Vaginal progesterone significantly helps to reduce preterm birth risk

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Treatment with vaginal progesterone reduced the risk of preterm birth, neonatal complications and death in pregnant women with twins and who have a short cervix – a risk factor for preterm birth – according to a meta-analysis of individual patient data by researchers at the National Institutes of Health, the Wayne State University School of Medicine, the Detroit Medical Centre, and other institutions in the US and abroad.

Births occurring before the 37th week of pregnancy are considered preterm. Preterm birth increases the risk for infant death and long term disability. Twin pregnancies present a five- to six-time increased risk for preterm birth.

In preparation for birth, the cervix (lower part of the uterus) thins and shortens during pregnancy. In some women, the cervix shortens prematurely, as early as the fourth or fifth month of pregnancy. The natural hormone progesterone (also called the “pregnancy hormone”), inserted in the vagina either as a gel or tablet has been shown to decrease the risk for preterm birth associated with a short cervix in women with a single foetus in previous conducted by NIH and WSU investigators.

“The findings represent persuasive evidence that treatment with vaginal progesterone in women with a short cervix and a twin gestation reduces the frequency of preterm birth, neonatal complications such as respiratory distress syndrome, and importantly, neonatal death,” said the study’s first author, Dr Roberto Romero, chief of the perinatology research branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Romero emphasised that individual patient data meta-analyses represent the “gold standard” in the hierarchy of scientific evidence to answer clinical questions.

“Currently there is no treatment for the prevention of preterm birth in twin gestations,” said Dr Sonia Hassan, a co-author of the study. Hassan is the associate dean for maternal, perinatal and child health at WSU, professor of obstetrics and gynaecology for the School of Medicine, and director of the Centre for Advanced Obstetrical Care and Research for the NIH’s perinatology research branch, hosted at Wayne State University and the Detroit Medical Centre.

The meta-analysis included the results of six studies, encompassing 303 women pregnant with twins, all of whom had a cervical length of 25 mm or less in the mid-trimester. Of these, 159 women received vaginal progesterone and 144 received a placebo or no treatment. Women who received vaginal progesterone were 31% less likely to deliver before 33 weeks of pregnancy (31% for those receiving vaginal progesterone, compared to 43% for those who did not). Vaginal progesterone also reduced the rate of preterm delivery before 32 weeks and 34 weeks. All results were statistically significant.

Infants born to patients who received vaginal progesterone had a 30% reduction in the rate of respiratory distress syndrome, the most common complication of prematurity (from 47% in the placebo/no treatment group, to 33% in the vaginal progesterone group), a 46% reduction in the rate of mechanical ventilation (from 27% in the placebo/no treatment group, to 16% in the vaginal progesterone group), and a 47% reduction in the risk of dying in the neonatal period (from 22% in the placebo/no treatment group, to 11% in the vaginal progesterone group). These results were all statistically significant, as well.

The authors conclude that the results of this individual patient data meta-analysis represents strong evidence that vaginal progesterone in twin gestations with a short cervix reduces preterm birth, neonatal complications and neonatal death. This is the first intervention to successfully reduce both preterm birth and neonatal death.

“One of the most serious complications of multiples in pregnancy is premature birth. In 2014, the Michigan rate of preterm birth due to plurality was over 60%,” said Kara Hamilton-McGraw, maternal child health director for the March of Dimes. “Discovering a successful intervention to address premature birth in multiples could largely impact the rate of babies born too soon and those that, sadly, do not live to see their first birthday.”

Objective: To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester.
Methods: This was an updated systematic review and meta-analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid-trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks’ gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated.
Results: IPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks’ gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51–0.93); moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks’ gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35–0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56–0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34–0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36–0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35–0.80)) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4–5 years of age between the vaginal progesterone and placebo groups.
Conclusion: Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid-trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

R Romero, A Conde-Agudelo, W El-Refaie, L Rode, ML Brizot, E Cetingoz, V Serra, E Da Fonseca, MS Abdelhafez, A Tabor, A Perales, SS Hassan, KH Nicolaides

Waye State University material
Ultrasound in Obstetrics & Gynaecology abstract

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