Pentadbiran pra‐natal progestogen untuk mencegah kelahiran pramatang secara spontan pada wanita dengan banyak kehamilan
Abstract
Background
Multiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe.
Objectives
To assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies.
Selection criteria
We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi‐randomised or cross‐over studies.
Data collection and analysis
Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence.
Main results
We included 17 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4773 women. The risk of bias for the majority of included studies was low, with the exception of four studies that had inadequate blinding, or significant loss to follow‐up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate.
1 IM progesterone versus no treatment or placebo
More women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low‐quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low‐quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow‐up.
There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high‐quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate‐quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate‐quality evidence)). No childhood outcomes were reported in the trials.
2 Vaginal progesterone versus no treatment or placebo by dose
There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.83, 95% CI 0.63 to 1.09; women = 1727; studies = 6; I2 = 46%; low‐quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low‐quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow‐up.
There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate‐quality evidence); preterm birth less than 28 weeks (RR 1.22, 95% CI 0.68 to 2.21; women = 1569; studies = 4; low‐quality evidence); infant birthweight less than 2500 g (RR 0.95, 95% CI 0.88 to 1.03; infants = 3079; studies = 4; I2 = 49%, moderate‐quality evidence)). No childhood outcomes were reported in the trials.
For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (7%) (RR 0.93, 95% CI 0.88 to 0.98; women = 2143; studies = 6; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.61, 95% CI 0.48 to 0.77; infants = 3134; studies = 5).
Authors' conclusions
Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes.
Future research could focus on a comprehensive individual participant data meta‐analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high‐risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).
PICO
Plain language summary
Progestogens pra‐natal untuk mencegah kelahiran pramatang pada wanita dengan banyak kehamilan
Apakah isunya?
Lebih separuh daripada wanita dengan kehamilan kembar melahirkan sebelum minggu ke 37 kehamilan (pramatang), dan wanita menjangka kembar tiga mempunyai kelahiran pramatang yang lebih berkemungkinan. Bayi yang lahir pramatang lebih cenderung untuk mati atau mengalami masalah kesihatan berbanding dengan bayi yang dilahirkan pada masa yang dijangka. Progesteron dihasilkan secara semulajadi di dalam badan dan dianggap membantu mengekalkan kehamilan.
Mengapakah ini penting?
Tidak diketahui sama ada memberi progesteron (melalui suntikan, secara oral atau oleh suppositori faraj atau gel) kepada wanita yang mempunyai banyak kehamilan semasa kehamilan adalah bermanfaat atau berbahaya kepada wanita dan bayinya.
Apakah bukit yang kami perolehi?
Kami mencari bukti pada 1 November 2016 dan mengenal pasti 17 kajian terkawal secara rawak yang melibatkan 4773 wanita untuk dimasukkan dalam ulasan.
Dalam kajian di mana wanita menerima progesteron dengan suntikan ke dalam otot berbanding dengan plasebo, lebih banyak wanita melahirkan sebelum minggu kehamilan ke 34 dalam kumpulan progesteron(kualiti bukti yang rendah). Tiada perbezaan yang jelas antara kuumpulan yang kemungkinan bayi mati sebelum atau tidak lama selepas kelahiran(kualiti bukti yang rendah). No studies reported whether any women died or whether any babies had longer‐term developmental problems or disability. Nampaknya terdapat sedikit atau tiada perbezaan antara wanita yang menerima progesteron atau plasebo untuk hasil penting lain, seperti kelahiran pramatang sebelum 37 minggu (bukti berkualiti tinggi); kelahiran pramatang sebelum 28 minggu (bukti berkualiti sederhana) atau berat lahir bayi kurang daripada 2500 gram (bukti berkualiti sederhana). Tiada hasil pada kanak‐kanak dilaporkan dalam kajian.
Dalam kajian di mana wanita menerima progesteron faraj mungkin terdapat sedikit atau tiada perbezaan antara wanita yang menerima progesteron atau plasebo dalam kelahiran pramatang sebelum 34 minggu (bukti berkualiti rendah); walaupun kelahiran yang lebih sedikit sebelum 34 minggu berlaku dalam kumpulan progesteron, penemuan ini mungkin berlaku secara kebetulan. Jumlah kematian bayi sebelum atau tidak lama selepas kelahiran adalah sama dalam kedua‐dua kumpulan(kualiti bukti yang rendah). Tiada kajian melaporkan kematian ibu atau hasil jangka panjang untuk bayi. Terdapat sedikit atau tiada perbezaan antara kumpulan yang menerima progesteron faraj berbanding plasebo dalam sebarang hasil penting lain (kelahiran pramatang sebelum 37 minggu (bukti berkualiti sederhana); kelahiran pramatang sebelum 28 minggu (bukti berkualiti rendah); atau berat lahir bayi kurang daripada 2500 gram (bukti berkualiti sederhana)). Tiada keputusan pada kanak‐kanak dilaporkan dalam kajian. Bagi hasil lain, penyelidik tidak menemui perbezaan kumpulan yang jelas, kecuali bagi pembedahan caesarean di mana wanita yang menerima progesteron faraj tidak mempunyai banyak pembedahan caesarean seperti yang terdapat dalam kumpulan plasebo (walaupun perbezaan antara kumpulan tidak besar (7%)). Bilangan bayi di mana ibu yang menerima progesteron melalui faraj memerlukan bantuan mekanikal dengan pernafasan adalah kurang.
Kami tidak menemui sebarang kajian yang melihat progesteron diambil melalui mulut.
Apakah maksudnya?
Secara keseluruhannya, bagi wanita yang mempunyai banyak kehamilan, rawatan dengan progesteron (sama ada intramuskular atau melalui faraj) tidak mengurangkan kebarangkalian kelahiran pramatang atau meningkatkan hasil untuk bayi.
Kajian selanjutnya boleh memberi tumpuan terhadap maklumat tentang wanita individu yang mengambil bahagian dalam kajian, supaya data mengenai kedua‐dua rawatan progesteron intramuskular dan melaui faraj dalam wanita dengan banyak kehamilan boleh dipertimbangkan bersama.
