MD Julie Blanc
email: julie.blanc@ap-hm.fr

Noémie Rességuier

Anderson Loundou

Laurent Boyer

Pascal Auquier

Barthélémy Tosello

Claude D'ercole

Claude D'ercole

Severe maternal morbidity in preterm cesarean delivery: a systematic review and metaanalysis

Objective: More than half of extremely preterm infants are delivered by cesarean section. Few data are available about severe maternal morbidity (SMM) of these extremely preterm cesarean. The objective was to determine whether gestational age under 26 weeks of gestation (weeks) was associated with an increased risk of SMM compared with gestational age between 26 and 34 weeks in women having a cesarean delivery.

Material and methods:

We searched MEDLINE, ISI Web of Science, the Cochrane Database, PROSPERO, and ClinicalTrials.gov on January 31, 2020. The search strategy clustered terms describing SMM and preterm cesarean delivery. No restrictions on language, publication status, and study design were applied. Abstracts were included if there was sufficient information to assess study quality. The authors of all identified studies were contacted to request for aggregated data. Relative risks (RR) were calculated using the inverse variance method. The primary outcome was SMM as defined in each study. We analyzed data on preterm cesarean deliveries between 22 and 34 weeks. The protocol was registered in PROSPERO (registration: CRD42019128644).

Results: Six studies involving 45,572 women (3,440 delivering < 26 weeks; 42,132 delivering between 26 and 34 weeks) were included. SMM occurred in 607 women (17.6%) < 26 weeks and 4,483 women (10.6%) between 26 and 34 weeks. Gestational age < 26 weeks was associated with an increased risk of SMM (RR, 1.65; 95% CI [Confidence Interval], 1.52-1.78; I 2 = 40%). Gestational age < 26 weeks remained associated with SMM in the subgroup

analyses depending on the type of the study (prospective or retrospective), country of the study (European or non-European), and high quality of the study. A sensitivity analysis showed that gestational age < 25 weeks was also associated with SMM in preterm cesarean delivery (RR, 1.66; 95% CI, 1.50-1.83; I 2 = 3%).

Conclusions: Gestational age < 26 weeks was associated with an increased risk of SMM in women having a preterm cesarean delivery. Obstetricians and neonatologists should be aware of the increased risk of SMM in cesarean.

Keywords: severe maternal morbidity, prematurity, extremely preterm birth, cesarean delivery The protocol was registered in PROSPERO (registration: CRD42019128644).

Main Text 1. Introduction

The survival of very preterm infants born between 22 and 28 weeks of gestation (weeks) has increased worldwide in recent decades. [START_REF] Stoll | Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network[END_REF][START_REF] Costeloe | Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies)[END_REF] Among these infants, more than half are delivered by cesarean section. [START_REF] Stoll | Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network[END_REF][START_REF] Costeloe | Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies)[END_REF][START_REF] Ancel | Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study[END_REF][START_REF] Express Group | One-year survival of extremely preterm infants after active perinatal care in Sweden[END_REF] Periviable birth has been defined as delivery occurring between 20 0/7 weeks to 25 6/7 weeks. [START_REF] Raju | Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists[END_REF] A wide variation in practices regarding the active treatment has been reported and related to the between-hospital differences in survival and survival without impairment in these extreme gestational ages. [START_REF] Rysavy | Between-hospital variation in treatment and outcomes in extremely preterm infants[END_REF] Cesarean delivery in case of fetal indications is one of such practices. Heterogeneous care practices could be related to the paucity of data on severe maternal morbidity (SMM) in periviable cesarean delivery, to poor neonatal survival and survival without impairment, and maybe to the preference of mothers and clinicians more considering the newborn in these clinical situations. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF][START_REF] Hesselman | Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section[END_REF][START_REF] Bertholdt | Intraoperative adverse events associated with extremely preterm cesarean deliveries[END_REF][START_REF] Rossi | Maternal Complications Associated With Periviable Birth[END_REF] The definition of SMM is not standardized in the literature and often referred to blood transfusion and/or hysterectomy in relation to severe postpartum hemorrhage, ICU admission, death, or unexpected procedures. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF][START_REF] Rossi | Maternal Complications Associated With Periviable Birth[END_REF][START_REF] Kawakita | Maternal outcomes associated with early preterm cesarean delivery[END_REF][START_REF] Blanc | Association between gestational age and severe maternal morbidity and mortality of preterm cesarean delivery: a population-based cohort study[END_REF] Some studies included infection criteria, any injury of adjacent organs, postnatal hypertensive complications, and/or thromboembolism events. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Hesselman | Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section[END_REF][START_REF] Kawakita | Maternal outcomes associated with early preterm cesarean delivery[END_REF] The reported rate of SMM of preterm cesarean delivery were between 8 and 15%. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Blanc | Association between gestational age and severe maternal morbidity and mortality of preterm cesarean delivery: a population-based cohort study[END_REF] A recent analysis of World Health Organization surveys found that compared with vaginal delivery, cesarean delivery is associated with an increased risk of maternal intensive care unit (ICU) admission and maternal near miss in women with preterm singletons, without a significant difference in Apgar score < 7 at 5 minutes and neonatal death. [START_REF] Thanh | Mode of delivery and pregnancy outcomes in preterm birth: a secondary analysis of the WHO Global and Multi-country Surveys[END_REF] Operative complications of periviable cesarean deliveries have been reported and related to the use of an often-needed vertical incision in the upper uterine segment and fetal delivery difficulties. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Bethune | The relationship between gestational age and the incidence of classical caesarean section[END_REF][START_REF] Baeza | Obstetrical prognosis of patients after a previous caesarean section performed before 32 weeks of amenorrhea[END_REF] We therefore hypothesize an increased risk of SMM in women having a cesarean delivery before 26 weeks compared with women having a cesarean delivery between 26 and 34 weeks. We recently reported that mothers undergoing a cesarean delivery before 26 weeks experienced a more than twofold increase in the risk of SMM compared with those undergoing a cesarean delivery between 26 and 34 weeks. [START_REF] Blanc | Association between gestational age and severe maternal morbidity and mortality of preterm cesarean delivery: a population-based cohort study[END_REF] We believe that other studies could help us obtain more evidence. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF][START_REF] Hesselman | Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section[END_REF][START_REF] Bertholdt | Intraoperative adverse events associated with extremely preterm cesarean deliveries[END_REF][START_REF] Rossi | Maternal Complications Associated With Periviable Birth[END_REF] Furthermore, collecting more information about SMM in cesarean delivery at periviable ages is important for the shared decision-making process with parents facing the maternal and neonatal risks of extremely preterm birth.

The objective of this meta-analysis was to determine whether gestational age under 26 weeks was associated with an increased risk of SMM compared with a gestational age between 26 and 34 weeks in women having a cesarean delivery.

Material and methods

Data sources

This systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [START_REF] Moher | Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement[END_REF] The electronic databases MEDLINE, ISI Web of Science, the Cochrane Database, PROSPERO, and ClinicalTrials.gov were searched from the inception of each database until January 31, 2020. The following keywords were used: "Severe Maternal morbidity", "Maternal morbidity", "maternal mortality", "extremely preterm", "periviable", "cesarean delivery", "cesarean", or "cesarean section". The bibliographies of articles were checked.

Eligibility criteria and main outcome measures

Two investigators (JB and CDE) independently selected the articles and the purpose was to reproduce one individual's results.

No restrictions on language, publication status, and study design were applied. Abstracts were included if there was sufficient information to assess study quality.

Studies that explored SMM in preterm cesarean delivery were eligible for inclusion. The exclusion criteria were studies dealing with neonatal outcomes only or long-term maternal morbidity only.

The primary outcome of this analysis was data on SMM (intraoperative adverse events and maternal short-term complications) as defined in each study and evaluated between 22 and 34 weeks.

Data collection and statistical analysis

All variables of interest concerning the studies and publications were independently extracted by two study authors (JB and NR) using a standardized form. The extracted data were authors, year of publication, sample size, type of study, period of inclusion, and country of the study.

The authors of all identified studies were contacted to request for data. We asked the authors for aggregated data, such as the numbers of women having preterm cesarean delivery and presenting SMM as well as the total numbers of women having preterm cesarean delivery per week of gestational age. These aggregated data were entered in the database by JB and the accuracy of the database was validated by NR. There was no patient involvement.

Two authors (JB and BT) assessed the risk of bias in each study. Study quality and risk of bias were evaluated for each study using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), [START_REF] Adams | Use of the STROBE Checklist to Evaluate the Reporting Quality of Observational Research in Obstetrics[END_REF] and verified with the Tool to assess Risk of Bias in Cohort Study (Cochrane Database). In case of discrepancy, consensus was reached through a third investigator (NR). Identifying the risk of bias allows assessing the quality of a study based on the median, which is either high quality over the median (i.e., a low risk of bias, ≥ 19) or low quality under the median (i.e., a high risk of bias, < 19).

Relative risks (RRs) with the fixed-effect model were calculated using the inverse variance method to evaluate the association of gestational age under 26 weeks and an increased risk of SMM.

Data analysis was performed using R (version 3.6.0) with meta package.

Heterogeneity between studies was quantified with the I-square statistic (I 2 ), in which an I 2 value lower than 0.50 was considered as a low risk of heterogeneity. [START_REF] Higgins | Measuring inconsistency in meta-analyses[END_REF] Publication bias was assessed by visual inspection of the funnel plot and use of the Egger test. [START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF][START_REF] Guyatt | GRADE: an emerging consensus on rating quality of evidence and strength of recommendations[END_REF] A first sensitivity analysis was conducted using the leave-one-out method.

A second sensitivity analysis was performed to calculate the RRs and explore the association of gestational age under 25 weeks and SMM. This threshold of 25 weeks may be related to the evolution of clinical care, with active antenatal care practices increasing in recent years at earlier gestational ages.

Subgroup analyses were used to evaluate the following factors that moderated the association between gestational age and SMM: (1) type of cohort (retrospective or prospective), (2) country of the study (European or non-European), and (3) quality of the study (high vs. low quality according to the STROBE and Tool to assess Risk of Bias in Cohort Study).

The protocol was registered at PROSPERO registry (CRD42019128644) and can be accessed at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128644. As a meta-analysis of existing data, our review was exempt from institutional review and there was no direct patient or public involvement.

Results

General characteristics of the studies

The electronic searches identified 369 articles, of which 277 were removed because they were duplicates and 80 were excluded after the abstract review. Twelve full texts were assessed for eligibility, of which nine were included after the agreement of the two independent investigators (Figure 1).

Because of the limited number of articles included, no article was excluded based on poor quality. After contacting the authors to request for data, we excluded three articles from the meta-analysis, as either the needed level of detail was not available in their datasets, or the authors no longer had access to their database. Six articles were finally eligible for the quantitative analysis (meta-analysis).

Synthesis of the results

The six included articles contained a broad variety of studied groups and evaluated outcomes described in Table 1. Four were retrospective cohort studies and two were prospective cohort studies involving a total of 45,572 women (3,440 delivering < 26 weeks; 42,132 delivering between 26 and 34 weeks). SMM occurred in 607 women (17.6%) < 26 weeks and 4,483 women (10.6%) between 26 and 34 weeks.

The details of the evaluation using the STROBE checklist and Tool to assess Risk of Bias in Cohort Study are presented in Table 1 and Figure 2.

No study addressed sample size calculation, and only two studies clearly addressed the potential source of bias and missing data.

Gestational age < 26 weeks was significantly associated with an increased risk of SMM (RR, 1.65; 95% CI, 1.52-1.78; I 2 = 40%) (Figure 3).

The funnel plot is reported in Figure 4, suggesting evidence of small-study effects, but this was not supported by the Egger's test (p = 0.46).

The first sensitivity analysis conducted using the leave-one-out method confirmed the association between gestational age < 26 weeks and SMM by omitting each study one by one, and particularly by omitting the study with the biggest weight (Table 2). This finding on gestational age < 26 weeks was confirmed with the analysis of gestational age < 25 weeks (RR, 1.66; 95% CI, 1.50-1.83; I 2 = 3%) (Figure 5).

Gestational age < 26 weeks remained associated with SMM in the subgroup analyses depending on the type of the study (prospective or retrospective), country of the study (European or non-European), and high quality of the study. The tests for heterogeneity between the two groups in terms of the type and country of the study were not significant. By contrast, the test for heterogeneity between the two groups in terms of quality of the study was significant, with high-quality articles presenting higher RR compared with the lowquality articles (Table 3).

Discussion

Main Findings

In this meta-analysis, we demonstrated that gestational age < 26 weeks was associated with an increased risk of SMM compared with a gestational age between 26 and 34 weeks.

Furthermore, gestational age < 25 weeks was associated with SMM in preterm cesarean delivery. We showed that the association between gestational age < 26 weeks and SMM remained stable in the subgroup analyses.

Strengths and Limitations

To our knowledge, this is the first systematic review and meta-analysis of SMM in preterm cesarean delivery. We performed this study using a structured search strategy and predefined eligibility criteria. We followed PRISMA guidelines and included trials without restrictions on publication date or language. To confirm our hypothesis, we used sensitivity and subgroup analyses.

The limitations of this study are inherent in meta-analyses and the included studies. Three studies were evaluated to be of low quality based on the STROBE checklist and Tool to assess Risk of Bias in Cohort Study. The test for heterogeneity between the two groups of studies in terms of quality was significant, but we can presume that the pooled RR is reliable because the RR is very close to that of the group of high-quality studies. One study represented a weight of 77.8% but the first sensitivity analysis using the leave-one-out method allowed us to verify the strength of our main analysis.

One limitation is the variable definition of SMM in each study. The definition of SMM is not standardized in the literature, and we chose to respect the definitions used in each article but there are common criteria between articles as shown in Table S1. SMM often referred to blood transfusion and/or hysterectomy in relation to severe postpartum hemorrhage, ICU admission, death, or unexpected procedures. Some studies included infection criteria, any injury of adjacent organs, postnatal hypertensive complications, and/or thromboembolism events. The study by Hesselman et al. used sepsis as inclusion criteria for SMM. [START_REF] Hesselman | Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section[END_REF] However, 3 of the 6 included studies included chorioamnionitis and/or endometritis as criteria for SMM. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF][START_REF] Rossi | Maternal Complications Associated With Periviable Birth[END_REF] Including infections as SMM is questionable since chorioamnionitis and endometritis are common complications of cesarean delivery and early preterm delivery may be necessitated by chorioamnionitis or may be the cause of preterm labor. Another limitation is that we could not use the recency of the inclusion period as a factor for the subgroup analysis; a relevant threshold could not be identified because of the large and old inclusion period of some studies, which was from 1998 for the oldest to 2015 for the most recent. Last, as pointed by Evans et al, the increased risk of maternal morbidity of extreme preterm cesarean could be attributable to pre-existing risk factors and some may be related with differences in operative details. [START_REF] Evans | Increased maternal morbidity after cesarean delivery before 28 weeks of gestation[END_REF] One limitation of the present study is so that it was not possible to adjust or control for comorbidities and confounding using aggregated data.

Interpretation

The threshold of 26 weeks could be relevant for old and large included cohorts in Australia, France, Sweden, and the US between 1998 and 2015 but is probably not relevant nowadays.

The management of preterm infants has greatly improved over the past years, with more and more active management being provided for infants born at extreme gestational ages and with improved neonatal survival without severe impairment before 26 weeks. [START_REF] Stoll | Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network[END_REF][START_REF] Costeloe | Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies)[END_REF][START_REF] Express Group | One-year survival of extremely preterm infants after active perinatal care in Sweden[END_REF][START_REF] Ancel | 2 Writing Group. EPIPAGE 2: a preterm birth cohort in France in 2011[END_REF][START_REF] Perlbarg | Delivery room management of extremely preterm infants: the EPIPAGE-2 study[END_REF] However, we demonstrated that gestational age under 25 weeks was associated with SMM in preterm cesarean delivery.

In some study, the authors excluded cesarean delivery due to maternal causes. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF] In other study, very few cesarean deliveries were performed in pregnancy with a periviable fetus. [START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF] So, the results of SMM may be conditioned by the cause of the cesarean. The design of this metaanalysis did not allow us to evaluate the effect of indication biases, but some included studies in this meta-analysis argued that SMM could be related to the surgical act of cesarean itself. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Thomas | The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study[END_REF][START_REF] Bertholdt | Intraoperative adverse events associated with extremely preterm cesarean deliveries[END_REF][START_REF] Rossi | Maternal Complications Associated With Periviable Birth[END_REF][START_REF] Blanc | Association between gestational age and severe maternal morbidity and mortality of preterm cesarean delivery: a population-based cohort study[END_REF] Preterm cesarean often includes a classical incision, which is-compared with a low transverse incision-known to be associated with an increased risk of SMM because of infection, postpartum hemorrhage, and ICU admission. [START_REF] Reddy | Serious maternal complications after early preterm delivery (24-33 weeks' gestation)[END_REF][START_REF] Luthra | Uterine incision-to-delivery interval and perinatal outcomes in transverse versus vertical incisions in preterm cesarean deliveries[END_REF] Furthermore, regardless of type, a deep myometrial incision is related to higher SMM. [START_REF] Sirgant | Lower gestational age is associated with severe maternal morbidity of preterm cesarean delivery[END_REF] The morphological changes in extracellular matrix materials in the uterine myometrium during pregnancy could also explain the morbidity of the surgical act of preterm cesarean, in which there is a high rate of collagen fibrils compared with elastic fibers. [START_REF] Nishinaka | Changes in extracellular matrix materials in the uterine myometrium of rats during pregnancy and postparturition[END_REF] The subgroup analyses showed that the association between gestational age under 26 weeks and SMM remained significant depending on the country of the study (European or non-European), whereas a wide variation in practices regarding the active antenatal care, including cesarean delivery, has been reported at periviable ages. [START_REF] Rysavy | Between-hospital variation in treatment and outcomes in extremely preterm infants[END_REF] In 2007, the WHO has indicated that there is insufficient evidence to inform which mode of delivery is optimal for preterm infants. [START_REF] Villar | Maternal and neonatal individual risks and benefits associated with caesarean delivery: multicentre prospective study[END_REF] Since then, the available data do not provide specific recommendations on the choice of delivery regardless of fetal presentation in case of spontaneous prematurity, which corresponds to 75% of preterm deliveries at periviable ages. [START_REF] Ancel | Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study[END_REF][START_REF] Mottet | Mode of delivery in spontaneous preterm birth[END_REF] However, the literature allows using data for shared decision-making process with parents about survival rates at periviable ages. [START_REF] Younge | Survival and Neurodevelopmental Outcomes among Periviable Infants[END_REF] This meta-analysis contributes to the body of knowledge on SMM in cesarean delivery. As stated by the Obstetric Care Consensus with regard to periviable birth, the "risks to a pregnant woman's short-term and long-term health need to be evaluated in the context of a newborn's predicted outcome and the degree to which the intervention in question is predicted to improve this outcome". [START_REF]Obstetric Care consensus No. 6: Periviable Birth[END_REF] In extremely preterm birth, women and couples need to face a dual burden according to Lyndon et al., which refers to neonatal morbidity in preterm birth in addition to SMM. [START_REF] Lyndon | A population-based study to identify the prevalence and correlates of the dual burden of severe maternal morbidity and preterm birth in California[END_REF] This dual burden occurs more often in cases of spontaneous preterm labor than in induced prematurity. Perinatal care should be coordinated with infant and maternal health care teams.

Professionals should be aware of the maternal perceptions of the quality of health care in case of SMM and should find preventive measures for women, parents, and children facing extreme prematurity. [START_REF] Norhayati | Experiences of Women with Severe Maternal Morbidity and Their Perception of the Quality of Health Care[END_REF]

Conclusions

This meta-analysis confirmed the association between gestational age < 26 weeks and SMM.

The results should encourage reflection, research, and teamwork between neonatologists and obstetricians to improve the agreement between clinicians and the shared decision-making process with parents.

Legends of Tables/Figures

Figure 1 :Figure 2 .Figure 3 .

 123 Figure 1: Flow diagram of studies through review process

Figure 4 .Figure 5 .

 45 Figure 4. The funnel plot of meta-analysis comparing the risk of severe maternal morbidity of

Table 1 :

 1 Characteristics of studies included in quantitative analysis

Table 2 .

 2 Sensitivity analysis using the leave-one-out method.

Table 3 .

 3 Subgroup analyses of Risk of severe maternal morbidity of cesarean < 26 weeks vs ≥

	26 weeks

Table 1 :

 1 Characteristics of studies included in quantitative analysis SMM Severe Maternal Morbidity; STROBE Strengthening the Reporting of Observational Studies in Epidemiology 414

	413
	Article	Sample	Sample	Type of study,	Country	Characteristics of	Gestational	Evaluated outcome	Quality
		size of	size	number of	of the	enrolled women	ages		category
		the	considered	centers, and	study				(STROBE
		study	for meta-	period of					check list
			analysis	inclusion					and Tool to
									assess Risk
									of bias in
									cohort
									study)
	Reddy et	1205	1198	Secondary	United	Women who had a	23 to 33	Serious maternal	Low
	al, 7 2015			analysis of	States	live fetus on	weeks	complications:
				observational		admission and		hemorrhage (blood loss
				prospective		delivered during the		≥1500 mL, blood
				cohort, 25		24-hour period		transfusion or
				medical				hysterectomy for
				centers, 2008				hemorrhage), infection
				to 2011				(endometritis, wound
								dehiscence or wound
								infection requiring
								antibiotics, repening or
								unexpected procedure),
								ICU admission or death
	Thomas et	265	265	Retrospective	Australia Mothers of all	23 to 26	Composite maternal	Low
	al, 8 2016			cohort study in		liveborn neonates	weeks	adverse outcome: death,
				a single center,		with a prenatally		adult ICU admission,
				from January		determined plan for		sepsis, hysterectomy,
				1998 to		active resuscitation		transfusion, postpartum
				December				hemorrhage >1000mL,
				2009				surgical injury,
								unplanned
								procedures/return to

Table 2 .

 2 Sensitivity analysis using the leave-one-out method. 415

	Studies	RR	95%-CI	p-value Tau 2	I 2	Weight
	Omitting Reddy 2015	1.65	[1.53-1.79]	<0.0001 0.0196	49.3%	4.3%
	Omitting Thomas 2016	1.66	[1.54-1.80]	<0.0001 0.0074	29.0%	2.2%
	Omitting Hesselman 2017 1.66	[1.53-1.79]	<0.0001 0.0079	31.5%	1.1%
	Omitting Bertholdt 2018	1.61	[1.49-1.75]	<0.0001 0.0084	24.7%	8.6%
	Omitting Rossi 2019	1.65	[1.40-1.94]	<0.0001 0.0421	52.0%	77.8%
	Omitting Blanc 2019	1.64	[1.52-1.78]	<0.0001 0.0235	51.6%	6.1%
	Pooled estimate	1.65	[1.52-1.78]	<0.0001 0.0137	40.0%	100%

Acknowledgements: The authors acknowledge the authors of each study included in metaanalysis who accepted to provide data: Uma Reddy, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network, United States of America; Penelope Thomas and Scott Petersen, Mater Mother's Hospital, Raymond Terrace, South Brisbane, Queensland, Australia; Susanne Hesselman, Department of Women's and Children's Health, Uppsala University, SE-751 85 Uppsala, Sweden; Charline Bertholdt and Camille Le Ray, Obstetric and Gynecology Unit, Regional university Hospital Center of Nancy, Nancy, France and Port Royal Maternity Unit, Cochin Hospital, Paris-Descartes University, APHP, Paris, France; Robert Rossi, Center for Prevention of Preterm birth, perinatal institute, Cincinnati Children's Hospital Medical Center, and the Division of Maternal-Fetal Medecine, Department of Obstetrics and Gynecology, University of Cincinnati College of Medecine, Cincinnati, Ohio, United States of America. The authors acknowledge Scribendi to help editing English.

Availability of Data and Materials: Individual participant data will not be available because aggregated data were used in this meta-analysis Funding information: None

Conflict of Interests statement: the authors did not report any potential conflict of interest.

Author Contributions: J.B., N.R., L.B., P.A., C.D.E. were responsible for the conception and design of this study. J.B., N.R., B.T. and C.D.E. were responsible for the data collection and data management. J.B., N.R., A.L. were responsible for conducting the analyses. All authors were involved in the interpretation of the data. J.B. drafted the initial manuscript, which was reviewed and critically revised by all authors. All authors approved the final manuscript as submitted. All authors gave agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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