What is the issue?
In approximately 0.4% of pregnancies, the unborn baby suffers from poor growth because the placenta is unable to provide adequate nutrition. These babies are at high risk of dying in the womb due to the poor supply of nutrition and oxygen. Because of this, doctors often deliver these babies before full term, in order to feed them outside the womb. But such early births mean the babies are premature and of very low birthweight. Because of this, these babies are at risk of severe health problems in the first months of life and in the long term. The aim of this Cochrane Review was to find out if drugs that affect the nitric oxide pathway (e.g. sildenafil, tadalafil, L-arginine, and nitroglycerin) might improve the outcomes for these babies. We only studied babies whose growth restriction was due to problems with the placenta. We collected and analysed all relevant studies to answer this question.
Why is this important?
Currently, there is no known effective treatment that will improve placental function, so early birth is the only option. There has been a lot of interest in drugs that may improve the blood flow from the mother to the placenta. The aim of this treatment is to improve how the placenta works so that the growth of the baby before birth is improved, which would allow doctors to delay birth, ultimately improving the chances of healthy survival.
What evidence did we find?
We searched for published studies on July 16th 2022 and eight studies address our research question. Four different relevant drugs have been investigated (sildenafil, tadalafil, L-arginine, and nitroglycerin). None of the four drugs led to more babies surviving. However, for three out of four treatments (tadalafil, L-arginine and nitroglycerin), the treatment was investigated in only small groups of pregnant women and so it is difficult to draw firm conclusions.
Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women)
Five studies (Canada, Australia and New Zealand, the Netherlands, the UK, and Brazil) involving 516 pregnant women with fetal growth restriction.
Sildenafil compared with placebo or no therapy probably makes no difference to the incidence of all-cause mortality, fetal mortality, and neonatal mortality.
Tadalafil compared with placebo or no therapy (1 study, 87 women)
One study (Japan) involving 87 pregnant women with fetal growth restriction.
Tadalafil probably makes no difference to the incidence of all-cause mortality, fetal mortality, and neonatal mortality.
L-Arginine compared with placebo or no therapy (1 study, 43 women)
One study (France) involving 43 pregnant women with fetal growth restriction. This study did not assess our primary outcomes.
Nitroglycerin compared with placebo or no therapy (1 study, 23 women)
One study (Brazil) involving 43 pregnant women with fetal growth restriction.
The effect on the primary outcomes is not estimable since no fetal or neonatal mortality occurred in the women participating in both intervention groups.
Sildenafil citrate compared with nitroglycerin (1 study, 23 women)
One study (Brazil) involving 23 pregnant women with fetal growth restriction.
The effect on the primary outcomes is not estimable since no fetal or neonatal mortality occurred in the women participating in both intervention groups.
What does this mean?
For drugs that have been investigated, sildenafil probably does not increase the chances of short-term (healthy) survival of babies suffering from growth restriction during pregnancy. For tadalafil, L-arginine, and nitroglycerin there are insufficient data to be able to form a judgement. For sildenafil we are moderately certain that this is the case, but for the other treatments more studies are needed to provide enough information to answer this question. Also, none of the studies reported on the long-term effects of these drugs, which is really important information to know.
Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin.
For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.
Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation.
The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR.
We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies.
We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review.
We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis.
We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin.
The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported.
Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women)
Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate.
Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect.
Tadalafil compared with placebo or no therapy (1 study, 87 women)
One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low.
Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women).
L-Arginine compared with placebo or no therapy (1 study, 43 women)
One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes.
Nitroglycerin compared to placebo or no therapy (1 studies, 23 women)
One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups.
Sildenafil citrate compared to nitroglycerin (1 study, 23 women)
One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low.
The effect on the primary outcomes is not estimable due to no events in women participating in both groups.