sildenafil-citrate and Fetal-Death

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. 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.

Topics: Female; Fetal Death; Fetal Growth Retardation; Humans; Infant, Newborn; Nitric Oxide; Nitroglycerin; Placenta; Pregnancy; Premature Birth; Sildenafil Citrate; Tadalafil

This study aimed to investigate the effects of sildenafil citrate on various fetal and physiological parameters, including fetal mortality, number of pups, placental weights and micro-albuminuria in pregnant, L-NAME treated Sprague-Dawley rats.. Twenty-four pregnant female Sprague-Dawley rats were divided into 3 groups (n=8). In the L-NAME treated group (PRE), l-NAME (0.3 g/l, drinking water) was used to induce pre-eclampsia-like symptoms on day 1 of the experiment. The experimental group (SCT) also received L-NAME (0.3 g/l, drinking water) on day 1 of the experiment. However, sildenafil citrate (10 mg/kg, s.c., daily) was administered as the test compound from day 7 until day 19. The experimental control (CON) did not receive either L-NAME or sildenafil citrate. L-NAME administration was discontinued in both the PRE and the SCT groups on day 19 of the experiment and the animals were given access to normal drinking water ad libitum. All the animals were sacrificed on day 20, at which time a laparotomy was performed and the various fetal parameters measured. On day 0 and day 20, blood pressure measurements were recorded non-invasively and protein estimations in 24h urine samples were conducted.. Sildenafil citrate decreased fetal mortality and protein excretion and further demonstrated a trend toward increasing birth and placental weights in pregnant, L-NAME treated, Sprague-Dawley rats. In addition, sildenafil citrate administration ameliorated the amplification of the L-NAME induced hypertension in the SCT group.. We speculate that sildenafil citrate by potentiating the effects of nitric oxide in vivo improves uterine artery blood flow resulting in improved fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats.

Topics: Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Female; Fetal Death; NG-Nitroarginine Methyl Ester; Piperazines; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents