series, four of thirteen live births did not survive [17].

Reversibility is the other side of the picture. There are documented cases of normalisation of amniotic fluid volume after withdrawal of the drug, with preserved neonatal renal function: in a review of eighty-three fetuses exposed to ARBs in the second or third trimesters, oligohydramnios was present in fifty-eight and resolved after withdrawal of the drug in nineteen, with outcomes ranging from perinatal death to complete recovery, and resolution generally occurred between one and six weeks, which suggests that the degree of damage depends on both the timing and the duration of exposure [56]. A case with two years of follow-up after exposure to valsartan at thirty weeks documented reversible anhydramnios and absence of renal dysfunction in that period [57], and an update from a Canadian teratology service stressed, as early as 2005, that the renal effects of ACE inhibitors could be reversible [58]. The counterpoint is pathological: the vascular lesions, glomerular cysts and interstitial fibrosis develop early and were detected in fetuses and infants at autopsy even when the oligohydramnios had been reversible after withdrawal of the drug, so that normalisation of the amniotic fluid does not guarantee the integrity of the parenchyma [13, 43].

3.5 Long-term course of exposed children

The study with the longest follow-up is the German cohort, the first to follow a series of exposed children beyond the neonatal period and to compare them with a group exposed to the antihypertensives recommended in pregnancy. Of the four survivors with fetopathy, three had renal diagnoses: one with congenital renal failure, pulmonary hypoplasia, pneumothorax, bronchopulmonary dysplasia and vena cava thrombosis, hospitalised for most of the eleven months of follow-up and undergoing several peritoneal dialyses; one with dysplastic and polycystic kidneys followed for 3.2 years, with admissions for urinary infection and tubulointerstitial nephritis and an outpatient diagnosis of unilateral renal agenesis, without renal replacement therapy; and one with congenital renal failure and stage 1 to 2 chronic kidney disease under regular surveillance at 7.4 years. The fourth had no renal diagnosis in 13.7 years of follow-up. None of the four had a diagnosis of arterial hypertension [13].

Among the one hundred and ninety-five exposed children without fetopathy diagnosed in the first six months, with a median follow-up of 4.0 years (25th to 75th centiles: 1.6 to 7.3), 27.2% followed for more than seven years and 10.8% for more than ten years, none had a code for kidney disease associated with renal failure, against sixteen of twenty-nine thousand three hundred and forty-six (0.1%) in the comparison group; five of the one hundred and ninety-five (2.6%) had urinary malformations, against four hundred and nineteen of twenty-nine thousand three hundred and forty-six (1.4%), including renal dysplasia and hypoplasia in two (1.0%) against eighty-six (0.3%); and three of the one hundred and ninety-five (1.5%) had a diagnosis of hypertension or a prescription for an antihypertensive, against one hundred and seventy-six (0.6%) [13]. Two of these three had major cardiac malformations, a combined atrial and ventricular septal defect and a hypoplastic left heart syndrome, which could by themselves justify the prescription [13]. The number of events was too small to build a multivariable model, and the authors note that adjustment for the available confounders would probably shift the risk ratio towards the absence of an effect [13]. The prudent reading is that most exposed children without neonatal signs did not develop chronic kidney disease or hypertension in the period observed, but that the follow-up may be insufficient to capture late manifestations [13].

The clinical series from specialist centres, being highly selected, describe worse courses. In a series of six survivors with fetopathy followed for between one and nine years, only one had normal renal function and five developed chronic renal failure; in another, with three survivors and one year of follow-up, all had renal failure and two had arterial hypertension; and in the Midwest series, with twenty-four children with affected renal function and a mean age of 4.7 years at last follow-up, eight of the seventeen with exposure after the first trimester required chronic renal replacement and six developed neonatal hypertension [13, 53]. Long follow-up of three children exposed to ACE inhibitors, from pregnancies without oligohydramnios and with transient anuria after delivery whose renal function recovered within three months, showed compromised renal function in two, severe hypertension with proteinuria in one and isolated polycythaemia in all three, with progressive deterioration at school age in two of them [13, 59].

The report with the most detailed follow-up documents the multiorgan character of the sequelae. A child with fetopathy from a renin-angiotensin system blocker, followed for ten years, required cranioplasty in the first year of life, on which occasion hypertrophy of the right frontal lobe was noted; she had persistent mild developmental delay, with a developmental quotient of 51 at 8 years and 9 months, and severe short stature, about three standard deviations below the mean, without improvement. She developed severe polyuria with hypernatraemia during the cranioplasty and in an episode of gastroenteritis at 2 years; study of water, sodium, urine osmolality, serum arginine vasopressin and urinary cyclic adenosine monophosphate showed preserved sodium reabsorption from the proximal tubule to the loop of Henle and impaired water reabsorption in the collecting duct, attributable to an alteration of aquaporin-2 in the principal cells. At 10 years, a renal biopsy performed for proteinuria showed chronic focal tubulointerstitial damage, markedly hypertrophied remaining glomeruli with segmental sclerosis and thickening of the intima and media of the interlobular arteries, and enalapril reduced the proteinuria [35].

3.6 The phenotype of the genetic form and its severity spectrum

Autosomal recessive renal tubular dysgenesis presents in the fetus with early and persistent anuria leading to severe oligohydramnios and the Potter sequence, with pulmonary hypoplasia, a flattened facies with large, low-set ears, positional limb defects and arthrogryposis; the ossification defect of the cranial vault, with very open sutures and fontanelles, is highly characteristic [5, 14]. After birth, the picture is one of arterial hypotension refractory to conventional vasopressors, anuric renal failure and respiratory failure from pulmonary hypoplasia [5]. Renal ultrasound shows normal-sized, echogenic, non-cystic kidneys with poor corticomedullary differentiation [5]. In the series of twenty-nine fetuses and newborns from eighteen families, the disease was uniformly severe, with perinatal death in every case from persistent anuria and hypoxia related to pulmonary hypoplasia [16].

The prognosis is no longer uniformly fatal. The first survivors of the neonatal period were reported in 2008 [33], and a series of five newborns with a prenatal diagnosis who survived the neonatal period, four of them with ACE variants and four belonging to an extended Bedouin family, describes them between 5 and 20 years of age, with variable stages of chronic kidney disease and a heterogeneous presentation, ranging from the need for peritoneal dialysis and vasopressors with plasma infusions for extremely low blood pressure to the absence of symptoms [21]. A literature review associated with a Japanese case found sixty-one genetically confirmed cases of ACE-related renal tubular dysgenesis, with overall survival of 24.6% [34]. In the reports of attenuation, with progressive chronic kidney disease instead of perinatal death, the gene implicated was ACE, and not AGTR1, so that extrapolation between genes is not legitimate [6]. The presentation may even be late: an adolescent with a homozygous missense AGT variant was born prematurely after detection of oligohydramnios, recovered from stage 3 acute kidney injury in the postnatal period and developed stage G3b chronic kidney disease over time, which shows that renal tubular dysgenesis may present as chronic kidney disease of variable phenotype and requires broad genetic analysis for diagnosis [50].

3.7 The first-trimester controversy

Exposure limited to the first trimester has a different status from late exposure, and the literature divides according to the comparison group chosen. The Oxford Desk Reference summarises the situation by saying that it is not clear whether first-trimester exposure to ACE inhibitors increases the risk of congenital anomaly, because studies have given contradictory results and suggest that maternal hypertension itself may be associated with a greater risk of certain major malformations in the fetus [9]. A review of the same period concluded, to the same effect, that the fetal effects of ACE inhibitors appear to be greater in the second and third trimesters, that the effect in the first trimester is controversial and that these effects may represent fetal hypoperfusion and not a teratogenic effect, with an effect of ARBs similar to that of ACE inhibitors; the practical recommendation was to avoid both classes in all pregnant women and to consider alternatives in women of childbearing age [60].

The study that gave rise to the controversy was the Tennessee Medicaid cohort, with 29,507 infants born between 1985 and 2000 to mothers without evidence of diabetes: 209 exposed to ACE inhibitors in the first trimester only, 202 exposed to other antihypertensives in the first trimester only and 29,096 without exposure to antihypertensives at any point of gestation, with major malformations identified from vital records and hospital claims in the first year of life and confirmed by record review. Infants exposed only to ACE inhibitors in the first trimester had an increased risk of major congenital malformation, with a relative risk of 2.71 and a 95% confidence interval of 1.72 to 4.27 compared with the unexposed, whereas exposure to other antihypertensives in the first trimester only conferred no increased risk, with a relative risk of 0.66 and an interval of 0.25 to 1.75; those exposed to ACE inhibitors had an increased risk of malformations of the cardiovascular system, with a relative risk of 3.72 and an interval of 1.89 to 7.30, and of the central nervous system, with a relative risk of 4.39 and an interval of 1.37 to 14.02. The authors concluded that first-trimester exposure to ACE inhibitors cannot be considered safe and should be avoided [61].

Two subsequent, larger studies with hypertensive controls reinterpreted the finding. In the Kaiser Permanente Northern California cohort, with 465,754 mother-infant pairs between 1995 and 2008, use of ACE inhibitors in the first trimester only appeared to be associated with a greater risk of congenital heart defects compared with normotensive controls not taking antihypertensives, with 15 of 381 cases (3.9%) against 6232 of 400,021 (1.6%) and an odds ratio of 1.54 with a 95% confidence interval of 0.90 to 2.62, but a similar association was observed for other antihypertensives, with 28 of 1090 cases (2.6%) and a ratio of 1.52 with an interval of 1.04 to 2.21; compared with hypertensive controls not taking antihypertensives, who had 708 of 29,735 cases (2.4%), neither ACE inhibitors nor other antihypertensives were associated with an increased risk, with ratios of 1.14 and an interval of 0.65 to 1.98 and of 1.12 with an interval of 0.76 to 1.64. The authors concluded that the apparent increase in risk is probably due to the underlying hypertension and not to the medication [62]. In the national Medicaid cohort from 2000 to 2010, with 1,333,624 pregnancies of which 4107 (0.31%) were exposed to ACE inhibitors in the first trimester, the prevalence of overall malformations in the exposed was 5.9% against 3.3% in the unexposed, with a crude relative risk of 1.82 and a 95% confidence interval of 1.61 to 2.06; of cardiac malformations 3.4% against 1.2%, with a relative risk of 2.95 and an interval of 2.50 to 3.47; and of central nervous system malformations 0.27% against 0.18%, with a relative risk of 1.46 and an interval of 0.81 to 2.64. After restricting the cohort to pregnancies complicated by chronic hypertension, exposed and unexposed, and controlling for the remaining confounders by propensity score, there was no significant increase in risk for any of the outcomes: 0.89 with an interval of 0.75 to 1.06 for overall malformations, 0.95 with an interval of 0.75 to 1.21 for cardiac ones and 0.54 with an interval of 0.26 to 1.11 for those of the central nervous system [63].

The observational cohorts of the German pharmacovigilance institute reached the same conclusion by a different route. Among 329 women exposed to ACE inhibitors in the first trimester, the risk of miscarriage was not increased compared with 654 women without antihypertensive treatment, with an adjusted hazard ratio of 1.20 and a 95% confidence interval of 0.74 to 1.92, whereas the risk of major congenital defects was significantly increased, with 14 of 255 cases (5.5%) against 19 of 567 (3.4%) and an adjusted odds ratio of 2.41 with an interval of 1.07 to 5.43; however, defect rates did not differ significantly between hypertensive women on ACE inhibitors and hypertensive women on methyldopa, and no defined pattern of defects was observed in the retrospectively collected cases, so that the authors attributed the excess to other factors associated with maternal hypertension and considered that inadvertently exposed women can be reassured, with a switch to antihypertensives recommended in pregnancy [64]. For ARBs, the cohort of 215 prospective pregnancies with first-trimester exposure compared with 642 pregnancies of non-hypertensive women gave a major defect rate of 9 in 168 (5.4%) against 17 in 570 (3.0%), with an adjusted odds ratio of 1.9 and a 95% confidence interval of 0.7 to 4.9, therefore not significant, without a distinct pattern of anomalies; the risk of miscarriage was not increased, with an adjusted hazard ratio of 0.9 and an interval of 0.5 to 1.6, although the cumulative incidence was at the upper limit of normal, at 0.22 with an interval of 0.15 to 0.32; higher rates of prematurity and reduced birth weight were observed after adjustment; and a sensitivity analysis comparing exposed hypertensive women with unexposed hypertensive women found no increased risk. The conclusion was that ARBs are not major teratogens and that patients inadvertently exposed in early pregnancy can be reassured, although women planning a pregnancy should avoid them [55].

Two meta-analyses keep the divergence open. A systematic review with meta-analysis of first-trimester exposure found a significant relative risk when the exposed group was compared with healthy controls, but not when compared with other antihypertensives, and the qualitative analysis did not demonstrate a specific pattern of major malformations; the authors concluded that first-trimester exposure to ACE inhibitors and ARBs is not associated with a raised risk of major malformations compared with other antihypertensives, and that exposure to antihypertensives in general in the first trimester may be associated with a raised risk [65]. A more recent meta-analysis, with studies reporting 6234 pregnancies exposed to ACE inhibitors or ARBs, 4104 exposed to other oral antihypertensives and 1,872,733 without exposure, found an increased risk of major congenital malformations, with an odds ratio of 1.82 and a 95% confidence interval of 1.42 to 2.34, of cardiovascular malformations, with a ratio of 2.50 and an interval of 1.62 to 3.87, and of stillbirth, with a ratio of 1.75 and an interval of 1.21 to 2.53, compared with unexposed controls, without a difference for other antihypertensives, with a ratio of 0.96 and an interval of 0.69 to 1.33; the authors interpreted this excess as independent of the underlying maternal hypertension, precisely because those exposed to other antihypertensives showed no risk above healthy controls, and recommended appropriate counselling for women planning a pregnancy while taking these drugs, including those with diabetic nephropathy [66]. The divergence of interpretation between this meta-analysis, which compares with unexposed controls, and the cohorts that compared with unexposed hypertensive women, is thus identified and is not resolved by the available data.

4. Clinical Recognition and Warning Signs

4.1 During pregnancy

Suspicion begins with a history-taking question, not with an imaging finding. In the assessment of any drug exposure in pregnancy, the essential points are to know which drugs and exposures occurred and at what dose, at what gestational age the pregnancy was exposed, what the maternal health status is, namely diabetes and obesity, and to construct a pedigree that allows one to determine whether the anomalies observed may have a genetic rather than a teratogenic basis [9]. In the specific context of oligohydramnios, the history should include a three-generation pedigree with detailed enquiry about renal tract problems, stillbirths and neonatal deaths, consanguinity, a careful teratogen history, with explicit reference to ACE inhibitors, and bleeding in the first weeks of gestation or early rupture of membranes [27]. The same recommendation to enquire about teratogens, including alcohol, diabetes, rubella and ACE inhibitors, forms part of the approach to congenital anomalies of the kidney and urinary tract [67].

The ultrasound finding that should trigger suspicion is oligohydramnios or anhydramnios without an evident obstetric cause in an exposed pregnancy. Amniotic fluid volume is estimated by ultrasound measurement of the largest fluid pocket, the deepest vertical pocket, which varies with gestational age; the normal range in the third trimester is above 3 cm, values below 3 cm indicate oligohydramnios and the complete absence of fluid defines anhydramnios. A deepest vertical pocket below 1 cm may be associated with very high perinatal mortality, above 95%, especially when it occurs between sixteen and twenty-four weeks [27]. The prevalence of oligohydramnios in pregnancy is about 5%, with an overall rate of associated congenital malformations of about 5%, in which renal tract malformations are the most frequent, so that most cases have an obstetric cause, such as uteroplacental insufficiency or premature rupture of membranes, which the obstetrician assesses first [27].

There are two particularly suggestive ultrasound combinations. The first is oligohydramnios with an empty fetal bladder and normal renal morphology, which should prompt consideration of renal tubular dysgenesis in the prenatal setting, in any of its aetiologies [68]. The second is the association of increased resistance of fetal renal blood flow, with reversed diastolic flow, with oligohydramnios and insufficient bladder filling, described for the first time in a series of four fetuses with the genetic form, and which indicates fetal renal failure irrespective of the presence of structural renal anomalies [69].

The approved prescribing information sets out the surveillance to be followed in inadvertent exposure. If there is no appropriate therapeutic alternative, the mother should be informed of the potential risk to the fetus, serial ultrasound scans should be performed to assess the intra-amniotic environment and fetal testing may be appropriate according to the week of gestation; if oligohydramnios is observed, the drug should be discontinued, unless it is considered life-saving for the mother [19]. The essential warning of the same document is that oligohydramnios may appear only after the fetus has sustained irreversible injury, which prevents its absence from being taken as proof of safety [19]. The summary of product characteristics in Portugal frames surveillance in equivalent terms: where exposure to ACE inhibitors or angiotensin II receptor antagonists has occurred from the second trimester onwards, ultrasound monitoring of renal function and of the skull bones is recommended [18, 70].

4.2 In the newborn

Renal tubular dysgenesis should be suspected in any newborn presenting with renal failure, refractory hypotension, a need for ventilation, hypoplastic lungs, renal ultrasound showing normal-sized, echogenic, non-cystic kidneys with poor corticomedullary differentiation, and a prenatal history of oligohydramnios [71]. The addition of skull ossification defects, with wide fontanelles, reinforces the suspicion and distinguishes the picture from other causes of neonatal renal failure [3, 5]. Faced with a normal or near-normal renal ultrasound, the error to avoid is excluding intrinsic renal disease: the presence of hypotension, respiratory failure and skull ossification defects with a normal renal ultrasound points precisely to renal tubular dysgenesis, and it is histology that establishes the definitive diagnosis [72].

The prescribing information sets out the mandatory neonatal surveillance of exposed infants: newborns with a history of intrauterine exposure should be closely observed for hypotension, oliguria and hyperkalaemia, and, if oliguria or hypotension arise, blood pressure and renal perfusion should be supported, exchange transfusion or dialysis possibly being required to reverse the hypotension and replace renal function [19, 73]. In Portugal, the summary of product characteristics states that newborns whose mothers were exposed should be carefully observed for the diagnosis of hypotension [18, 70].

The German cohort adds a recommendation aimed at asymptomatic exposed infants: renal ultrasound may be indicated in exposed newborns without clinical signs of fetopathy, in order to detect sequelae that require subsequent clinical surveillance [13]. This recommendation follows directly from the observation that two of the children without fetopathy diagnosed in the first six months later received diagnoses of renal dysplasia and hypoplasia, one of them with secondary hypertension, and that all the children in that situation had congenital cardiac or renal defects detectable by ultrasound in the neonatal period [13].

4.3 Warning signs and emergencies

During pregnancy, warning signs are the detection of oligohydramnios or anhydramnios in any pregnancy on ACE inhibitors, ARBs, aliskiren or sacubitril/valsartan, the absence of a visible fetal bladder and increased resistance of fetal renal flow [19, 68, 69]. Any of these findings entails immediate withdrawal of the drug, replacement by an antihypertensive compatible with pregnancy and serial ultrasound reassessment, because the possibility of recovery of amniotic fluid volume justifies continuing the pregnancy while fetal wellbeing persists, rather than proposing termination on the basis of the initial finding [12, 56].

In the neonatal period, arterial hypotension refractory to conventional support, persistent anuria, hyperkalaemia and respiratory failure from pulmonary hypoplasia are emergencies [5, 19]. Aggressive treatment of the hypotension in the first hours is described as critical for survival and for the subsequent prognosis [21]. In children who survive, a late warning sign is added: episodes of dehydration from polyuria, with prerenal acute kidney injury, hyponatraemia, hyperkalaemia and non-anion gap metabolic acidosis, triggered by trivial intercurrent infections [22].

4.4 Newborn screening

There is no population newborn screening for this condition, in any of its forms, and the sources consulted describe no biomarker suitable for dried blood spot screening. The relevant screening is targeted: identification, at the antenatal consultation, of women of childbearing age taking drugs that block the renin-angiotensin system, and ultrasound and laboratory surveillance of exposed newborns [13, 74]. In families with a known genetic form, screening is molecular and prenatal, after identification of the family variants [14].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria and operational definitions

There are no formal diagnostic criteria published by a scientific society for fetopathy due to renin-angiotensin system inhibitors. The definitions in use are operational and come from the cohorts. The prospective cohort of the teratology services defined as indicative of AT1 antagonist fetopathy oligohydramnios or anhydramnios, renal failure, pulmonary hypoplasia, joint contractures, skull hypoplasia and fetal or neonatal death [17], and, in the 2020 work, classified as having evidence of fetopathy those pregnancies with these manifestations after exposure beyond the first trimester [12]. The German cohort, working with administrative data, defined fetopathy by the presence, in the first 180 days of life, of diagnoses of congenital pulmonary hypoplasia and dysplasia or other congenital lung malformation, Potter syndrome, renal dysplasia, anuria and oliguria, severe renal failure, chronic renal failure, dialysis or transplantation, cystic kidney disease or other congenital malformations of the kidney, embolism and thrombosis of the vena cava, and contractures and congenital dislocation or subluxation of the hip [13]. The authors themselves note the decisive limitation of this type of definition: there is no single International Classification of Diseases code specific to this fetopathy, so that even in the cohort exposed to metoprolol or methyldopa there was a small percentage of children with compatible diagnoses, and 2.5% of those exposed to renin-angiotensin-aldosterone system inhibitors against 0.3% of those exposed to the recommended antihypertensives had codes for renal anomaly [13]. The diagnosis is therefore clinical and by causal attribution, supported by the dating of exposure.

For renal tubular dysgenesis, the definition is pathological. Orphanet describes the entity as a rare disease of the fetus characterised by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios leading to the Potter sequence, with facial dysmorphism and large, flattened, low-set ears, pulmonary hypoplasia, arthrogryposis and positional limb defects, and skull ossification defects [11]. Diagnosis of the genetic form requires the identification of biallelic variants in ACE, REN, AGT or AGTR1, and diagnosis of the drug-induced form requires documentation of exposure within the critical window and reasonable exclusion of a genetic cause and of other causes of fetal renal hypoperfusion [14, 72]. The general principle of clinical genetics applies: the diagnosis of a teratogenic syndrome is as a rule made after a genetic or other cause has been excluded, and caution is required when the data on use of a drug in pregnancy are very limited or the teratogenic phenotype was proposed on the basis of few case reports with limited genetic investigation [9].

5.2 Biomarkers and non-molecular tests

Prenatal surveillance has two markers tested together in a French retrospective series of twenty-one fetuses exposed to renin-angiotensin system blockers: amniotic fluid volume and fetal serum beta-2-microglobulin. Only one of the twenty-one fetuses had normal postnatal renal function, the one in which the oligohydramnios regressed and beta-2-microglobulin was normal; all fetuses with persistent oligohydramnios or with beta-2-microglobulin of 5 mg/L or above had an adverse renal course, defined by postnatal glomerular filtration rate or by the presence of renal histological lesions. The authors proposed a prenatal approach based on monitoring of amniotic fluid volume and fetal serum beta-2-microglobulin, noting that the preliminary results need confirmation in a larger series [75]. The proposal has the drawback that measurement of fetal serum beta-2-microglobulin requires fetal blood sampling, an invasive procedure not available in all centres.

Functional assessment of the renin-angiotensin system contributes to diagnosis and helps to localise the defect in the genetic forms. The demonstration of absent circulating angiotensinogen with elevated renin specifically supports the AGT form [36], and very high plasma renin with inappropriately low aldosterone was documented in a survivor with an ACE variant, with renin of 18.5 ng/ml/h for a reference range of 0.2 to 3.9 ng/ml/h [22]. Measurement of plasma converting enzyme activity does not serve as a test, because a lethal variant may produce enzymatically active, secreted enzyme without membrane insertion [5, 45]. A Japanese case report illustrates the interpretative difficulty: it showed a discrepancy between low plasma renin activity and a high active renin concentration, suggesting a negative feedback response of the system [3].

Postnatal clinical monitoring rests on urine output, serum creatinine, electrolytes, with emphasis on potassium, and continuously recorded blood pressure; to these are added chest imaging and blood gases for the pulmonary hypoplasia, renal ultrasound and skull radiography or examination of the vault for the ossification defects [5].

5.3 Renal histology

Renal histology, obtained by biopsy or at post-mortem examination, is the non-molecular confirmatory test: the absence or paucity of differentiated proximal tubules, with glomeruli and distal tubules relatively preserved, is described in all sources as the histopathological hallmark of renal tubular dysgenesis [5, 10]. The examination is diagnostic of the disease but not of the gene or of the aetiology, because an identical lesion is produced by variants in any of the four genes and also by the acquired forms, including exposure to renin-angiotensin system drugs and twin-to-twin transfusion; histology establishes renal tubular dysgenesis and it is molecular testing that attributes it to a gene [5]. A published case documents the usefulness of tissue from a deceased sibling: review of the renal material from a sibling who died shortly after birth established the histological diagnosis for a surviving child [76].

Immunohistochemical characterisation adds localising information. Staining for renin, angiotensinogen and converting enzyme allows a defect upstream to be distinguished from one downstream of renin: markedly increased renal renin immunostaining corresponds to the pattern of downstream defects, as in AGTR1, and its absence points to the REN form [6, 16]. In pathology practice, demonstration of the proximal tubules relies on the absence of a brush border on periodic acid-Schiff staining and on the absence of CD10 staining in the tubules, with epithelial membrane antigen highlighting the distal tubules present [72]. The paediatric pathology review devoted to congenital anomalies of the kidney with insufficient or abnormal nephron development, which includes renal dysplasia, renal hypoplasia and renal tubular dysgenesis, emphasises the importance of perinatal autopsy and of examination of surgical specimens in establishing the diagnosis and the prognosis, and discusses the indications for and the type of genetic test to request [77].

5.4 Molecular testing and its limits

The molecular test that establishes the genetic form is sequencing of ACE, REN, AGT and AGTR1, by renal disease panel, exome or genome [5, 14]. Recent reports rely predominantly on exome or genome sequencing, including trio sequencing, for three reasons: it allows variants in all four genes to be detected at once, it identifies mimics that do not belong to the pathway, and it resolves situations in which one of the alleles arises de novo [78, 79]. In a series of three patients from three independent families, each had a completely different type of ACE variant, which illustrates the absence of recurrent variants outside founder populations [80].

The limits of the tests should appear in the report and in the conversation with the family. Panel or exome sequencing does not reliably detect structural variants or copy number variation, does not cover deep intronic or regulatory regions, and does not resolve low-level mosaicism; a negative result in the four genes of the renin-angiotensin system does not exclude renal tubular dysgenesis, as shown by the cases in which genome sequencing identified biallelic variants of RMND1, a mitochondrial disease gene, in fetuses with a phenotype resembling renal tubular dysgenesis and low renal renin expression, without variants in the pathway genes [79]. The proportion of families with an identified variant in a reference series is not the clinical sensitivity of the test in an individual patient, because the published series consist of cases with a typical phenotype and histological confirmation [14].

There are also situations in which the genetic result found does not explain the phenotype. In a Portuguese case, the karyotype of peripheral blood leucocytes revealed 46,XX,dup(1)(q24.1q25.1), a 9.3 Mb interstitial duplication of the long arm of chromosome 1 spanning 109 genes, confirmed by array comparative genomic hybridisation and by exome sequencing; the duplication contained neither the causal genes of renal tubular dysgenesis nor deleterious variants in those genes, the parental karyotypes were normal, which points to a de novo occurrence, and antemortem active renin levels were normal, so that the duplication was not considered explanatory [72]. The finding illustrates that a de novo structural variant found in a patient with this phenotype requires the demonstration of mechanistic plausibility before being accepted as the cause.

The sample for prenatal testing may be difficult to obtain. Anhydramnios simultaneously hampers amniocentesis for diagnosis and morphological assessment by ultrasound; amnioinfusion is described as a useful technique in cases of oligohydramnios or anhydramnios with suspected urinary tract anomaly, because it allows amniotic fluid to be obtained for genetic diagnosis, a strategy with which two Vietnamese fetuses with homozygous ACE variants were diagnosed [47]. Alternatively, the Oxford Desk Reference recommends, in the context of oligohydramnios with bilateral renal involvement or another ultrasound finding, fetal karyotype and genomic array analysis, with chorionic villus sampling, placental biopsy, fetal blood or non-invasive prenatal diagnosis as alternatives when amniocentesis is not possible, and stresses the usefulness of storing DNA from the fetus and the parents as a trio, together with fetal magnetic resonance imaging when ultrasound does not give adequate images and renal ultrasound of the parents before counselling on recurrence risks [27].

5.5 Content of the report and classification of variants

The molecular report should identify the gene, the reference transcript with its version, the HGVS description in coding and protein coordinates, the zygosity and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, with reference to the database consulted. The MANE transcripts to be used are NM_000789.4 for ACE, NM_000029.4 for AGT, NM_000685.5 for AGTR1 and NM_000537 for REN [7, 48].

Standardisation of nomenclature is indispensable because the literature of this disease largely uses amino acid numbering without the signal peptide and one-letter abbreviations. The conversion is not done by hand: it is confirmed in VariantValidator or in ClinVar. A concrete example of the need for this discipline is the ACE variant c.2503G>T, described as p.Glu853Ter in the paper that reported it and converted as p.(Glu835Ter) by VariantValidator with the MANE transcript NM_000789.4 [47, 48]. The variant table in section 2 records the confirmed conversions and the nomenclatures of origin.

A variant of uncertain significance in one of these genes, in a fetus with oligohydramnios and anuria, does not establish the diagnosis. Family segregation, confirmation that the two alleles are in trans, demonstration of loss of function where an assay is available and consistency with the renal immunohistochemical pattern are the elements that allow reclassification. The published functional studies for ACE and REN show that the relevant assay is not enzymatic activity but cellular localisation and intracellular trafficking, which limits the availability of confirmatory assays in clinical practice [45, 46].

5.6 Prenatal and preimplantation diagnosis

Once the family variants have been identified, early prenatal diagnosis is possible and is presented by the authors of the largest series as one of the direct gains of molecular characterisation, alongside genetic counselling [14]. Diagnosis can be made by chorionic villus sampling in the first trimester or by amniocentesis, and in the two Vietnamese fetuses diagnosed by clinical exome from amniotic fluid obtained by amnioinfusion the prognosis was considered guarded and the couples opted to terminate the pregnancies [47]. Preimplantation genetic testing is technically applicable to an autosomal recessive disease with known variants, and the reproductive options are discussed in section 8.

In pregnancies where the problem is exposure and not genetics, “prenatal diagnosis” consists of serial ultrasound surveillance of amniotic fluid volume, renal morphology and skull ossification after withdrawal of the drug, with the possibility of recovery conditioning the decision [12, 19, 56].

5.7 Diagnostic algorithm

In a fetus with unexplained oligohydramnios or anhydramnios in the second or third trimester, the first step is the exclusion of obstetric causes, namely premature rupture of membranes and uteroplacental insufficiency, a task for the obstetrician [27]. The second step is a complete review of the maternal medication with dating of the exposure, with attention to ACE inhibitors, ARBs, aliskiren, combinations with hydrochlorothiazide and sacubitril/valsartan, and also to non-steroidal anti-inflammatory drugs, which can produce the same lesion [19, 72]. The third step is targeted ultrasound assessment: renal morphology and echogenicity, visualisation of the bladder, Doppler study of renal flow resistance, biometry and examination of the cranial vault, with fetal magnetic resonance imaging when ultrasound is not conclusive [27, 68, 69]. The fourth step depends on the result: if there is documented exposure within the critical window and the kidneys are structurally normal, the approach is to withdraw the drug, replace it and repeat the ultrasound, reserving genetic investigation for cases without exposure, with a family history, with consanguinity or with persistence of the picture after withdrawal; if there is no exposure, genetic testing is undertaken, ideally by trio exome or genome sequencing, with amnioinfusion if required to obtain a sample [12, 47, 78]. In the newborn, assessment includes urine output, creatinine, potassium, blood gases, continuous blood pressure, renal ultrasound, skull radiography and chest imaging, and genetic testing remains indicated even when there is documented exposure, because the coexistence of the two aetiologies cannot be excluded from the history [5, 71]. Renal histology, by biopsy or autopsy, establishes the diagnosis of renal tubular dysgenesis when the preceding investigations have not, and is decisive for counselling the family [72, 77].

6. Differential Diagnosis

6.1 Comparative table

6.2 The distinction between the pharmacological and the genetic form

The central problem of the differential diagnosis of this condition is that the pharmacological form and the genetic form are mutual phenocopies and are not distinguished by any morphological or histological finding. The pharmacological form has been explicitly described as a phenocopy of autosomal recessive renal tubular dysgenesis through maternal therapy with ACE inhibitors [27], and the same lesion follows renal hypoperfusion of any cause, genetic or secondary, so that the drug-induced and twin-to-twin transfusion forms are histologically identical to the genetic form [5]. The practical consequence is that the drug history of the pregnancy is a mandatory part of the assessment before a genetic cause is assumed [5].

Three elements help to distinguish them. The first is the dated history: exposure within the critical window from about twenty weeks is the necessary condition for pharmacological attribution [12, 13]. The second is the response to withdrawal: recovery of the amniotic fluid index within one to six weeks after withdrawal of the drug is characteristic of the pharmacological form and does not occur in the genetic form, in which the anuria is persistent [14, 56]. The third is family history and consanguinity, which point to the recessive form, although their absence does not exclude it, as shown by sporadic cases with a de novo variant in one of the alleles [78]. In case of doubt, genetic testing should be performed even when exposure is documented, because the two situations may coexist and the difference in recurrence risk is substantial [71].

6.3 The differential diagnoses of oligohydramnios in the fetus

The role of the geneticist faced with oligohydramnios is to identify the monogenic diseases with a high recurrence risk [27]. Targeted examination looks for renal tract anomalies, including cysts, and the entities that correspond to them: congenital bladder outlet obstruction, megacystis-microcolon, the hyperechogenic kidneys of Meckel-Gruber, of recessive polycystic disease and of HNF1B-associated disease, the renal agenesis of Fraser syndrome, of the branchio-oto-renal spectrum and of RET and HNF1B variants, the absent fetal bladder with non-functioning kidneys, joint contractures, pulmonary morphology and, specifically, skull ossification defects, which point to recessive renal tubular dysgenesis or to maternal exposure to ACE inhibitors [27]. In the child and the fetus with renal agenesis, the syndromic causes to consider include the branchio-oto-renal spectrum in every case, so that branchial fistulae are sought, deafness is enquired about and renal ultrasound of the parents is performed, besides Fraser syndrome and the association of Müllerian duct anomalies with renal aplasia and cervicothoracic somite dysplasia [27]. Faced with bilateral renal agenesis or dysgenesis, or agenesis of one kidney with dysgenesis of the other, renal ultrasound assessment of the parents and siblings is recommended, because 9% of first-degree relatives had asymptomatic renal malformations in a classical study [8].

6.4 The differential diagnoses of the large fontanelle and hypocalvaria

When the dominant finding is the skull ossification defect, the differential diagnosis is different. In the approach to a large fontanelle, the pregnancy history should include congenital infection and exposure to aminopterin or to ACE inhibitors, and examination looks for skull asymmetry, scalp defects, exorbitism, clavicles and parietal foramina [54]. The genetic entities to consider include cleidocranial dysplasia, parietal foramina from haploinsufficiency of ALX4 or MSX2, Kenny-Caffey syndrome, in the autosomal dominant form from heterozygous FAM111A variants, allelic with perinatally lethal gracile bone dysplasia, and in the autosomal recessive form from biallelic TBCE variants, with severe growth restriction and congenital hypoparathyroidism, besides congenital hypothyroidism, chromosomal abnormalities and congenital infections [54]. In that same context, recessive renal tubular dysgenesis is listed as a differential diagnosis, with the description of absent or scanty differentiated proximal tubules and causation by biallelic variants in genes of the renin-angiotensin pathway [54].

6.5 Molecular mimics

Not all fetuses with a renal tubular dysgenesis phenotype have variants in the four genes of the pathway. Genome sequencing in an unresolved case with low renal renin expression identified a rare homozygous variant of RMND1, a gene responsible for an autosomal recessive mitochondrial disease, with severe reduction of subunits of complexes I and IV of oxidative phosphorylation combined; a second homozygous variant of the same gene was then found in another unresolved case, from a consanguineous family with recurrent fetal deaths. The authors conclude that biallelic RMND1 variants probably cause severe prenatal renal disease with a phenotype resembling renal tubular dysgenesis and recommend screening this gene in unexplained severe fetal nephropathies, noting that the link between RMND1-associated mitochondrial dysfunction and renin expression remains poorly understood [79]. Cases with de novo chromosomal abnormalities that do not involve the pathway genes, and without alteration of active renin, remain unexplained and suggest alternative mechanisms not yet characterised [72].

6.6 The pitfall of administrative data

A methodological observation with clinical consequence: in the German cohort, the group exposed to the antihypertensives recommended in pregnancy, metoprolol and methyldopa, also had diagnoses compatible with fetopathy in 1.1% of cases, and renal anomaly codes in 0.3% [13]. This means that the set of diagnoses that operationally defines the fetopathy is not specific, and that attributing causality from administrative records, without dating of the exposure and without exclusion of the alternatives listed above, overestimates the frequency of the condition.

7. Treatments and Risk Management Strategies

7.1 General principle

There is no targeted treatment for fetopathy due to renin-angiotensin system inhibitors or for renal tubular dysgenesis, in any of its forms. The effective intervention is prevention: not exposing the fetus, or interrupting the exposure as quickly as possible. Once the lesion is established, management is supportive, and its intensity determines survival. There is no clinical trial or clinical practice guideline devoted to renal tubular dysgenesis; the treatment evidence consists of series and case reports [5].

7.2 Prevention: withdrawal, replacement and contraception

All the guidelines reviewed agree on strict avoidance of these drugs in pregnancy, but they diverge on the practical aspects of prescribing to women of childbearing age, on contraception, on the timing of withdrawal and on breastfeeding [41]. The divergences are set out in the following table.

Sources of the table: the comparative review of guidelines and the statement of the British and Irish hypertension society, for the NICE, ESH, KDIGO and UK Kidney Association rows [41, 74], whose source documents are, respectively, the hypertension guideline of the European society of hypertension [82] and the chronic kidney disease guideline of the international kidney disease outcomes organisation [83]; the text of the section devoted to renin-angiotensin-aldosterone system inhibitors of the European guideline on cardiovascular disease and pregnancy [84]; the supporting text of the hypertension and pregnancy section of the United States guideline [20]; and the numbered recommendations of the pregnancy section of the standards of care in diabetes [85].

The prescribing framework warrants attention. The NICE guidelines recommend renin-angiotensin-aldosterone system blockers as first-line antihypertensive treatment in men and women under 55 years, except people of African or African-Caribbean origin, and in those with type 2 diabetes of any age and origin, and from the second step of the algorithm they recommend them to everyone with hypertension [74]. This position, combined with the high proportion of unplanned pregnancies, explains the persistence of exposures. A United Kingdom survey in 2010 indicated that 86% of women sought antenatal care by week 12, which implies a potential delay in 14% of them until after the first trimester [41], and in Germany, as in other countries, at least one third of pregnancies is unplanned [13].

The statement of the British and Irish hypertension society frames the most operational advice for the consultation: discuss pregnancy plans with women of childbearing age who are not planning a pregnancy and are not pregnant, explain the benefits and risks, support the informed decision and document the conversation; advise safe and effective contraception while they are taking the drugs; advise withdrawal two to three months before trying to conceive, with a switch to amlodipine, nifedipine, labetalol or methyldopa and folic acid supplementation; and, in the event of contraceptive failure, withdraw as quickly as possible [74]. The same document notes that NICE gives no specific guidance on the management of women with an unplanned pregnancy taking these drugs, a gap that the British group considers relevant [74].

The United Kingdom teratology information service takes a distinct position on the first trimester: it considers that there is no strong evidence that exposure to ACE inhibitors in that period is associated with congenital malformations, and that the lack of data prevents quantification of the malformation risk after exposure to ARBs; it advises women exposed to an ACE inhibitor or an ARB in the first trimester that no additional surveillance for congenital defects is required, and recommends close surveillance of those using these drugs in the second and third trimesters [74]. This reassuring position on the first trimester is consistent with the cohorts that compared women exposed to ACE inhibitors with unexposed hypertensive women and found no excess risk [62–64].

The United States guideline of 2025 broadened the warning relative to the previous edition and lists the drugs to be avoided: ACE inhibitors, ARBs and direct renin inhibitors are fetotoxic in the second and third trimesters, through their effects on the developing renal system, with oligohydramnios and acute kidney injury; atenolol is associated with growth restriction and lower fetal weight and should be avoided, which is probably not a class effect, since other beta-1-selective agents such as metoprolol have not shown a similar association and labetalol is the preferred agent, with the most reassuring fetal safety data; spironolactone may, through its mechanism of action and the animal data, cause feminisation of a male fetus or growth restriction, in a dose-dependent manner, and is not recommended, even in women with primary hyperaldosteronism; and nitroprusside crosses the placenta and may cause fetal cyanide toxicity, with few human data available [20]. The European guideline adds that the aldosterone antagonists, canrenone and spironolactone, have an antiandrogenic effect and are contraindicated in pregnancy, that spironolactone is considered safe in lactation, and that case reports of eplerenone in pregnant women with resistant hypertension found no adverse effects [84].

7.3 Antihypertensive replacement in pregnancy, with doses

The doses that follow are those of the 2025 United States guideline, reproduced from the publication of the American college of obstetricians and gynecologists, and constitute the reference standard for replacement [20]. None of these drugs is a treatment for the fetopathy; they are the alternatives that avoid exposure to renin-angiotensin system blockade.

Source of the doses: AHA/ACC 2025 guideline, table of common oral antihypertensive agents in pregnancy [20]. The choice between labetalol and extended-release nifedipine is not determined by comparative data: the United States guideline states that neither agent is preferred over the other for lack of data supporting one of the two, noting only that nifedipine is given once daily, which may improve adherence [20]. The European guidelines expand the comparison, attributing the greatest safety evidence to labetalol and nifedipine, and NICE presents labetalol, nifedipine and methyldopa as equally suitable alternatives [41]. An ongoing trial, comparing the effect of labetalol and nifedipine on blood pressure control in pregnancy, may come to alter the British guidance [41].

Two accessory measures of primary prevention in hypertensive pregnant women deserve recording, as they form part of the same care plan. The United States guideline recommends counselling women with elevated blood pressure who are planning a pregnancy or are pregnant about low-dose aspirin, on the basis of a meta-analysis in which daily low-dose aspirin after 12 weeks of gestation significantly reduced the risk of pre-eclampsia in women at moderate or high risk, with a pooled relative risk of 0.85 and a 95% confidence interval of 0.75 to 0.95, with reductions also in preterm birth, small-for-gestational-age infants and perinatal mortality, without an increased risk of postpartum haemorrhage; aspirin should be advised only for those without previous adverse events or allergy to the drug [20]. As to the blood pressure target, the trial that randomised 2408 women with chronic hypertension to antihypertensive treatment with a target below 140/90 mmHg, against no treatment unless systolic pressure reached 160 mmHg or diastolic 105 mmHg, demonstrated an absolute risk reduction of 18% in the primary composite outcome of pre-eclampsia with severe features, preterm birth, placental abruption or fetal or neonatal death, without evidence of an increased risk of fetal growth restriction [20].

7.4 Management when exposure has already occurred

When exposure has occurred, management is sequential. First, withdraw the drug immediately: the prescribing information requires the drug to be discontinued as soon as pregnancy is detected [19, 73, 86, 87], and the summary of product characteristics in Portugal states that, when pregnancy is diagnosed, treatment with ACE inhibitors or with angiotensin II receptor antagonists should be stopped immediately and, if appropriate, alternative therapy started [18, 70]. Second, replace it with one of the agents compatible with pregnancy, at the doses of the preceding section [20]. Third, monitor: serial ultrasound scans to assess the intra-amniotic environment, with ultrasound monitoring of renal function and of the skull bones from the second trimester, and fetal testing appropriate to the gestational age [18, 19]. Fourth, do not rush the decision to terminate the pregnancy: as the signs may improve in cases of oligohydramnios induced by these drugs, the pregnancy should be continued while fetal wellbeing persists, and serial ultrasound surveillance should precede any recommendation of termination, because early withdrawal of the drug may restore the amniotic fluid and allow normal neonatal outcomes [12, 56]. Fifth, if the exposure occurred in the second half of pregnancy, maintain careful surveillance of the pregnancy, including assessment of the amniotic fluid, and of the newborn [13].

The choice between classes, when renin-angiotensin system blockade cannot be avoided in a woman of reproductive age, should favour ACE inhibitors over ARBs, because of the consistent difference in fetal risk, and the woman should be informed that the drug must be withdrawn before conception or, at the latest, as soon as pregnancy is detected [13].

7.5 Neonatal treatment

Neonatal treatment is organ support and its aggressiveness has a demonstrated prognostic consequence. The prescribing information sets out the essentials: observe exposed newborns closely for hypotension, oliguria and hyperkalaemia; if oliguria or hypotension arise, support blood pressure and renal perfusion; exchange transfusion or dialysis may be needed to reverse the hypotension and replace renal function [19, 73].

In the severe forms, aggressive treatment of refractory arterial hypotension in the immediate postnatal period is described as critical for survival and for the subsequent prognosis, and is carried out with vasopressors and plasma infusions; to this are added respiratory support for the pulmonary hypoplasia, which in the reported cases included mechanical ventilation and treatment of pneumothoraces, and renal replacement therapy, in the published series in the form of peritoneal dialysis [5, 21]. In a case of a 34-week preterm infant with a homozygous truncating ACE variant and total anuria, initial support included mechanical ventilation, nitric oxide, vasopressin for the refractory hypotension and strict fluid and electrolyte restriction, with enteral lactulose from day 32 of life to attenuate the uraemic symptoms, in an attempt to favour the excretion of nitrogenous products through the immature intestinal mucosa; the patient survived 61 days without renal replacement therapy, which constitutes the longest survival reported in complete anuria [34]. In another series of three patients with distinct ACE variants, two died shortly after birth despite treatment, and one improved with symptomatic treatment that included raising blood pressure, respiratory support, diuretics and continuous renal replacement therapy, with normal renal function and ultrasound at 27 months of follow-up; the authors emphasise, for fetuses with an established diagnosis, treatment of the oligohydramnios and interventions that promote fetal maturation before preterm delivery [80]. A recent report describes a preterm infant with genetically confirmed ACE-related renal tubular dysgenesis who survived beyond the neonatal period with early initiation of peritoneal dialysis and targeted supportive treatment, and stresses that early genetic diagnosis clarified the pathophysiology and supported the continuation of intensive care despite the severity of the presentation; the same work draws attention to the postnatal course of urine output as an element to use in counselling families and in the decision on the appropriateness and potential benefit of offering neonatal dialysis [88].

The sources consulted describe no doses of vasopressors, of plasma infusions or of dialysis prescriptions specific to this condition; the doses used are those of neonatal intensive care protocols for refractory hypotension and acute kidney injury, applied by general indication and not by an indication specific to the disease.

7.6 Fludrocortisone in survivors

The only pharmacological treatment with a documented effect on the residual pathophysiology of survivors is fludrocortisone, a synthetic mineralocorticoid that replaces the action of the absent aldosterone downstream of the pathway blockade. The rationale is direct: in the primary form, interruption of the renin-angiotensin system reduces angiotensin II, which normally increases renal sodium reabsorption in the proximal tubule, stimulates aldosterone production in the adrenal cortex and promotes vasopressin release from the posterior pituitary, so that administration of vasopressin and fludrocortisone can bypass these deficiencies; the available data are empirical and of variable outcome [72].

The first report of a response describes an infant with a clinical diagnosis of renal tubular dysgenesis who survived the neonatal period after two weeks of anuria that subsequently resolved; the hypotension and hyperkalaemia normalised with the administration of fludrocortisone, and at 3 years he had stage 4 chronic kidney disease with normal neurodevelopment [76]. Documentation of long-term efficacy came from a Japanese case with ten years of follow-up. A girl with autosomal recessive renal tubular dysgenesis from a homozygous ACE variant had recurrent episodes of dehydration, electrolyte disturbance and prerenal acute kidney injury, triggered by polyuria, with serum potassium usually between 5 and 6 mEq/L and values up to 6.3 mEq/L, bicarbonate of 18.8 mEq/L, sodium of 136 mEq/L and urine output of about 7.8 and 6.6 ml/kg/h during the episodes; renin was markedly elevated, at 18.5 ng/ml/h for a reference range of 0.2 to 3.9, and aldosterone inappropriately low. Oral fludrocortisone was started at 4 years at 0.025 mg daily; at 10 years, on 0.04 mg daily, together with sodium bicarbonate 3.6 g daily and sodium chloride 1.5 g daily, there were no further episodes of acute kidney injury or hyperkalaemia, potassium normalised, hyponatraemia became infrequent, the estimated glomerular filtration rate rose from about 35 to about 45 ml/min/1.73 m² and was 48.47 ml/min/1.73 m² at the last assessment, with normal height, weight and neurodevelopment; the fractional excretion of sodium remained between 1.7% and 2.2%, without a difference before and after starting the drug [22]. The same work reports efficacy also at very early ages, at 6 days and at one month of life, and in the correction of hypotension at 18 months, attributed to the references it cites [22]. Another report describes a child with compound heterozygous ACE variants who did not require renal replacement therapy and in whom fludrocortisone achieved electrolyte and acid-base balance [89].

The use is off-label and this should be said to the family. The approved prescribing information for fludrocortisone acetate tablets, effective 19 May 2025, indicates the drug only as partial replacement therapy in primary and secondary adrenocortical insufficiency in Addison's disease and in the treatment of salt-losing adrenogenital syndrome; in Addison's disease, “the usual dose is 0.1 mg of fludrocortisone acetate tablets daily”, with a dosage range running from 0.1 mg three times weekly to 0.2 mg daily, reduction to 0.05 mg daily if transient hypertension arises as a consequence of therapy, and administration preferably together with cortisone, 10 to 37.5 mg daily in divided doses, or hydrocortisone, 10 to 30 mg daily in divided doses; in salt-losing adrenogenital syndrome, the recommended dose is 0.1 to 0.2 mg daily. The same document states that safety and efficacy in children have not been established and that the growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed [23]. There is no dose published by a guideline for renal tubular dysgenesis; the practical reference is therefore the dose of the published cases, 0.025 to 0.04 mg daily in the child [22], substantially lower than that of the adult label, with the label serving as a comparison and providing the safety limits, namely dose reduction if hypertension arises. Monitoring should include blood pressure, potassium, sodium, bicarbonate, renal function and, in the child, growth [22, 23].

In survivors with hypotension and hyperkalaemia a therapeutic trial is reasonable, but it rests on repeated single-case observations and not on comparative evidence [5, 76].

7.7 Regulatory table

The table assembles the regulatory information for the four representative agents consulted, in the two jurisdictions and, where applicable, in Portugal.

The European reference text for aliskiren adds a detail relevant to the interpretation of the data: there are no data on the use of aliskiren in pregnant women and the drug was not teratogenic in rats or rabbits, but other substances acting directly on the renin-angiotensin-aldosterone system have been associated with severe fetal malformations and neonatal death, so that the restriction is mechanistic and class-wide, and not based on data specific to the drug [90]. The American information for the same drug also makes explicit the epidemiological framework of the background risk: in the general United States population, the estimated risk of major malformations and of miscarriage in clinically recognised pregnancies is 2% to 4% and 15% to 20%, respectively, and most epidemiological studies of fetal anomalies after first-trimester exposure to antihypertensives did not distinguish drugs acting on the renin-angiotensin system from the rest [73]. This last observation is precisely the methodological problem that the cohorts with hypertensive controls resolved.

As to Brazil, the sources consulted do not include Brazilian package inserts: the electronic package insert database of the national health surveillance agency returns no records on automated query, and Brazilian regulatory information remains a limitation of this article.

7.8 Evidence of intervention and trials

There is no clinical trial of intervention in fetopathy from renin-angiotensin system blockade or in renal tubular dysgenesis, and a search of the United States clinical trials registry under these terms returned no studies of the condition [5]. The following table assembles the studies cited by the guidelines as the basis of the replacement and prevention recommendations in hypertensive pregnant women, and the trials of the agent in development acting on the same pathway, because they are the source of the applicable recommendations and not because they are trials of this disease.

The limits of reading these data must be made explicit. None of the studies in the table tested an intervention in the fetopathy, and the first three assess the treatment of maternal hypertension, of which prevention of exposure is a desirable side effect and not the outcome measured. It is not legitimate to compare indirectly the rates of fetopathy between the prospective cohort of the teratology services and the German reimbursement data cohort, because the case definitions and the populations differ, as the authors themselves demonstrate [13]. The relative risk reduction of the aspirin meta-analyses should be read together with the absolute rate of pre-eclampsia of the population concerned, which the risk ratio does not provide. The zilebesiran trials are included not as therapy but as context: this is an agent that reduces angiotensinogen, that is, that pharmacologically reproduces the defect of the AGT form, and none of the studies included pregnant women.

7.9 Developments of the past twelve months, with the level of evidence

Five developments belong to the past twelve months and should be classified for what they are.

In published observational evidence, the German reimbursement data cohort is the largest series of exposed children analysed to date and the only one with long-term data both on the cases with fetopathy and on those without; its contribution is the follow-up of 203 exposed live births beyond the neonatal period and the comparison with about 29,000 children exposed to the recommended antihypertensives [13]. In a published case report with long follow-up, the ten-year description of a child with fetopathy documented the multiorgan sequelae, including the need for cranioplasty, developmental delay, short stature, the urinary concentrating defect from an alteration of aquaporin-2 and progressive renal damage with proteinuria [35]. In a case report of reversibility, the first case of reversible anhydramnios associated with exposure to olmesartan in the first and second trimesters was described, with normalisation of the amniotic fluid index within two weeks of withdrawal and a favourable neonatal outcome [56]. In preclinical research, olmesartan derivatives modified with polyethylene glycol retained AT1 receptor inhibitory activity in vitro, and the selected compound, a dimer with an ionisable tertiary amine, showed placental transfer of about 7% of that of olmesartan in a model of pregnant mice treated with angiotensin II and minimal transfer in an ex vivo human placental perfusion model, comparable to that of insulin used as a negative control; as to fetal toxicity, olmesartan induced neonatal renal toxicity at doses as low as one tenth of the minimum effective dose, whereas the modified compound induced it only above the effective dose, which indicates a discernible safety margin. This is preclinical proof of concept that AT1 receptor inhibition might come to be a therapeutic strategy in pre-eclampsia if placental transfer were restricted, and not an available drug [92]. In the clinical development of an agent of the same pathway, zilebesiran, an interfering ribonucleic acid directed at hepatic angiotensinogen, has a phase 3 trial recruiting since September 2025 in hypertension, with 11,000 participants planned, and completed phases 1 and 2; there is no authorisation or approved label, and the mechanism is the opposite of what a patient with angiotensinogen deficiency needs, so that it is not and could not be a treatment for this disease [36, 91]. The link between this agent and the disease is pathophysiological and not therapeutic: the demonstration, in a patient with a homozygous AGT variant, of compensatory renin regulation in response to substrate depletion was explicitly compared by the authors with what is observed in the hepatic silencing of AGT used in the treatment of hypertension [50].

7.10 Agents to avoid, perioperative care and transition

For the woman who is pregnant or planning a pregnancy, the list of agents to avoid includes ACE inhibitors, ARBs, direct renin inhibitors, combinations containing them, sacubitril/valsartan, mineralocorticoid receptor antagonists because of their antiandrogenic effect, atenolol because of growth restriction and nitroprusside because of cyanide toxicity [20, 84, 85]. Non-steroidal anti-inflammatory drugs deserve a mention of their own in this article, because maternal exposure to this class is one of the recognised causes of secondary renal tubular dysgenesis, alongside ACE inhibitors [71, 72].

For the surviving child, the perioperative problem is hypotension. A 7-year-old child with autosomal recessive renal tubular dysgenesis developed life-threatening hypotension requiring cardiopulmonary resuscitation immediately after induction of anaesthesia for surgery; when the surgery was rescheduled a year later, haemodynamic stability was maintained with perioperative fluid administration and careful titration of anaesthetics and vasopressors during general anaesthesia. Anaesthetists should be alert to the risk of life-threatening hypotension during general anaesthesia in these children, and anaesthesia requires detailed preoperative planning, with adequate perianaesthetic fluid administration, careful titration of anaesthetics and use of vasopressors to prevent lethal hypotension [93]. The same principle applies to situations of volume depletion from intercurrent illness, in which polyuria leads to dehydration and prerenal acute kidney injury [22].

As to transition to adult care, the sources consulted describe no specific protocols. Survivors follow the course of patients with chronic kidney disease of paediatric onset, with prolonged follow-up by paediatric nephrology and the need for organised transfer to adult nephrology; the oldest patient described in the series was 20 years of age [5, 21]. The disease itself adds a specific transition theme: a woman surviving renal tubular dysgenesis, or a woman with chronic kidney disease of any cause, enters the group in which the prescription of renin-angiotensin system blockers for renal protection collides with reproductive planning, a situation for which the chronic kidney disease guideline recommends an individualised multidisciplinary approach with contraception and preconception consultation [41, 83].

8. Reproductive Options and Family Counselling

8.1 Recurrence risk by scenario

Counselling depends entirely on the aetiology established, and that is the clinical reason for insisting on the distinction between the forms. When the oligohydramnios arises from renal tubular dysgenesis, an autosomal recessive disease, the recurrence risk is 25% in each subsequent pregnancy of the same couple [3, 8]. When it is associated with twin-to-twin transfusion, with certain cardiac malformations or with prenatal exposure to ACE inhibitors or angiotensin II receptor antagonists in the second and third trimesters, the recurrence risk is determined by the underlying aetiology of the oligohydramnios and not by a pattern of inheritance [8].

In the pharmacological form, the recurrence risk is high but avoidable, and the problem is the continuation of the prescription. For a woman with a child with a probable teratogenic syndrome, the recurrence risk is high if she remains on the same drug at the same dose, and review of the medication before a new pregnancy should be seriously considered, in liaison with the doctor who prescribes it [9]. The same source adds a note of caution about predictability: although the overall recurrence risk is high, the severity of any effect may be poorly predictable, being influenced by the drug metabolism of the fetoplacental unit, in part genetically determined, and may vary between siblings [9]. This observation prevents any guarantee to a woman that the next pregnancy will be equally affected, or equally spared.

Practical management follows from the preconception recommendations already described in section 7: withdraw the renin-angiotensin system blocker two to three months before trying to conceive, switch to amlodipine, nifedipine, labetalol or methyldopa with folic acid supplementation, and maintain safe and effective contraception while the drug is being taken [74]. In women with diabetes, the recommendation is formally graded: withdraw before conception and avoid in sexually active people of childbearing potential not using reliable contraception, grade B, and discuss and implement a contraceptive plan with all people with diabetes of reproductive potential, grade A [85].

8.2 Cascade testing and carriers in the genetic form

In Mendelian renal tubular dysgenesis, once the two variants have been identified in the proband and their parental origin confirmed, the parents are obligate carriers and testing targeted at the family variants allows the carrier status of healthy siblings and other relatives to be determined, with the aim of informing their own reproductive decisions. Heterozygous carriers do not have the fetal disease: biallelic inactivation is necessary to abolish the pathway during fetal life [10].

Two findings qualify the apparent neutrality of carrier status. The first is biochemical: in the Taiwanese population, heterozygous carriers of the recurrent AGT variant had a significantly higher serum angiotensinogen concentration than wild-type individuals, without a difference in blood pressure [15]. The second is gene-specific: heterozygous REN variants, in specific domains, cause a distinct autosomal dominant disease, REN-associated tubulointerstitial kidney disease, so that a carrier result in this gene requires interpretation of the domain affected and cannot be reported as benign without that analysis [7]. The gene AGT appears in reproductive carrier screening panels in population programmes, which means that carrier status may be identified outside any context of disease in the family [36].

8.3 Consanguinity and founder populations

Several of the families described in the literature are consanguineous, including Turkish, Tunisian, North African and Palestinian families and an extended Bedouin family with four of the five survivors of one series [3, 21, 37, 38]. Parental consanguinity increases the probability of homozygosity and should be enquired about systematically; in a case with a homozygous AGTR1 variant there was parental consanguinity without any family history of renal disease, which shows that the absence of a family history does not diminish the value of consanguinity as an indicator [51].

The existence of a recurrent AGT variant in Taiwan, with a heterozygous allele frequency of 1% in a sample of 5000 healthy individuals, alters the a priori risk calculation in that population and justifies, according to the authors, making available a rapid test targeted at that variant, for the purposes of genetic counselling; the same frequency suggests that the disease may be more common in Taiwan than was thought [15]. Outside those populations, there are no recurrent variants, and each family tends to have private variants [80].

8.4 Germline mosaicism and de novo variants

The sources consulted describe no documented cases of germline mosaicism in renal tubular dysgenesis. There is, however, a demonstration that one of the two alleles may arise de novo: in a child with biallelic loss-of-function variants in ACE, identified by trio genome sequencing, one variant was presumed de novo and the other was of maternal origin [78]. The consequence for counselling is that the recurrence risk in a couple in which only one parent is a carrier is not 25%, but rather the empirical risk of a new de novo occurrence, which is not quantified; formal demonstration of the origin of each allele is therefore a necessary part of the work-up before counselling.

The entity described in OMIM as renal tubular dysgenesis with choanal atresia and athelia illustrates the difficulty of assigning inheritance from a single family. In the original sibship of three brothers, X-linked recessive inheritance was possible, but there were four healthy maternal uncles, and autosomal dominant inheritance with gonadal mosaicism could not be excluded, nor could a subtle chromosomal abnormality with a contiguous gene effect [3]. In this entity, therefore, more than one pattern of inheritance remains possible, and counselling should state that uncertainty.

8.5 Prenatal diagnosis and preimplantation testing

Once the family variants have been identified, early prenatal diagnosis is possible, by chorionic villus sampling or amniocentesis, and constitutes one of the direct gains of molecular characterisation, alongside counselling itself [14]. In cases where the diagnosis is made for the first time in an ongoing pregnancy, obtaining the sample may require amnioinfusion when there is anhydramnios, and the clinical exome from amniotic fluid allowed the diagnosis in two Vietnamese fetuses; the prognosis was considered guarded and the couples opted to terminate the pregnancies [47]. Preimplantation genetic testing is applicable to an autosomal recessive disease with known variants and constitutes the alternative for couples who do not wish to face the decision to terminate.

The information to be given about prognosis has changed over the past fifteen years and should be communicated with that nuance. Until 2008 the disease was presented as universally fatal; today there are survivors followed to the age of 20, with variable stages of chronic kidney disease, and overall survival in genetically confirmed ACE-related cases is 24.6%, with substantial variation according to the type of variant, from 8.6% in biallelic truncating variants [21, 33, 34]. The family of a diagnosed fetus should be told that early diagnosis, even when the prognosis is guarded, allows delivery to be planned in a centre with ventilation and dialysis capacity, supports informed decisions about the intensity of care and gives time for genetic counselling and family bonding [5, 34, 88]. At the same time, the option of neonatal dialysis cannot be presented as routine: the recent literature explicitly discusses the appropriateness and potential benefit of offering it, using the postnatal course of urine output as an element of the decision [88].

8.6 Special populations and particular clinical scenarios

Women with chronic kidney disease, heart failure, ischaemic heart disease or diabetes with nephropathy constitute the group in which the indication for the drug is strongest and the conflict with reproductive planning greatest. Guideline coverage is uneven: recommendations on pregnancy exist in developed form in the hypertension guidelines of NICE, the European society of hypertension, the European society of cardiology and the United States societies, are missing from several heart failure and ischaemic heart disease guidelines, and are developed in those on chronic kidney disease of the British renal association and of the international kidney disease outcomes organisation [41]. The United States ischaemic heart disease guideline recommends multidisciplinary preconception care in women with this disease, detailing the potential fetal harm [41].

There are situations in which the indication for an agent acting on the system is particularly strong, such as mineralocorticoid receptor antagonists in primary hyperaldosteronism from adenoma, hyperplasia or familial forms. Women of childbearing age with these conditions are at risk from the adverse effects of these drugs in pregnancy, but may simultaneously benefit from pregnancy, because progesterone acts physiologically as a mineralocorticoid antagonist, which reinforces the importance of an individualised decision [41].

There is also a dimension of equity. The absence of consideration of women of childbearing age in some guidelines may translate into an implicit distinction in treatment between pregnant and non-pregnant women, leaving wide discretion to the clinician and potentially contributing to avoidable sex-based health inequalities; a study cited in the same review documented significant prescribing disparities between the sexes, with women less likely to receive ACE inhibitors than men, which reinforces the need for documented counselling and contraceptive advice rather than simple avoidance of prescription [41].

8.7 Breastfeeding

The divergences between guidelines in this matter are set out in the table in section 7 and deserve a counselling note. The European society of hypertension states that ACE inhibitors are compatible with breastfeeding and that ARBs are not currently recommended in lactating women because of limited safety evidence; the 2024 European hypertension guideline names benazepril, captopril, enalapril and quinapril; the United States heart failure and ischaemic heart disease guidelines consider enalapril, benazepril and captopril safe during breastfeeding, a position supported by studies showing concentrations of these ACE inhibitors in breast milk low enough to pose no danger to the infant; and NICE states that ACE inhibitors and ARBs are not advised, but not absolutely prohibited, without specifying drugs [41]. The summary of product characteristics for enalapril in Portugal is more cautious: limited pharmacokinetic data have shown very low concentrations in breast milk, but the drug is not recommended during the breastfeeding of preterm infants or in the first weeks after birth, because of the hypothetical risk of cardiovascular and renal effects and insufficient clinical experience; in an older child, use by the mother may be considered if the therapy is necessary and the child is monitored for adverse effects [18]. Prematurity is a factor to be considered explicitly, because preterm infants are more sensitive to modulation of the renin-angiotensin system and to accumulation of the drugs [41]. For sacubitril/valsartan, the limited data available show excretion of sacubitril and its active metabolite in human milk in very small amounts, with an estimated relative infant dose of 0.01% for sacubitril and 0.46% for the active metabolite at a dose of 24 mg/26 mg twice daily, valsartan being below the limit of detection, but the information on effects in newborns is insufficient and the drug is not recommended in breastfeeding women [42]. The British and Irish hypertension society summarises the state of the evidence: robust evidence is lacking both on the concentration of these drugs in breast milk and on the subsequent effect in newborns, and the decision to reintroduce depends on maternal blood pressure not controlled by other therapies, on a medical and obstetric history that makes the drug critical, and on the health and prematurity of the infant [74]. The drugs and lactation database maintained by the United States national library of medicine is the source recommended by the United States guideline for this decision [20].

8.8 The postpartum period

The postpartum period is a frequently missed clinical opportunity and has direct relevance to the counselling of women who have had an affected pregnancy. Hypertensive disorders of pregnancy affect about 9% of pregnancies in the United States and are a leading cause of maternal morbidity and mortality; postpartum hypertension peaks between the third and sixth day after delivery and is undervalued, in a period that concentrates the greatest risk of preventable maternal death, with cardiovascular causes accounting for more than a third of pregnancy-related deaths. Beyond the acute phase, women with hypertensive pregnancies face accelerated trajectories towards chronic hypertension, chronic kidney disease and cardiometabolic risk that accumulates with each affected pregnancy, and the postpartum visit is the occasion to identify those who need nephrological assessment and to start renoprotective therapy [94]. A study cited by the British society showed that optimisation of blood pressure control in the first two to three months postpartum, after a hypertensive pregnancy, was associated with better cardiac remodelling [74]. Reintroduction of the renin-angiotensin system blocker, when indicated, should be articulated with the decision on breastfeeding and with the planning of the next pregnancy.

9. Special Considerations: Population Diversity and Epidemiology

9.1 What is measured when the frequency of this condition is measured

Neither of the two entities of this article has a published population prevalence, and it is important to understand why. For the pharmacological form, the frequency depends on two factors that vary between countries and over time: the proportion of women of childbearing age taking drugs that block the renin-angiotensin system, which depends on first-line recommendations and on the prevalence of hypertension and diabetes, and the proportion of those pregnancies that reach the critical window without the drug being withdrawn, which depends on access to antenatal care and on the planning of pregnancies. For the genetic form, Orphanet classifies renal tubular dysgenesis and its genetic subtype as rare diseases but publishes no prevalence estimate for either code, and the publications count families and not rates [5, 11]. A rate for renal tubular dysgenesis as a whole would not, moreover, be a rate of genetic disease, because it would be contaminated by the acquired forms, drug-induced and twin-to-twin transfusion, which Orphanet classifies as distinct entities [5].

9.2 Exposure and risk in the United States

The scale of the problem in the United States was quantified in a population-based study of antihypertensive utilisation patterns in pregnant women with pre-existing hypertension, using a commercial database from 2011 to 2020. A total of 1,950,292 pregnancies were identified, of which 20,576 with pre-existing hypertension, 12,978 with a live birth and 7598 without; in the six months before pregnancy, 80.1% and 81.0% of the two groups were using antihypertensives. In pregnancies ending in a live birth, 13.9% of baseline users discontinued treatment during pregnancy, 28.9% of non-users started antihypertensives during pregnancy and 17.2% started postpartum. Before pregnancy, the predominant antihypertensives were thiazide diuretics (21.9%), combined alpha and beta blockers (18.4%) and dihydropyridines (16.2%). During pregnancy, the use of thiazide diuretics, cardioselective beta blockers and ACE inhibitors declined, reaching in the third trimester 3.0%, 4.2% and 0.8% respectively; the use of dihydropyridines remained stable, but the preference shifted from amlodipine to nifedipine in the third trimester, from 2.2% to 10.8%; central alpha-2 agonists rose to 15.2% in the third trimester, against 9.8% before and 5.7% after pregnancy; angiotensin II receptor antagonists followed the ACE inhibitors, with use below 1% in the late trimesters; and combinations fell from 10.8% before pregnancy to 0.8% in the third trimester, recovering to 7.3% postpartum [95].

The German cohort cites the same study with figures that give the measure of residual exposure: before pregnancy, the prevalence of use of renin-angiotensin-aldosterone system inhibitors was 19.5% (2537 of 12,978) in pregnancies ending in a live birth and 24.7% (1875 of 7598) in those ending in a loss, and, although most women switched to more appropriate medication during pregnancy, 0.5% (68 of 12,881) and 0.6% (71 of 12,881) of pregnancies with a live birth maintained exposure to ACE inhibitors and to ARBs, respectively, in the third trimester [13]. These are small proportions of a large population, which makes this a rare but persistently avoidable condition.

The United States cohorts of first-trimester risk also give the measure of the rarity of exposure in that period: in the Tennessee Medicaid cohort, 209 of 29,507 infants were exposed to ACE inhibitors in the first trimester only [61]; in the Kaiser Permanente Northern California cohort, the prevalence of ACE inhibitor use in the first trimester only was 0.9 per 1000 pregnancies, against 2.4 per 1000 for other antihypertensives [62]; and in the national Medicaid cohort, 4107 of 1,333,624 pregnancies (0.31%) were exposed to ACE inhibitors in the first trimester [63].

9.3 Exposure and risk in Europe

The European data come mainly from Germany. In the German pharmacoepidemiological database, which covers about 20% of the country's population, 203 live births with exposure to renin-angiotensin-aldosterone system inhibitors after day 140 of gestation were identified, in pregnancies beginning between 2006 and 2019, against 29,674 exposed to metoprolol or methyldopa in the same period; the mothers who used the former were older, with a median of 34 against 33 years, had less formal education and used antidiabetic drugs and diuretics more frequently before and during pregnancy, and the exposed children were more often female and less often from multiple pregnancies, without a difference in median gestational age at birth [13]. The rate of fetopathy in that cohort was 3.9% of those exposed, with the distribution by class already described [13]. The European network of teratology information services, with six centres, contributed 89 pregnancies exposed to ACE inhibitors and 101 to ARBs beyond the first trimester [12], and the Berlin institute 29 prospective and 16 retrospective cases of exposure to AT1 antagonists [17]. The German cohorts of first-trimester exposure assembled 329 women exposed to ACE inhibitors and 215 prospective pregnancies exposed to ARBs [55, 64].

The European prescribing context is relevant to interpretation: the recommendation of renin-angiotensin-aldosterone system blockers as first line in adults under 55 years and in people with diabetes of any age means that a substantial proportion of women of childbearing age with hypertension are taking these drugs before any pregnancy [74].

9.4 Founder populations and geographical variation of the genetic form

The only founder population characterised is the Taiwanese. A homozygous deletion-insertion variant in the AGT gene is frequently reported in Taiwan, and determination of the allele frequency in a sample of 5000 healthy individuals, by real-time polymerase chain reaction with a probe validated by Sanger sequencing, gave an overall heterozygosity frequency of 1% (50 of 5000); the authors conclude that, given this high prevalence, autosomal recessive renal tubular dysgenesis may be more common in the Taiwanese population than was thought, and that rapid detection of this variant is relevant for genetic counselling and for estimating the a priori risk [15]. This is the only population estimate of allele frequency available for any of the four genes.

The reference series of 48 unrelated families includes families of very diverse origins, with cases reported from centres in continental Europe, the United Kingdom, North America, South America, Israel, North Africa and Oceania, according to the list of authors and the origins described in the allelic variant entries [3, 14]. The consanguineous families described include Turkish, Tunisian, North African, Palestinian and Bedouin origins [3, 21, 37, 38]. Individual cases have been reported from Japan, China, Vietnam, Qatar, Australia, the United Kingdom, the United States and Portugal [22, 34, 47, 51, 72, 78, 80, 88, 89]. These origins reflect the distribution of the centres that publish and not the distribution of the disease.

9.5 Data from Portugal and Brazil

The sources consulted include one Portuguese case, described by a team from the Centro Materno-Infantil do Norte Albino Aroso and the Centro de Genética Médica Doutor Jacinto Magalhães, of the Unidade Local de Saúde de Santo António, in Porto, bringing together neonatology, medical genetics and paediatric nephrology; it concerns a late preterm female newborn with histologically confirmed renal tubular dysgenesis, without maternal drug exposure and without variants in the pathway genes, and it is the illustrative case of section 10 of this article [72]. No prevalence estimates or Portuguese or Brazilian case series of this condition were found in the sources consulted, nor national data on the frequency of exposure to renin-angiotensin system blockers in pregnancy. Portuguese regulatory information is available and was used in this article, through the summaries of product characteristics for enalapril and for the losartan with hydrochlorothiazide combination obtained from the INFARMED information system [18, 70]. For Brazil, the electronic package insert database of the national health surveillance agency returns no records on automated query, and Brazilian regulatory information remains a declared limitation.

9.6 Declared epidemiological gaps

Three gaps should be made explicit rather than circumvented. First: there is no population estimate of the incidence of fetopathy from renin-angiotensin system blockade, and the proportions of 3.2% to 29.2% or of 0.7% to 11.5% are risks conditional on exposure, measured in different populations and with different definitions, which cannot be converted into incidence or compared directly with one another [12, 13]. Second: the absence of prevalence data for the genetic form in Orphanet and the counting of families rather than rates in the literature mean that any figure presented as the prevalence of this disease would be an invention [5]. Third: the absence of data in the sources consulted on Portugal and Brazil, beyond the clinical case and the regulatory information, does not demonstrate the absence of published data, only the limit of the search performed.

9.7 Reference networks and resources

The relevant European reference network is ERKNet, the European reference network for rare kidney disease, which brings together the European paediatric and adult nephrology centres with expertise in rare kidney diseases [24]. For congenital anomalies and dysmorphic syndromes with multisystem involvement, the applicable network is ERN ITHACA.

For the assessment of exposures in pregnancy, the specific resources are the teratology information services, which provide free information and counselling to health professionals and maintain registries of exposure and outcome for surveillance purposes. The British service, the UK Teratology Information Service, maintains online reviews and patient information leaflets [9, 25], and the European network bringing together the equivalent national services is the European Network of Teratology Information Services [9, 26]. In the United States and Canada there are analogous services, respectively MotherToBaby, of the organisation of teratology information specialists, and the Canadian drugs in pregnancy information service [9]. It is precisely to these services that we owe the prospective cohorts that quantified the risk conditional on exposure [12, 17].

As to patient associations, the sources consulted identify no association dedicated to renal tubular dysgenesis or to fetopathy from renin-angiotensin system blockade. The support group indicated by the Oxford Desk Reference for families facing adverse prenatal results is the British association Antenatal Results and Choices [27]. Families with chronic kidney disease of paediatric onset turn to the national kidney patient associations, and families with a drug-induced embryofetopathy have, according to the sources consulted, no association structure of their own.

10. Illustrative Clinical Case

10.1 A case of renal tubular dysgenesis without an identified cause, Porto

The case that follows was published by a team from neonatology, medical genetics and paediatric nephrology of the Centro Materno-Infantil do Norte Albino Aroso and the Centro de Genética Médica Doutor Jacinto Magalhães, of the Unidade Local de Saúde de Santo António, in Porto [72].

The patient was a late preterm female newborn, the child of non-consanguineous, healthy parents, without a family history of renal disease and without a maternal history of drug exposure. The pregnancy was complicated by oligohydramnios, with an amniotic fluid index of 2.4 cm detected at 31 weeks of gestation, and by fetal growth restriction at the 6.8th centile at 33 weeks, which prompted maternal admission from that point. Doppler parameters of the uterine arteries and of the middle cerebral artery showed no abnormality, and fetal ultrasound revealed no malformation of the kidney or urinary tract. After antenatal corticosteroids for lung maturation, an elective caesarean section was performed at 35 weeks. Apgar scores were 9 at one and five minutes, and anthropometry was appropriate for gestational age, with a weight of 2190 g at the 26th centile. The newborn had hypotonia and features consistent with the Potter sequence, including low-set ears with abnormal morphology, a flattened nose, arthrogryposis and talipes [72].

Immediately after birth she developed respiratory distress, requiring continuous positive airway pressure ventilation, with a maximum inspired oxygen fraction of 0.4 and positive end-expiratory pressure of 5 cmH₂O, complicated by a right pneumothorax treated by needle thoracocentesis. She had transient hypotension responsive to fluids, without ultrasound evidence of structural heart disease. Anuric renal failure developed, with a maximum serum creatinine of 5.5 mg/dL and serum urea of 123 mg/dL, accompanied by non-anion gap metabolic acidosis, hyperkalaemia with a maximum potassium of 7.5 mmol/L and hyponatraemia with a minimum sodium of 124 mmol/L. Renal ultrasound showed kidneys of normal size and normal echogenicity [72].

Despite diuretic therapy, the renal failure persisted with increasing signs of volume overload, which required peritoneal dialysis from the third day of life. Dialysis was compromised by catheter leaks, and the course was complicated by peritonitis, anasarca and coagulopathy with lower gastrointestinal bleeding. Despite organ support and broad-spectrum antibiotic therapy, the condition deteriorated progressively and the patient died on the twentieth day of life [72].

Faced with refractory anuric renal failure in a newborn with structurally normal kidneys on ultrasound, a presumptive diagnosis of renal tubular dysgenesis was made, reinforced by the detection of skull ossification defects on radiography. The diagnosis was confirmed by renal biopsy and by the autopsy findings, which showed a reduced number of proximal tubules: on haematoxylin and eosin staining, glomeruli and only distal tubules were identified; the proximal tubules were not identifiable, as shown by the absence of a brush border on periodic acid-Schiff staining and by the absence of CD10 staining in the tubules; immunohistochemical analysis with epithelial membrane antigen highlighted the distal tubules present. The images of these four panels are reproduced in figure 1 of the paper, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC11847405/figure/FIG1/ [72].

The aetiological investigation was broad and inconclusive. Classical cytogenetic analysis of peripheral blood leucocytes revealed the karyotype 46,XX,dup(1)(q24.1q25.1); the 9.3 Mb interstitial duplication of the long arm of chromosome 1, spanning 109 genes, was confirmed by array comparative genomic hybridisation and by exome sequencing. The duplication had not been described before, contained neither the causal genes of renal tubular dysgenesis, ACE, REN, AGT and AGTR1, nor any deleterious variants in those genes, and the parental karyotypes were normal, which points to a de novo occurrence. Antemortem levels of active renin, at 47 pg/mL, and of ferritin, at 80 μg/L, were within normal limits. Placental histopathology revealed a small area, of 1 cm, of ischaemic necrosis [72].

The authors concluded that no definitive cause was identified. The chromosomal abnormality described did not involve the genes of the renin-angiotensin system, which is supported by the absence of altered renin activity and by the absence of major haemodynamic instability; and, although an area of placental ischaemia was documented, its limited extent weakens the causal link with the renal tubular dysgenesis in this patient. The identification of a de novo chromosomal abnormality of considerable size, associated with an atypical clinical presentation without major cardiovascular dysfunction, led the authors to consider the possibility of an alternative secondary pathophysiological mechanism, a possibility already suggested in the literature [72].

Three lessons from this case deserve emphasis, with the caveat that the management described in a single report does not constitute routine. The first is diagnostic: a normal renal ultrasound does not exclude severe intrinsic renal disease, and faced with neonatal renal failure with normal kidneys on ultrasound, renal tubular dysgenesis should be considered, with histological confirmation [72]. The second is aetiological: the investigation should be comprehensive, and the attribution of causality to a genetic finding requires mechanistic plausibility, its rarity or its de novo character not being sufficient [72]. The third concerns the organisation of care: the authors stress the need for a multidisciplinary approach with neonatology, nephrology, genetics and obstetrics, and identify as an unmet need the lack of markers for early prenatal diagnosis, which would allow families to make informed decisions [72]. Peritoneal dialysis in this case was started for volume overload and was complicated by peritonitis and catheter leaks, which illustrates the technical difficulty of renal replacement in the preterm newborn and should not be read as an argument against offering it, which the recent literature discusses case by case according to the course of urine output [72, 88].

10.2 Contrasting case: reversible anhydramnios from exposure to olmesartan

To illustrate the other extreme of the spectrum, a recent case of drug exposure with a favourable outcome is described [56].

A 30-year-old primigravida with chronic hypertension presented at 24 weeks and 3 days with severe-range blood pressures, in a picture compatible with worsening chronic hypertension or superimposed pre-eclampsia. She had been taking olmesartan and the triamterene with hydrochlorothiazide combination since before the pregnancy was recognised, with reported adherence. Ultrasound showed anhydramnios with a normal-appearing fetal genitourinary system, and rupture of membranes was excluded by an amniotic fluid dye test. Intravenous antihypertensives were used in the acute phase and the patient was switched to labetalol 400 mg three times daily; she was discharged with a diagnosis of worsening chronic hypertension [56].

Outpatient surveillance with serial ultrasound followed. One week later, amniotic fluid volume was normal. Two weeks after withdrawal, the amniotic fluid index was 14.0 cm. Subsequent scans, at 29 weeks and 3 days and at 33 weeks and 5 days, showed indices of 20.6 cm and 14.0 cm, respectively, and complete fetal anatomy revealed no abnormality. At 33 weeks and 4 days superimposed pre-eclampsia with severe features was diagnosed, labour was induced at 34 weeks and a viable male infant weighing 2390 g was born vaginally, with Apgar scores of 6 and 7 at one and five minutes. Creatinine at birth was 0.7 mg/dL and remained between 0.7 and 0.8 mg/dL during the admission. The neonatal intensive care course was complicated only by a renal ultrasound showing mild left central calyceal dilatation, and the infant was discharged on the seventeenth day of life, under follow-up for that dilatation, which is improving. The images of the normal-appearing fetal kidneys, of the course of amniotic fluid volume by gestational age and of the renal ultrasounds on day one and at about six months of age are in figures 1 to 4 of the paper, consulted on the figure pages of the open access article [56].

The authors consider it the first reported case of reversible anhydramnios associated with exposure to olmesartan in the first and second trimesters, and draw from it a recommendation for management: the favourable outcome highlights the potential for reversibility of fetopathy related to angiotensin II receptor antagonists when withdrawal is timely, and clinicians should consider serial ultrasound surveillance before recommending termination of pregnancy, because early withdrawal of the drug may restore the amniotic fluid and allow normal neonatal outcomes [56]. The same paper assembles in its review nine published cases of exposure to AT1 antagonists, with outcomes ranging from intrauterine fetal death after exposure to valsartan at 24 weeks, with anhydramnios, pulmonary hypoplasia and a very small placenta, to neonatal survival without long-term effects after exposure to olmesartan at 29 weeks, by way of acute renal failure without resolution by the third day of life with telmisartan, inferior vena cava thrombosis after resolution of the oligohydramnios with losartan, renal tubular acidosis with losartan, and limb contractures with skull hypoplasia, microcephaly, underdeveloped calvarial bones and neurocognitive difficulties with candesartan, a case originally reported as non-lethal fetal toxicity of that drug [56, 96]. In a larger review, of 83 fetuses exposed to these drugs in the second or third trimesters, oligohydramnios was present in 58 cases, with resolution after withdrawal of the drug in 19, and outcomes ranged from perinatal death to complete recovery, with resolution generally occurring between one and six weeks, which suggests that the degree of damage depends on both the timing and the duration of exposure [56]. The management of this case is consistent with the recommendation of the prospective cohort to continue the pregnancy while fetal wellbeing persists [12], and the replacement with labetalol corresponds to the first-line alternative of the guidelines, albeit at a dose of 400 mg three times daily, that is, 1200 mg daily, which lies within the range of 200 to 2400 mg daily of the United States guideline [20].

11. Prognosis and Long-Term Follow-Up

11.1 Perinatal prognosis

The prognosis depends on the aetiology, on the window and duration of exposure or on the nature of the variant, and on the intensity of neonatal support. In the pharmacological form, among the eight newborns with fetopathy of the German cohort, six were born preterm and four died in the first week of life, and similar lethality has been reported in case series, with five deaths in eleven live births with fetopathy in one series and four in seven in another; the teratology services cohort reported lower lethality, with seven neonatal deaths and three deaths in the first year among fifty-four live births with fetopathy [13]. In the Berlin institute series, four of thirteen live births did not survive [17]. In the systematic review of published cases, the long-term course is described as positive in only 50% of exposed children, and the neonatal and long-term complications are considered significant [1].

In the genetic form, the prognosis has changed. The reference series of twenty-nine fetuses and newborns from eighteen families recorded perinatal death in every case [16], but survivors have accumulated since 2008 [33]. The most recent literature review found sixty-one genetically confirmed cases of ACE-related renal tubular dysgenesis, with overall survival of 24.6%, significantly lower in patients with biallelic truncating variants, at 8.6%, than in those with at least one non-truncating allele; there were exceptions, and the location of the variant within the gene did not consistently predict prognosis [34]. In a series of five survivors of the neonatal period, four with ACE variants, ages at the date of publication ranged from 5 to 20 years, with variable stages of chronic kidney disease and a presentation ranging from the need for peritoneal dialysis and vasopressors with plasma infusions to the absence of symptoms; the authors conclude that the spectrum is broader than previously reported and that intensive treatment of low blood pressure in the postnatal period is critical for survival and for a better prognosis [21]. The overall prognosis of patients with renal tubular dysgenesis continues to improve with better ventilatory management and with renal replacement therapies [71].

11.2 Long-term renal prognosis

In survivors of the genetic form, the course is one of chronic kidney disease of variable stage, with the need for prolonged follow-up by paediatric nephrology [5]. There are cases with remarkable recovery: a patient followed for 27 months after symptomatic treatment that included continuous renal replacement therapy had normal renal function and renal ultrasound [80], and a 10-year-old patient on fludrocortisone maintained an estimated glomerular filtration rate of 48.47 ml/min/1.73 m², with normal height, weight and neurodevelopment [22]. At the other extreme, an adolescent with a homozygous AGT variant progressed to stage G3b chronic kidney disease after recovering from stage 3 acute kidney injury in the neonatal period [50], and a patient with a novel ACE variant had stage 4 chronic kidney disease at 3 years, with normal neurodevelopment [76].

In the pharmacological form, the most robust follow-up data come from the German cohort and have already been presented in section 3: among the four survivors with fetopathy, three had renal diagnoses and none had arterial hypertension; among the one hundred and ninety-five exposed children without fetopathy diagnosed in the first six months, with a median follow-up of 4.0 years, none had a code for kidney disease associated with renal failure, 2.6% had urinary malformations and 1.5% had a diagnosis of hypertension or a prescription for an antihypertensive, against 1.4% and 0.6% in the comparison group [13]. The series from paediatric nephrology centres, being highly selected, describe worse courses, with chronic renal failure in five of six survivors in one series, in all three of another, and a need for chronic renal replacement in eight of seventeen with exposure after the first trimester in the Midwest consortium series [13, 53]. Read together, the persistence of renal compromise in a high proportion of survivors with fetopathy is consistent across all series, whereas the frequency of concomitant arterial hypertension varies between them [13].

The risk of late manifestation is the main reason for prolonged follow-up. Three children exposed to ACE inhibitors, from pregnancies without oligohydramnios and with transient anuria that recovered within three months, showed at school age progressive renal compromise in two of them, one with arterial hypertension, and isolated polycythaemia in all three [13, 59]. The pathological basis of this pattern is the persistence of the vascular lesions, glomerular cysts and interstitial fibrosis established before birth, detectable even when the oligohydramnios had been reversible [43]. The authors of the German cohort stress that the median follow-up of 4.0 years, with a little more than a tenth of the children followed for more than ten years and a little more than a quarter for more than seven years, may not have been long enough to capture all the children with clinical sequelae, because chronic kidney disease and arterial hypertension do not necessarily manifest in the first years of life [13].

11.3 Extrarenal prognosis

The report with ten years of follow-up documents that the sequelae may be multiorgan and persistent: the need for cranioplasty in the first year of life, persistent mild developmental delay with a developmental quotient of 51 at 8 years and 9 months, severe short stature of about three standard deviations below the mean without improvement, and a urinary concentrating defect with severe polyuria and a risk of hypernatraemia in situations of stress, attributable to an alteration of aquaporin-2 in the principal cells of the collecting duct, with preserved sodium reabsorption from the proximal tubule to the loop of Henle [35]. The neurological manifestations described in the Midwest series, including cystic encephalomalacia, cortical blindness, sensorineural deafness and arachnoid cysts, add domains to be monitored [53]. By contrast, several survivors have normal neurodevelopment, among them the patient with stage 4 chronic kidney disease at 3 years and the 10-year-old Japanese patient on fludrocortisone [22, 76].

11.4 Surveillance table

The table that follows assembles the surveillance supported by the sources consulted. There is no surveillance protocol published by a scientific society for this condition; the items with a regulatory or guideline source are identified as such, and the remainder derive from the explicit recommendations of the cohorts and the case reports.

The intervals in this table are the same as those section 7 indicates for therapeutic management: immediate withdrawal of the drug with replacement, serial ultrasound surveillance during the exposed pregnancy, neonatal surveillance of blood pressure, urine output and potassium, and prolonged nephrological follow-up of survivors.

11.5 Limitations of knowledge about prognosis

Three limitations should be declared. The first is that there is no prospective long-term follow-up study of sufficient duration to characterise the risk of chronic kidney disease and hypertension in adulthood among exposed children without neonatal fetopathy, and the authors of the largest study acknowledge this themselves [13]. The second is that the series from specialist centres overestimate severity, being made up of patients referred to paediatric nephrology, whereas the population-based cohorts underestimate frequency, because they depend on non-specific diagnostic codes [13]. The third is that decisions on the intensity of neonatal care have no basis in comparative evidence: the statement that aggressive treatment of hypotension is critical for survival derives from the observation of series of survivors, not from comparison between strategies [21, 88].

12. Summary and Final Considerations

Fetopathy due to renin-angiotensin system inhibitors is a drug-induced embryofetopathy in which pharmacological blockade of a pathway necessary to fetal renal development reproduces, point by point, an autosomal recessive Mendelian disease. The lesion is renal tubular dysgenesis, with absent or scanty differentiated proximal tubules, and the clinical sequence is predictable from the mechanism: inactivity of the pathway, hypoperfusion of the fetal kidney, anuria, oligohydramnios or anhydramnios, fetal compression with pulmonary hypoplasia and contractures, refractory neonatal arterial hypotension, anuric renal failure and, from that same prolonged hypotension, an ossification defect of the membranous bone of the skull.

The critical window lies from about twenty weeks of gestation. The risk is conditional on exposure and differs between classes: in the prospective cohorts of teratology services, fetopathy occurred in 3.2% of pregnancies exposed to converting enzyme inhibitors and in 29.2% of those exposed to angiotensin II receptor antagonists from that gestational age; in the largest population cohort, in 0.7% and 11.5% of exposed live births. The difference between these figures reflects different case definitions and populations, not a discrepancy of observation, and the consistently higher risk with the receptor antagonists justifies preferring converting enzyme inhibitors when blockade of the pathway cannot be avoided in a woman of reproductive age.

For the first trimester, the evidence resolves according to the choice of comparison group. The studies that compared exposed women with women without hypertension found an excess of malformations, whereas those that compared exposed women with unexposed hypertensive women or with women treated with other agents did not. The dominant interpretation is that the apparent excess is due to the underlying hypertension and not to the drug, a position taken by the teratology information services, which do not require additional surveillance for congenital defects after first-trimester exposure; a recent meta-analysis maintains the opposite interpretation, and the divergence is recorded. The practical consequence is that a woman inadvertently exposed in early pregnancy can be reassured as to teratogenic risk, provided the drug is withdrawn immediately, whereas exposure in the second half of pregnancy requires close surveillance.

Reversibility is the aspect of the picture with the greatest consequence for clinical decision-making. Oligohydramnios and anhydramnios may normalise within one to six weeks of withdrawal of the drug, the probability of recovery is greater with withdrawal before thirty weeks and with a longer drug-free interval before delivery, and there are cases with preserved neonatal renal function and favourable follow-up. For this reason the approach to anhydramnios in an exposed pregnancy is to withdraw, replace and monitor serially, continuing the pregnancy while fetal wellbeing persists, and not to propose termination on the basis of the initial finding. The pathological counterpoint is mandatory in counselling: the vascular lesions, glomerular cysts and interstitial fibrosis are established early and have been documented even in cases in which the oligohydramnios had been reversible, so that normalisation of the amniotic fluid does not guarantee the integrity of the parenchyma and does not dispense with follow-up.

The diagnosis depends on a dated drug history, because no morphological or histological finding distinguishes the drug-induced form from the genetic form. A normal renal ultrasound does not exclude severe intrinsic renal disease: the pattern of normal-sized, echogenic, non-cystic kidneys with poor corticomedullary differentiation, associated with anuria and skull ossification defects, is precisely that of renal tubular dysgenesis. Confirmation is histological, with the absence of a brush border and the absence of CD10 staining in the tubules demonstrating the lack of proximal tubules, and it is molecular testing that attributes the disease to a gene. Genetic testing remains indicated even when exposure is documented, because the difference in recurrence risk, 25% in the recessive form and dependent on prescribing in the pharmacological form, is the information the family needs to have. A negative result in the four genes of the pathway does not exclude the disease, as shown by the cases attributed to biallelic RMND1 variants.

The treatment is prevention. The guidelines agree on strict avoidance in pregnancy and diverge on what matters most to outpatient practice: the timing of withdrawal, which ranges from two to three months before conception, in the British recommendation, to two working days after notification of the pregnancy, in the guidance of the British appraisal agency, by way of withdrawal in the first trimester in the European society of hypertension; the presence or absence of explicit contraceptive advice; and compatibility with breastfeeding, in which captopril, enalapril and benazepril are considered safe by several societies, with angiotensin II receptor antagonists not recommended because of limited evidence. Replacement is with labetalol, 200 to 2400 mg daily in two to three doses, or extended-release nifedipine, 30 to 120 mg daily, without an established preference between the two, with amlodipine and methyldopa as alternatives. Faced with the use of these drugs in a woman of childbearing age, the defensible approach is to discuss and document reproductive plans, advise effective contraception and have a replacement plan ready, rather than simply avoiding the prescription, which would aggravate sex-based inequalities in treatment.

In the newborn, treatment is supportive, and its intensity determines survival: aggressive correction of the refractory hypotension with vasopressors and plasma infusions, ventilatory support for the pulmonary hypoplasia and renal replacement therapy, usually peritoneal dialysis, with early genetic diagnosis supporting the continuation of intensive care and informing the decision on the appropriateness of neonatal dialysis. In survivors with hyperkalaemia, acidosis, hypotension and polyuria, fludrocortisone corrects the mineralocorticoid deficit downstream of the pathway blockade, at paediatric doses of 0.025 to 0.04 mg daily in the published cases, substantially lower than the adult label dose of 0.1 mg daily in Addison's disease; the use is off-label, without safety or efficacy established in children in the approved label, and rests on repeated single-case observations.

The prognosis is no longer uniformly fatal, in either form. In genetically confirmed ACE-related renal tubular dysgenesis, overall survival is 24.6%, with 8.6% in biallelic truncating variants, and there are survivors followed to the age of twenty, with variable stages of chronic kidney disease. Among exposed children, most of those without neonatal signs of fetopathy did not develop chronic kidney disease or hypertension within the median follow-up of four years of the largest cohort, but three of the one hundred and ninety-five children received a diagnosis of hypertension or a prescription for an antihypertensive, two had cardiac malformations that explained it, and two later received diagnoses of renal dysplasia and hypoplasia. The follow-up available is short for a disease whose sequelae may manifest at school age or later, as shown by the long follow-up of three children with progressive renal compromise and polycythaemia, and by the ten-year case with cranioplasty, developmental delay, severe short stature, a urinary concentrating defect and proteinuric nephropathy.

What remains for the clinician is a set of simple obligations. Always ask about the medication of the pregnancy when assessing a fetus with oligohydramnios or a newborn with renal failure. Date the exposure. Withdraw and replace, without waiting. Monitor serially before deciding. Perform the genetic study even when there is exposure. Record that histology does not distinguish the aetiologies and that a normal renal ultrasound does not absolve. And, in the consultation of any woman of childbearing age taking a renin-angiotensin system blocker, have the conversation about contraception and reproductive planning before there is a pregnancy.

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