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Support for induction at 41 weeks' pregnancy, especially for first-time mothers — meta-analysis

There is growing evidence that pregnant women who go beyond term, especially first time mothers and their infants, will benefit from induction of labour at 41 weeks, instead of expectant management with subsequent induction of labour at 42 weeks if labour will not start spontaneously, found an analysis by Swedish and Dutch researchers.

This is clearer now that researchers from Sweden and the Netherlands have appraised results from three previous investigations. The present study, an individual participant data meta-analysis, is published in the journal PLOS Medicine.

In Sweden and the Netherlands, the risk of a baby dying before, during or shortly after birth ("perinatal death") is generally very low. The same is true of the risk of harm or injury to the baby in conjunction with the birth. However, these risks – of perinatal death and morbidity (ill-health, trauma or other injury) alike – are known to rise somewhat, from a low level, the longer a pregnancy goes on after the 40th week.

The purpose of the meta-analysis was to compare outcomes from induction at 41 and expectant management and if not delivered induction at 42 weeks, by combining individual studies addressing the same question. To date, in some respects, it has been unclear what measures best protect the woman and child.

Three randomized studies of the same question have been published, all since the year 2000: SWEPIS (the SWEdish Post-term Induction Study), covering 2,760 women; a Dutch INDEX study (INDuction or Expectant management) of 1,801 women; and a Turkish study of 600 women.

The Swedish and Dutch studies were able to contribute findings at individual level, and the Turkish study was also included in the aggregate appraisal of perinatal death and the proportion of cesarean deliveries. All the women had reached 41 weeks, were healthy and expecting one baby when they participated in the respective studies.

Of the 4,561 women included in the analysis of individual data, 2,281 were assigned for induction at 41 full week. In this group, 80 percent underwent induction. For the others, the delivery started spontaneously.

In the Expectant Management group of 2,280 women, spontaneous delivery start was awaited until 42 weeks when induction was otherwise planned. This has been the routine management practice at most birth centers in Sweden and the Netherlands in uncomplicated pregnancies. In the Expectant Management group, 30 percent of the women needed to be induced, while for the others labor began spontaneously.

In terms of the combination of perinatal death and severe morbidity, 10 (0.4%) were affected in the group induced at 41 weeks and 23 (1.0%) in the 42 week group. The difference between the groups is statistically significant. These results hold for women who deliver for the first time. For women who already gave birth once the number of perinatal deaths and morbidity was too low to demonstrate any effect.

There was no difference in the women's state of health after birth between the groups. The proportions of cesarean sections and of instrumental births, using a ventouse (suction cup) or forceps, were also comparable.

Mårten Alkmark, a doctoral student in obstetrics and gynaecology at Sahlgrenska Academy, University of Gothenburg, and senior consultant physician at the University Hospital, is one of the two first authors of the study.

"Being able to combine studies at individual level is a good, robust way of investigating questions where what we're studying is very unusual. It means that we've increased the number of women taking part, thereby also boosting the reliability of the results," Alkmark says.

"Our study shows, in agreement with previous research, that the risks of morbidity and perinatal death are lower when induction is carried out at 41 weeks than when it's done at 42 weeks, while it doesn't increase the risks of impaired health in the mothers."

Esteriek de Miranda, assistant professor of Amsterdam UMC of the University of Amsterdam and one of both last authors: "This reduction in risk was only found for women having their first childbirth, not for women who had given birth already one or more times, earlier induction had no benefit for these women and their babies."

Henrik Hagberg, professor of obstetrics and gynecology at Sahlgrenska Academy at the University of Gothenburg and senior consultant physician at the Sahlgrenska University Hospital, is one of the co-authors.

"If these results are extrapolated to Swedish conditions, where roughly 20,000 women a year are still pregnant at 41 weeks, one might prevent at least 100 cases a year of severe illness or death in the babies when they're induced at 41 weeks' gestation. The other side of the coin is that a lot of inductions then have to be done. To save one child from severe illness or death, statistically, 175 women have to undergo induction at 41 weeks," Hagberg says.

Judit Keulen, doctoral student of Amsterdam UMC and University of Amsterdam and one of both first authors:"Choosing for expectant management means an overall 99% chance of a good perinatal outcome for all women, for multiparous women choosing expectant management, the chance of a good outcome is not different than after induction of labour."

Ulla-Britt Wennerholm, senior clinical physician and associate professor of obstetrics and gynecology at Sahlgrenska Academy at the University of Gothenburg, is one of the two senior authors.

"Pregnant women whose pregnancies last 41 weeks should be informed about the advantages and disadvantages of induction, and those who then want to be induced should be offered this option," Wennerholm says.

Study details

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomized trials

Mårten Alkmark, Judit K. J. Keulen, Joep C. Kortekaas, Christina Bergh, Jeroen Van Dillen, Ruben G. Duijnhoven, Henrik Hagberg, Ben Willem Mol, Mattias Molin, Joris A. M. Van Der Post, Sissel Saltvedt, Anna-Karin Wikström, Ulla-Britt Wennerholm, Esteriek De Miranda.

PLOS Medicine, 8 December 2020

Abstract

Background

The risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject.

Methods and findings

We searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available.

From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] −57/10,000 [95% CI −106/10,000 to −8/10,000], I2 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267).

Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD −31/10,000, [95% CI −56/10,000 to −5/10,000], I2 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD −97/10,000 [95% CI −169/10,000 to −26/10,000], I2 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results.

Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD −127/10,000, [95% CI −204/10,000 to −50/10,000], I2 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI −29/10,000 to 84/10,000], I2 55%).

A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited.

Conclusions

In this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks.

 

[link url="http://dx.doi.org/10.1371/journal.pmed.1003436"]Full text in PLOS Medicine (open access)[/link]

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