Progestogens, Betamimetics, Calcium Channel Blockers. Oxytocin Receptor Antagonists For Preventing Preterm Labour

Preterm birth occurs in up to 6% to 10% of all births and is the major complication of pregnancy associated with perinatal mortality and morbidity. Previous preterm delivery is a strong predictor for preterm labour, and the earlier the birth, the more likely it is to be repeated at the same gestation. In the acute setting, betamimetics can decrease contraction frequency or delay preterm birth by 24 to 48 hours.

Some studies systematically reviewed the effectiveness of progestogens for prevention of preterm birth among women with prior spontaneous preterm birth, multiple gestations, preterm labor, short cervix, or other indications. These studies searched MEDLINE and EMBASE databases for English language articles published from January 1966 to October 2011. Two reviewers independently extracted data and assigned overall quality ratings based on predetermined criteria. Among women with prior preterm birth and a singleton pregnancy (five randomized controlled trials), progestogen treatment decreased the median risk of preterm birth by 22% and neonatal death by 42%. The evidence suggests progestogen treatment does not prevent prematurity for neonatal death in multiple gestations. Limited evidence suggests progestogen treatment may prevent prematurity in women with preterm labor and short cervix. Across indications, evidence about maternal, fetal, or neonatal health outcomes, other than reducing preterm birth and neonatal mortality, is inconsistent, insufficient, or absent.

Progestogens prevent preterm birth when used in singleton pregnancies for women with a prior preterm birth. In contrast, evidence suggests lack of effectiveness for multiple gestations. Evidence supporting all other uses is insufficient to guide clinical care. Overall, clinicians and patients lack longer-term information to understand whether intervention has the ultimately desired outcome of preventing morbidity and promoting normal childhood development.

Prophylactic oral betamimetics for preventing preterm labour.

Some women who have threatened to give birth prematurely, subsequently settle. They may then take oral tocolytic maintenance therapy to prevent preterm birth and to prolong gestation.

Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis.

Some studies assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with singleton pregnancies at high risk of preterm delivery. These studies searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (October 2007), CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE (January 1966 to December 2006), EMBASE (January 1985 to December 2006), and reference lists.

Randomised controlled trials in singleton pregnancies at high risk of preterm labour comparing prophylactic oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. One trial (64 singleton pregnancies) was included. The trial compared the oral betamimetic agent isoxuprine with placebo. No difference was seen for perinatal mortality rate. There was no evidence of an effect of oral betamimetic agents in reduction of spontaneous onset of preterm labour or preterm birth, less than 37 weeks’ gestation. There was no significant association between the use of oral betamimetics and side effects sufficient to stop therapy. No differences were found for infant outcomes; birthweight less than 2500 grams or neonatal death. This trial had adequate methodological quality; however the sample size was inappropriate to determine any significance in neonatal outcome differences between the treatment groups. There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women at high risk of preterm labour with a singleton pregnancy.

Two review authors independently applied the selection criteria and carried out data extraction and quality assessment of studies. Eleven randomised controlled trials (RCTs) were included. No differences were seen for admission to the neonatal intensive care unit when betamimetics were compared with placebo 0.64 to 2.60; one RCT of terbutaline with 140 women) or with magnesium. The rate of preterm birth (less than 37 weeks) showed no significant difference in four RCTs, two comparing ritodrine with placebo/no treatment and two comparing terbutaline with placebo/no treatment. No differences between betamimetics and placebo, no treatment or other tocolytics were seen for perinatal mortality and morbidity outcomes. Some adverse effects such as tachycardia were more frequent in the betamimetics groups than the groups allocated to placebo, no treatment or another type of tocolytic. Available evidence does not support the use of oral betamimetics for maintenance therapy after threatened preterm labour.

Betamimetics help to delay delivery for women transferred to tertiary care or completed a course ofaCollaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data.

Twelve randomised controlled trials involving 1029 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within seven days of receiving treatment. Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction, the frequency of neonatal respiratory distress syndrome, intraventricular haemorrhage.

When tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to other tocolytic agents compared, mainly betamimetics. Further research should address the effects of different dosage regimens and formulations of calcium channel blockers on maternal and neonatal outcomes.

Oxytocin receptor antagonists

Preterm birth, defined as birth before 37 completed weeks, is the single most important cause of perinatal mortality and morbidity in high-income countries. Oxytocin receptor antagonists have been proposed as effective tocolytic agents for women in preterm labour to postpone the birth, with fewer side-effects than other tocolytic agents.

SOme studies assess the effects on maternal, fetal and neonatal outcomes of tocolysis with oxytocin receptor antagonists for women with preterm labour compared with placebo or no intervention and compared with any other tocolytic agent. These studies searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (September 2004), CENTRAL (The Cochrane Library, Issue 3, 2004), MEDLINE (1965 to June 2004), EMBASE (1988 to June 2004). Randomised trials of oxytocin receptor antagonists for tocolysis in the management of women in labour between 20 and 36 weeks’ gestation.

Six trials (1695 women) were included. Compared with placebo, atosiban did not reduce incidence of preterm birth or improve neonatal outcome. In one trial (583 infants), atosiban was associated with an increase in infant deaths at 12 months of age compared with placebo. However, this trial randomised significantly more women to atosiban before 26 weeks’ gestation. Use of atosiban resulted in lower infant birthweight and more maternal adverse drug reactions. Compared with betamimetics, atosiban increased the numbers of infants born under 1500 gm. Atosiban was associated with fewer maternal drug reactions requiring treatment cessation.

This review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes. The finding of an increase in infant deaths in one placebo controlled trial warrants caution. A recent Cochrane review suggests that calcium channel blockers (mainly nifedipine) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics. However, a randomised comparison of nifedipine with placebo is not available. Further well-designed randomised controlled trials of tocolytic therapy are needed. Such trials should incorporate a placebo arm.

Cyclo-oxygenase (COX) inhibitors

Preterm birth is a major cause of perinatal mortality and morbidity. Cyclo-oxygenase (COX) inhibitors inhibit uterine contractions, are easily administered and have fewer maternal side-effects compared to conventional tocolytics. However, adverse effects have been reported on the fetus and newborn as a result of exposure to COX inhibitors.

King reported studies outcome data from 13 trials with a total of 713 women. The non-selective COX inhibitor, indomethacin was used in 10 trials. When compared with placebo, COX inhibition (indomethacin only) resulted in a reduction in birth before 37 weeks’ gestation (relative risk (RR) 0.21; one trial, 36 women), an increase in gestational age (weighted mean difference (WMD) 3.53 weeks) and birthweight. Compared to any other tocolytic, COX inhibition resulted in a reduction in birth before 37 weeks’ gestation and a reduction in maternal drug reaction requiring cessation of treatment . A comparison of non-selective COX inhibitors versus any COX-2 inhibitor did not demonstrate any differences in maternal or neonatal outcomes. Due to small numbers, all estimates of effect are imprecise and need to be interpreted with caution. Potential adverse effects of COX inhibition on the fetus, newborn or mother could not be adequately assessed due to insufficient data. There is insufficient information on which to base decisions about the role of COX inhibition for women in preterm labour. Further well designed trials are needed.

References:

Likis FE, et al. Progestogens for preterm birth prevention: a systematic review and meta-analysis. Obstet Gynecol. 2012 Oct;120(4):897-907.

Whitworth M, et al. Prophylactic oral betamimetics for preventing preterm labour in singleton pregnancies. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006395.

Anotayanonth S, et al. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004352.

Dodd JM, et al. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003927.

King JF, et al. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2003;(1):CD002255.

Papatsonis D, et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004452

King J, et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD001992

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