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Editor’s comment: Prof. Yves Ville: To treat or not to treat. The Shakespearean dilemma in fetal medicine.

The possibilities of treating the sick or malformed fetus have developed with the precocity and the increasing relevance of prenatal diagnosis. Although less spectacular, medical treatment of a sick fetus or more often a fetus at risk of developing a serious congenital disease involves the placental transfer of a drug administered to the pregnant woman.

The most emblematic example is that of the antenatal administration of betamethasone to women at risk of preterm delivery between 24 and 34 weeks’. It decreases both the prevalence and the severity of neonatal death, respiratory distress and other respiratory problems, but also those of intraventricular hemorrhage, necrotizing enterocolitis and neonatal infection. This was demonstrated with the highest degree of evidence through meta-analyzes of more several randomized controlled trials (RCT) considering the efficacy of prenatal treatment for deliveries occuring before 34 weeks’, within 7 days and at least 24 hours after the first steroid injection.
However, despite high-evidence evaluation, there are still pending issues. One is that of the benefit of betamethasone administration to singleton pregnancies between 34 0/7 and 36 6/7 weeks of gestation at imminent risk of preterm birth within 7 days. In this issue of the journal Kamath-Rayne et al (1) review the evidence from the Antenatal Late Preterm Steroids Trial, which led the American Congress of Obstetricians and Gynecologists to recommend changing practice. This review of the literature balances the reduction of transient tachypnea of the newborn infant with the risk of potential unanticipated outcomes, such as neonatal hypoglycemia, and unknowns about long-term neurodevelopmental follow up and metabolic risks. Another unanswered question is the extent of the benefits of prenatal steroids demonstrated in singletons to twins. Indeed, data in twin pregnancies are limited because of the insufficient number of women with twins enrolled in randomized controlled trials on antenatal corticosteroids and who delivered within 7 days. Melamed et al conducted a large retrospective cohort study showing that when given in appropriate conditions, prenatal steroids administration in twins is associated with a clinically significant decrease in neonatal mortality, short-term respiratory morbidity, and severe neurological injury that is similar in magnitude to that observed among singletons (2).

Congenital infection with human cytomegalovirus (cCMV) is a major cause of morbidity and mortality. With around 8,000 damaged neonates born each year in the United States the impact of cCMV overcomes that impact of Down syndrome, fetal alcohol syndrome and of spina bifida. Vertical transmission of maternal CMV infection causes symptoms in 10% to 20% of infants ranging from hearing loss to severe brain damage. The administration of hyper-immune immunoglobulin to prevent transmission and its consequences with the waning of maternal primary infection appears ineffective, as was shown by a randomized trial, which, however, might have been underpowered. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Leruez-Ville et al (3) evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although this study is not an RCT, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.

There are few randomized clinical trials (RCT) in fetal medicine and as discussed above, even successsful ones often require further evidence. Severe prematurity and its consequences can be seen as a frequent condition and outcome respectively. However, in rare disease, most trials are interrupted for recruitment failure. Indeed RCT in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. It is therefore important to consider alternatives to randomization, adapted to the low numbers of illnesses with poor prognosis. It could be Phase II trials by sequential evaluation or sufficiently informed observations of records to help assess the phenotypic variation and supported.

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Commentaries by Editor Prof. Jim Thornton