Pulmonary Hypoplasia Induced by Oligohydramnios

Lung growth in utero is influenced by physical factors such as the intrauterine space, lung liquid volume and pressure, and fetal breathing movements. Lung hypoplasia is a substantial cause of death in newborn infants, and oligohydramnios is one of the most associated causes (1,2).

Underdevelopment of the fetal lungs can be secondary to severe reduction of the amniotic fluid volume. This is often precipitated by premature rupture of membranes or conditions resulting in either underproduction in fetal urine or impairment of excretion of fetal urine into the amniotic cavity. Pulmonary hypoplasia secondary to oligohydramnios is a major cause of neonatal morbidity and mortality (1,2).

Pulmonary hypoplasia is a rare condition, affecting nine to 11 per 10,000 live births. In approximately 30% of cases it is due to oligohydramnios (3).

This diagnosis results in a spectrum of respiratory complications ranging from neonatal death to less severe manifestations, including chronic respiratory failure, pulmonary haemorrhage, bronchopulmonary dysplasia, or even transient respiratory distress (4). The severity of pulmonary hypoplasia relates to the timing of injury in relation to embryologic lung development (4).

Normal structural and functional lung development requires adequate thoracic space for the growing lungs, as well as sufficient fluid exchange to distend the developing airways. Many fetal and obstetric complications may lead to pulmonary hypoplasia, and the timing of these insults influences the severity of pulmonary disease (5).

Conditions resulting in inadequate thoracic space may be related to restriction of the thorax. Amniotic fluid volume is essential for fetal lungs as it is intimately linked to all the physical factors involved in normal lung development and growth such as intrauterine space, lung liquid volume and pressure, and fetal breathing movements (1,5).

A critical amount of amniotic fluid volume appears to be vital to appropriate lung development. Oligohydramnios, especially if chronic, is often an indicator of reduced fetal urine output and renal function. It is also associated with the development of pulmonary hypoplasia (6, 7).

Oligohydramnios leading to pulmonary hypoplasia results from two main categories of conditions. These conditions are either a consequence of congenital anomalies or pregnancy complications that inhibit lung development due to a reduction in the amount of amniotic fluid:

1.            Oligohydramnios related to renal or urinary tract anomalies

a.            Renal dysplasia 

b.            Bilateral renal agenesis

c.             Low urinary tract obstruction (LUTO)

d.            Bilateral cystic kidneys

e.            Oligohydramnios induced by drugs:

i.              Angiotensin converting enzyme inhibitors (ACE-inhibitors) (8).

ii.             Angiotension receptor antagonists (ARB) (9).

2.            Prolonged preterm rupture of membranes. (PROM) The onset of membrane rupture, the duration and the degree of oligohydramnios are clinical factors which have been proposed as prognostic factors of pulmonary hypoplasia.

Oligohydramnios may retard fetal lung growth and can result in pulmonary hypoplasia in experimental animals and human fetuses with prolonged rupture of membranes. Neonates exposed to oligohydramnios caused by premature rupture of membranes have an increased risk of acute respiratory morbidity, including higher ventilator settings, increased incidences of hypoxemia and hypercapnia, and pulmonary hypertension, and a trend toward more air leaks (1).

A small case control study found that infants exposed to prolonged oligohydramnios born following the preterm premature rupture of the membranes prior to 25 weeks’ gestation were at a high risk of prolonged initial hospitalization and major respiratory morbidity in their first 2 years of life. However, the long-term effects of oligohydramnios on the respiratory system are unknown (1). Latency and severity of the oligohydramnios have been identified as significant risk factors. Latency period was defined as the duration between rupture of membranes and delivery. The presence of absolute oligohydramnios at any time during the latency period influenced the probability of pulmonary hypoplasia. A latency period of <7 days, nor the degree of oligohydramnios did not have a significant effect on the development of pulmonary hypoplasia. The more severe the oligohydramnios or the longer the latency period, the greater the impact will be on the development of pulmonary hypoplasia (6).

The most extreme form of fetal oligohydramnios resulting in pulmonary hypoplasia is Potter’s syndrome from bilateral renal agenesis. This condition is incompatible with life. Unfortunately, the term Potter “sequence” is still sometimes used in these cases. This may add confusion and should be abandoned and replaced by stating specific diagnoses (7).

Detailed scans are difficult in the context of oligohydramnios. If the patient had PROM after a normal anomaly scan the risk of associated anomalies is low.

Renal tract urinary anomalies are associated with a higher incidence in perinatal mortality from all causes (i.e stillbirth, pre-viable births and neonatal demise) compared with PPROM pregnancies. Polycystic and dysplastic kidneys are associated with an increased risk of abnormalities of the contralateral kidney and the lower urogenital tract.

Severe oligohydramnios also results in other compression defects outside the fetal thorax and involving the limbs. Such defects include spade-like bands, talipes equinovarus and flexion contractures at the level of the elbows, knees and feet. Fortunately, many of these limb defects are easily treated with physiotherapy and do not require surgery.

The recurrence risk of pulmonary hypoplasia depends on the congenital anomaly underlying the condition. The presence of associated malformations should raise the suspicion of an underlying genetic syndrome, frequently showing an autosomal recessive inheritance pattern (e.g. Bardet-Biedl, Meckel-Gruber, Beemer syndromes). Detailed fetal ultrasound examination, fetal karyotyping, family history and ultrasound examination of the urinary system in parents are all important in the work up (10).

Oligohydramnios

There is some variation in the definition of amniotic fluid (AF) volume estimation. Even obstetric textbooks define adequate AF volume differently and some authors have changed their definitions over time. Although it has long been typically diagnosed by ultrasound examination by a qualitative description (eg, reduced amniotic fluid volume), it is better to perform a quantitative analysis either by measuring the maximum vertical pocket or by including the amniotic fluid index. For instance, some authorities changed their definition from a 1-cm pocket in one plane to a 1-cm pocket in two perpendicular planes, and, finally, to a 2-cm vertical pocket with a 1-cm horizontal measurement (7). The most accepted definition is the ultrasound measurement of a deepest vertical amniotic fluid pocket of less than 2.0 cm. Quantification of the amniotic fluid index requires the ultrasound measurement of the maximum vertical pocket in each of the four equal quadrants of the uterus. The deepest pocket of AF should be measured in each quadrant, making sure that the ultrasound transducer is perpendicular to the floor and that fetal body parts and the umbilical cord do not interfere with such measurement. Thus, the sum of the maximum vertical pocket in each quadrant equals the amniotic fluid index. However, because the AFV depends on the gestational age, oligohydramnios has been defined as an amniotic fluid index below the 5th centile according to the expected for the gestational age (11).

A detailed clinical history guides us to drug-induced oligohydramnios such as indomethacin (12).

Renal Tract Anomalies

In renal dysplasia on prenatal ultrasound, kidneys are usually moderately enlarged (+1-2 SD) with hyperechoic cortex and hypoechoic medulla (persisting corticomedullary differentiation) but other patterns are described, including absent or decreased corticomedullary differentiation or totally normal appearance. The absence of identification of renal arteries originating from the abdominal aorta, unilaterally or bilaterally suggests some degree of renal agenesia (10).

The ultrasound features of fetuses with low urinary tract obstruction (LUTO) are a dilated proximal urethra (keyhole sign), a megabladder with a thick, hyperechogenic bladder wall and severe bilateral hydro-ureteronephrosis or signs of obstructive renal dysplasia (hyperechogenic appearance of the renal parenchyma with cortical cysts) occurring in a male fetus.

Multicystic kidney disease (MCKD) is a developmental disorder of the kidney, in which the normal renal parenchyma is replaced by multiple, non-communicating cysts of varying size. The renal outline is difficult to delineate and can be irregular (10).

Many biometric parameters using two-dimensional ultrasound have been used to assess risk for pulmonary hypoplasia. In the past, several ultrasonographic techniques have been used to predict pulmonary hypoplasia: thoracic circumference (TC) measurements are obtained in a transverse plane at the level of the four-chamber view of the heart, either by delineating the external borders of the fetal thorax or by tracing a circle along the outer edges of the ribs, sternum, and spine. The ratio of TC to abdominal circumference (AC), HC or TC/femur length (FL) is useful in the diagnosis of pulmonary hypoplasia. These ratios are constant, especially the TC/AC ratio which appears to have the least variability and has been shown to be >0.80 in nearly all normal fetuses after midpregnancy. This serial ratio measurement is a reliable predictor of pulmonary hypoplasia (13).

There may be differing performances of various measurements dependent upon the risk factors for pulmonary hypoplasia. In fetuses with mid-trimester PPROM, thoracic length or lung length had >90% sensitivity and correlated well with post-mortem lung weight. Other, less frequently used parameters include thoracic area, thoracic area minus heart area, lung diameter, and lung area/thoracic area (14).

The lung-head ratio (LHR) has been reported to predict pulmonary hypoplasia. Three different methods have been reported for calculating the LHR (tracing, maximum diameters, or anterior-posterior diameters). All of the methods compare relative lung area measured at the level of the four-chamber cardiac view divided by the head circumference. Although the use of the head circumference allows for some correction based on gestational age, the LHR has been found to be most useful in the third trimester, making its predictive value questionable at the time of fetal survey (14). This measurement however, requires training to acquire competence and stringent criteria for image acquisition (15).

In the subset of cases from PROM, the 3 combined clinical parameters (time of onset, duration and degree of oligohydramnios) have a higher PPV to detect lung hypoplasia and accuracy than Doppler velocimetry. In fetuses with severe pulmonary hypoplasia, blood flow impedance in the intrapulmonary vessels increases and even absent or reversed diastolic blood flow can be observed in extremely severe cases (14).

The majority of the Doppler velocity parameters from both proximal and middle arterial pulmonary branches showed even higher PPV to detect lung hypoplasia and overall accuracy than the biometric parameters. Doppler measurements can be difficult to perform, however, due of the lack of amniotic fluid (16).

The lung/body weight ratio (FLB) ratio is considered the simplest and most frequently used parameter for the diagnosis of pulmonary hypoplasia. FLB ratio is calculated as the ratio between the mean fetal lung volume on 3D ultrasound (summing the mean left and the mean right pulmonary volumes) and the mean estimated fetal weight (using Hadlock mathematical equation which includes the measurements of biparietal diameter, head circumference, abdominal circumference and femur length) (13,16). Pulmonary hypoplasia is diagnosed using the same cut-offs that are considered at autopsy, when the FLB ratio was <0.012 at a gestational age of ≥28 weeks, and <0.015 at <28 weeks (17).

Fetal magnetic resonance imaging (MRI) constitutes a new method to investigate lung volumes in vivo during the second and third trimester.

The techniques of MRI volumetry, assessment of signal intensities, and MRI spectroscopy of the fetal lung have been applied clinically to identify abnormal fetal lung growth.

Marked reduction of signal intensities and lung volumes are characteristic findings in fetuses with pulmonary hypoplasia. Both parameters should always be combined to achieve a high sensitivity and specificity in detecting fetuses at risk for respiratory complications at birth (18).

Ultrasound and MRI are the only diagnostic tools by which to non-invasively examine fetal lungs. Because MRI provides not only detailed structural, but also biochemical and functional information, which cannot be obtained by ultrasound, it is definitely a valuable adjunct to the diagnostic repertoire in the assessment of fetal lung development (18).

Oligohydramnios is associated with many conditions/complications of pregnancy, and the differential breaks down into the following categories: maternal, fetal, placental, and idiopathic (19).

Maternal causes: Oligohydramnios has correlations with any medical or obstetric condition leading to uteroplacental insufficiency (8% of all gestations). Possible causes include chronic hypertension, vascular disease, thrombophilia, and preeclampsia. It also correlates with certain drugs (angiotensin-converting enzyme inhibitors, NSAIDs, and cocaine use) and maternal diabetes (19).

Fetal causes: Rupture of membranes is the most common cause. Preterm premature rupture of membranes (PPROM) alone accounts for greater than 37% of oligohydramnios cases diagnosed in the second and third trimesters. Genitourinary tract abnormalities (renal agenesis, obstructive nephropathy) are associated with oligohydramnios and occur at an incidence of 3 to 7 per 1000 live births. Post-term pregnancies, fetal growth restriction (5% of the second trimester and 20.5% of third-trimester diagnoses), chromosomal abnormalities (10% of oligohydramnios cases in the second trimester), and fetal demise are also associated with oligohydramnios (20).

Placental causes: Placental causes of oligohydramnios include abruption (8.6% of all oligohydramnios cases) and twin-twin transfusion syndrome (oligohydramnios-polyhydramnios sequence) (20).

Idiopathic/unexplained: The majority of oligohydramnios cases, 50.7% diagnosed in the third trimester, are of unexplained etiology and, typically, associated with better outcomes (20).

The assessment of amniotic fluid volume plays an important role in the prediction of lung hypoplasia. Ultrasonography is a technique that allows appropriate obstetric management and parental counselling in the presence of lung hypoplasia due to oligohydramnios.

With the introduction of fetal ultrasound in the 1980s, anatomical diseases could be detected even before birth, and this had important implications for the management of urinary tract malformations (UTM). These occur relatively frequently in up to 0.2–1% of newborns (7).

It is realized that the underlying mechanism of oligohydramnios in PROM is different from that in fetal renal malformations (16).

Overall, a finding of persistent oligohydramnios, defined as the largest vertical pocket less than 2 cm more than 7 days, has a sensitivity of 52-100%, specificity of 41-82%, positive predictive value of 22-64%, and a negative predictive value of 89-100% for pulmonary hypoplasia (21).

First-trimester ultrasound is a fundamental element of screening policy. Over the past few decades, technical improvements in ultrasound equipment have ameliorated understanding and visualization of fetal anatomy in the first trimester. Thus, first-trimester ultrasound seems ready to evolve from a simple screening examination to a detailed anatomical examination traditionally performed in the second trimester of pregnancy. Megacystis in the first trimester of pregnancy is usually defined by a bladder size > 7mm between 11 and 13+6 weeks of gestation and can lead to early identification of fetuses at trisk for oligohydramnios and lung hypoplasia (22).

Even when ultrasonography is not necessary to confirm PROM, it may help to determine the position of the fetus, placental location, estimated fetal weight, and presence of any structural anomalies. When ultrasonography is inconclusive or the clinical situation depends on a precise diagnosis (e.g., when contemplating transport to a tertiary care facility), an amnioinfusion may help to determine whether the membranes are ruptured.

Ideally, all fetuses with renal oligohydramnios should be counselled by a pediatric nephrologist who is also able to communicate specific burdens of renal replacement therapy appropriately. In addition, manifestation in first trimester of renal oligohydramnios, proven associated chromosomal abnormalities, and suspicion of congenital anomalies of kidney and urinary tract have also been regarded as indicators of poor outcome (4,7).

Counselling depends primarily on the cause of oligohydramnios and in centers where termination of pregnancy is allowed, legal abortion of severe cases can also be considered.

Prenatal diagnosis of associated genetic disorders by amniocentesis can be difficult in the setting of severe oligohydramnios and other sampling approaches such as cordocentesis must be employed. In cases of LUTO, vesicocentesis from a distended bladder can provide a fetal sample for genetic studies. Chorionic villous sampling is an alternative option even in cases above 15 weeks of gestation (23).

Management mainly depends on the cause of oligohydramnios and the weeks of gestation at the time of appearance.

Several treatments have been suggested to limit the risk of pulmonary hypoplasia. There is considerable debate about specific antenatal urological interventions. In fetuses with oligohydramnios secondary to LUTO, different interventions have been proposed such as vesicoamniotic shunt as well as laser ablation of posterior urethral valves by fetal cystoscopy. In the largest series including 3 countries (France, Brazil and Mexico), fetal cystoscopy demonstrated to be feasible, allowed an accurate diagnosis of the etiology of LUTO, and showed 60% of survival rate with adequate preserved normal renal function in up to 70% of the survivors (24). Hopefully, standardized protocols and, possibly, controlled studies will help to resolve the problems in the near future. 

 1. Wu, C. S., Chen, C. M., & Chou, H. C. (2017). Pulmonary Hypoplasia Induced by Oligohydramnios: Findings from Animal Models and a Population-Based Study. Pediatrics and neonatology, 58(1), 3–7. https://doi.org/10.1016/j.pedneo.2016.04.001

2. Kitterman JA, Chapin CJ, et al. Effects of oligohydramnios on lung growth and maturation in the fetal rat. Am J Physiol Lung Cell Mol Physiol 2002;282:L431e9.

3. Moessinger, A. C., Santiago, A., Paneth, N. S., Rey, H. R., Blanc, W. A., & Jr, J. M. D. (1989). Time-trends in necropsy prevalence and birth prevalence of lung hypoplasia. Paediatric and Perinatal Epidemiology, 3(4), 421–431.

4. Triebwasser JE, Treadwell MC, Prenatal prediction of pulmonary hypoplasia, Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.03.001

5. Laudy JA, Wladimiroff JW. The fetal lung. 2: Pulmonary hypoplasia. Ultrasound Obstet Gynecol. 2000 Oct;16(5):482-94.

6. Winn HN, Chen M, Amon E, Leet TL, Shumway JB, Mostello D. Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes-prognosis and counseling-a critical analysis. Am J Obstet Gynecol. 2000 Jun;182(6):1638-44.

7. Kemper MJ, Mueller-Wiefel DE. Prognosis of antenatally diagnosed oligohydramnios of renal origin. Eur J Pediatr. 2007 May;166(5):393-8.

8. Buttar HS. An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem. 1997 Nov;176(1-2):61-71.

9. Kato K, Okuda M, Ishikawa H, Takahashi T, Hirahara F. Oligohydramnios and pulmonary hypoplasia: a case in which involvement of an angiotensin II receptor antagonist was suspected. J Obstet Gynaecol Res. 2008 Apr;34(2):242-6.

10. Hindryckx A, De Catte L. Prenatal diagnosis of congenital renal and urinary tract malformations. Facts Views Vis Obgyn. 2011;3(3):165-174

11. Krispin E, Berezowsky A, Chen R, Meizner I, Wiznitzer A, Hadar E, Bardin R. Updating the amniotic fluid index nomograms according to perinatal outcome. J Matern Fetal Neonatal Med. 2020;33(1):113-119.

12. Sandruck JC, Grobman WA, Gerber SE. The effect of short-term indomethacin therapy on amniotic fluid volume. Am J Obstet Gynecol 2005 192(5):1443-5.

13. Gerards FA, Twisk JW, Fetter WP, Wijnaendts LC, Van Vugt JM. Two- or three-dimensional ultrasonography to predict pulmonary hypoplasia in pregnancies complicated by preterm premature rupture of the membranes. Prenat Diagn. 2007 Mar;27(3):216-21

14. Cruz-Martinez R, Martínez-Rodríguez M, Nieto-Castro B, Gámez-Varela A, Cruz-Lemini M, et al. Longitudinal changes in lung size and intrapulmonary-artery Doppler during the second half of pregnancy in fetuses with congenital diaphragmatic hernia. Prenat Diagn. 2019 Jan;39(1):45-51.

15. Cruz-Martinez R, Figueras F, Moreno-Alvarez O, Martinez JM, Gomez O, Hernandez-Andrade E, Gratacos E. Learning curve for lung area to head circumference ratio measurement in fetuses with congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. 2010 Jul;36(1):32-6.

16. Laudy JA, Tibboel D, Robben SG, de Krijger RR, de Ridder MA, Wladimiroff JW. Prenatal prediction of pulmonary hypoplasia: clinical, biometric, and Doppler velocity correlates. Pediatrics. 2002;109(2):250-8.

17. Ruano R, Martinovic J, Aubry MC, Dumez Y, Benachi A. Predicting pulmonary hypoplasia using the sonographic fetal lung volume to body weight ratio--how precise and accurate is it? Ultrasound Obstet Gynecol. 2006;28(7):958-62

18. Kasprian G, Balassy C, Brugger PC, Prayer D. MRI of normal and pathological fetal lung development. Eur J Radiol. 2006;57(2):261-70.

19. Peipert JF, Donnenfeld AE. Oligohydramnios: a review. Obstet Gynecol Surv. 1991;46(6):325-39

20. Shipp TD, Bromley B, Pauker S, Frigoletto FD, Benacerraf BR. Outcome of singleton pregnancies with severe oligohydramnios in the second and third trimesters. Ultrasound Obstet Gynecol. 1996;7(2):108-13.

21. Waters TP, Mercer BM. The management of preterm premature rupture of the membranes near the limit of fetal viability. Am J Obstet Gynecol. 2009;201(3):230-40.

22. Lesieur E, Barrois M, Bourdon M, Blanc J, Loeuillet L, Delteil C, et al. (2021) Megacystis in the first trimester of pregnancy: Prognostic factors and perinatal outcomes. PLoS ONE 2021; 16(9): e0255890.

23. Mendez A, Juárez-Martínez I, Rebolledo-Fernández C, Cruz-Lemini M, Cruz-Martinez R. Feasibility of chorionic villus sampling after 15 weeks of pregnancy in cases with severe oligohydramnios. Ultrasound Obstet Gynecol 2015; 46(S1):185-228.

24. Sananes N, Cruz-Martinez R, Favre R, Ordorica-Flores R, Moog R, Zaloszy A, Giron AM, Ruano R. Two-year outcomes after diagnostic and therapeutic fetal cystoscopy for lower urinary tract obstruction. Prenat Diagn. 2016 Apr;36(4):297-303

Please note that the maximum upload size is 5MB, and larger images and video clips can be sent to [email protected].