Effects and side effects of maternal administration of indomethacin for fetal tricuspid valve dysplasia

Abstract

We report on the course of two fetuses with tricuspid valve dysplasia (TVD) who were treated with indomethacin. Case 1 presented at 24 weeks' gestation with severe tricuspid regurgitation (TR), retrograde flow in the arterial duct, no antegrade flow across the pulmonary valve and free pulmonary regurgitation (PR). There was cardiomegaly and fetal hydrops with ascites, skin edema and pleural effusion. The Simpson–Andrews–Sharland (SAS) prenatal severity score for TVD was 7, which predicted fetal demise. The SAS score ranges from 0 to 10, with no predicted survivors scoring ≥ 51. Case 2 presented at 16 weeks' gestation with moderate TR, antegrade flow across the pulmonary valve, progressing to functional pulmonary atresia by 21 weeks' gestation, and a SAS score of 4. At 33 + 5 weeks, there was evidence of further progression with increasing cardiomegaly (cardiothoracic ratio (CTR): 0.80), severe TR and PR and a SAS score of 8. Estimated fetal weight (EFW) dropped from 17th to 3rd centile, umbilical artery (UA) pulsatility index was > 95th centile and amniotic fluid index (AFI) was normal (8.9 cm). Maternal indomethacin (100 mg three times a day (TDS)) was commenced in both cases (Figure 1), leading to constriction/closure of the arterial duct, reduction in PR and antegrade flow across the pulmonary valve. In Case 1, by 26 weeks' gestation, fetal hydrops had completely resolved, indomethacin was replaced by ibuprofen (200 mg TDS) due to a more favorable side-effect profile. However, the arterial duct reopened and indomethacin was reintroduced. Following this, the arterial duct constricted, but oligohydramnios developed (AFI: 4.4 cm). At 30 weeks' gestation, there was faltering growth, EFW of 1.2 kg and anhydramnios. Indomethacin was stopped and the AFI normalized (17.1 cm), but cardiomegaly persisted with severe TR. Intrauterine death occurred at 31 + 6 weeks' gestation. In Case 2, following commencement of indomethacin, CTR reduced to 0.65 but oligohydramnios worsened (AFI: 4.2 cm). Indomethacin was stopped and AFI normalized. Indomethacin was restarted at a lower dose (50 mg TDS), but despite failure to constrict the arterial duct, oligohydramnios recurred (AFI: 1.5 cm) and therapy was ceased. The baby was delivered at 36 weeks' gestation due to absent end-diastolic UA flow, weighing 1.4 kg, and was stable without intervention at 1 year of age. Prenatally detected cases of TVD are often those at the most severe end of the spectrum, presenting with cardiomegaly secondary to severe TR1. Cardiomegaly leads to compression of the developing lung tissue, pulmonary hypoplasia and increased risk of postnatal demise. The fetal environment is disadvantageous for the fetus with TVD as the right ventricle (RV) faces systemic pressures and high pulmonary vascular resistance, worsening TR and subsequent right atrial dilatation, which in itself will exacerbate TR. Severe TR causes reduced antegrade flow across the pulmonary valve and reversal of flow in the arterial duct. This ‘steal’ from the systemic arterial circulation inhibits antegrade pulmonary blood flow and causes PR, which results in further volume loading of the RV. Furthermore, RV dilatation has an adverse effect on left ventricular geometry and function, causing additional fetal hemodynamic compromise2, explaining the high perinatal mortality of 45–71%3. Whilst there have been apparently favorable reports of indomethacin for a circular shunt in TVD2, 4, this treatment led to anhydramnios/oligohydramnios in both our cases. This may be due to pre-existing renal hypoperfusion secondary to poor ventricular-ventricular interaction and ductal steal. Furthermore, through its action on prostaglandins, indomethacin can lead to renal vasoconstriction and may cause oligohydramnios5. The potential benefits of ductal constriction for circular shunts need to be balanced against the risk of renal perfusion, necessitating close cardiac and fetal medicine supervision for affected fetuses. A prospective trial is needed to evaluate the risk-benefit ratio of this new treatment for fetal TVD. We acknowledge the contribution of Dr Wayne Tworetzky from the Children's Hospital in Boston, USA, whose group published the rationale for indomethacin therapy in this group of fetuses. Dr Tworetzky advised on the indomethacin and ibuprofen treatment used in the first case. Data available on request due to privacy/ethical restrictions