Synopsis

Study question

Antepartum severe maternal morbidity (SMM), that is before labour, presents specific challenges in its need to optimise the risk-benefit balance for mother and child, but its specific features remain inadequately explored. We explored risk factors of antepartum SMM and described adverse delivery and neonatal outcomes associated with antepartum SMM.

What's already known

Often explored without distinction by the timing of the morbid event, previous studies of SMM are mostly confined to risk assessments in the postpartum period.

What this study adds

This study highlights antepartum SMM risk factors and the magnitude of its associated adverse maternal and neonatal outcomes.

1 BACKGROUND

Severe maternal morbidity (SMM), defined as a potentially life-threatening complication occurring during pregnancy or just afterwards, is a major indicator of maternal health. Data about the incidence of SMM are increasingly available: it ranges from 0.5 to 1.5% of deliveries in the most recent population-based studies.1-4 SMM is generally explored globally, without consideration of the timing of the morbid event relative to the delivery. But as the most frequent cause of SMM is postpartum haemorrhage (at least half of all SMM events),5, 6 results from studies exploring SMM mostly reflect postpartum SMM and postpartum haemorrhage. Indeed, the main risk factors for SMM are related to an increased risk of bleeding, such as caesarean delivery, abnormal placenta implantation or multiple pregnancy and may not be associated with SMM unrelated to postpartum haemorrhage.7, 8 On the contrary, some individual characteristics are also reported as risk factors for SMM overall, such as maternal age, ethnicity, obesity and parity, that could also be associated with SMM unrelated to haemorrhage, but these associations remain poorly explored.8, 9 The study of antepartum SMM—before labour—remains inadequate, as information about the timing of the morbid event is rarely available. It may, however, have specific characteristics, with a different profile of causes, risk factors and adverse consequences. Additionally, its management presents a unique challenge, in its need to optimise the risk-benefit balance for both mother and the child.10 Better knowledge of antepartum SMM might help to anticipate the occurrence of this complex situation and prevent its adverse outcomes.

EPIMOMS is a French population-based study specifically designed to explore SMM.11 Its prospective inclusion of women with SMM allows the exploration of antepartum SMM separately from intra and postpartum SMM. The objectives of this study were to explore causes and risk factors of antepartum SMM, and to describe the adverse delivery and neonatal outcomes associated with antepartum SMM.

2 METHODS 2.1 Study population

We conducted a population-based nested case-control study. Data came from the EPIMOMS population-based study, conducted in 6 French regions (May 2012 - November 2013).12 The EPIMOMS study was funded with support from the French National Research Agency (Agence Nationale de la Recherche (ANR), Paris France; grant no. ANR-10-BLAN-1134–01) and the Ile de France Regional Health Agency (Agence Régionale de Santé Ile de France, Paris, France; grant no. PPS784). The first step of EPIMOMS was to define SMM through an extensive national Delphi expert consensus process. This definition of SMM combined 6 diagnostic criteria (major obstetric bleeding, eclampsia, severe preeclampsia, pulmonary embolism, stroke or psychiatric disorder), 6 organ dysfunction criteria (cardiovascular, respiratory, renal, neurologic, hepatic or hematologic) and 2 intervention criteria (admission to an intensive care unit (ICU) or laparotomy after delivery), as well as maternal death (Table S1).

The source population included all women (N = 182,309) who gave birth in the 119 maternity units of 6 French regions, during the study period, which account for one fifth of all deliveries in France. The characteristics of women and maternity units were similar to the national profile.13 All women who experienced a morbid event meeting the EPIMOMS SMM definition between 22 weeks of gestation and 42 days after delivery were prospectively included (n = 2540). The prospective inclusion of women with SMM allowed to take into account the timing of the morbid event relative to the delivery, and to make the distinction between antepartum, intrapartum and postpartum SMM. Besides, a 2% unmatched control sample of women without SMM was randomly selected among women who gave birth in the same maternity units during the same time period retrospectively from delivery logbooks (control group, n = 3651 women). In the EPIMOMS study, detailed data were collected not for all the women who delivered in the 119 maternity units, but for all the women with SMM and for all the women included in the random sample.

This analysis excludes among the women with SMM those for whom the date of the morbid event was missing (n = 3) and those with intrapartum or postpartum (or both) SMM only (n = 1936). Finally, we included all women who experienced SMM in the antepartum period, defined as a morbid event occurring from 22 weeks of gestation and before the onset of labour. Women with antepartum SMM but also intrapartum and/or postpartum SMM were included in the study population. Furthermore, this analysis included the entire group of control women (n = 3651) (Figure 1).

Flow Chart of the study population. The source population included all women (N = 182,309) who gave birth in the 119 maternity units of 6 French regions, during the study period. All women who experienced a morbid event between 22 weeks of gestation and 42 days after delivery were prospectively included (n = 2540). The analysis excluded among the women with SMM those for whom the date of the morbid event was missing (n = 3) and those with intrapartum or postpartum (or both) SMM only (n = 1936). Finally, we included all women who experienced SMM in the antepartum period, defined as a morbid event occurring from 22 weeks of gestation and before the onset of labour (n = 601). Besides, a 2% unmatched control sample of women without SMM was randomly selected among women who gave birth in the same maternity units during the same period (control group, n = 3651 women)

2.2 Outcomes

The primary outcome was antepartum SMM, defined according to the EPIMOMS definition as a morbid event occurring from 22 weeks of gestation and before the onset of labour. The causes of antepartum SMM, gestational age at occurrence of the morbid event and at delivery (in weeks) were prospectively collected by the clinician responsible for the woman.

2.3 Characteristics studied

Data were collected from a manual review of all available medical files by research midwives trained for this study similarly for cases and controls. They included women's social and demographic characteristics (age, pre-pregnancy BMI, maternal place of birth, living alone), pre-existing medical and obstetric conditions (parity, prior pregnancy-related hypertensive disorders, prior caesarean, prior postpartum haemorrhage), pregnancy (in vitro fertilisation, multiple pregnancy, irregular prenatal follow-up) and delivery characteristics (mode of delivery, anaesthesia for delivery), and neonatal outcomes (gestational age at birth, status at birth, birthweight, arterial umbilical pH, Apgar score, transfer to NICU, neonatal death <7 days); they were entered into an electronic case report form specifically designed for this study and used for the women in both the case and control groups.

2.4 Statistical analysis

We calculated the incidence of antepartum SMM among all deliveries and the proportion of antepartum SMM among all women with SMM. We described causes of antepartum SMM and the characteristics of cases and controls. Using logistic regression models, we explored risk factors for antepartum SMM in relation to social and demographic characteristics, medical and obstetric pre-existing conditions, and features of current pregnancy. The linearity of the association between quantitative variables and antepartum SMM was tested using fractional polynomials. Pre-pregnancy BMI did not show any deviation from linearity and was then entered as a continuous variable in the multivariable model. The selection of the variables included in the multivariable model was based first a priori on the available literature and secondly on the results of the bivariate analysis. We repeated the model for most frequent causes of antepartum SMM.

We then described and compared the characteristics of delivery and neonatal outcomes for cases and controls. Gestational age at onset of the morbid event and at delivery was described for cases. STATA software was used for all analyses (Version 13; Stata Corp).

2.5 Missing data

The proportion of women with missing data in the multivariable model was 32.1%. As the comparison of the characteristics of women with and without missing data supported the missing-at-random hypothesis, we performed multiple imputation with chained equations for missing data according to Rubin's rule (30 datasets, Table S2).14 Results of multivariable analysis are all presented with imputed data.

2.6 Ethics approval

The Commission Nationale de l’Informatique et des Libertés (CNIL, no 912210), the French data protection agency, approved the EPIMOMS study. The requirement for written informed consent was waived, in accordance with French legislation at that time, because all women received standard care and all data were anonymised.

3 RESULTS

Among the source population of 182,109 deliveries, 601 women experienced antepartum SMM (0.33% of all deliveries, 95% CI 0.30, 0.36). They accounted for 23.1% (95% CI 23.1, 24.1) of all women with SMM (601/2,540). Severe pregnancy-related hypertensive disorders were the leading cause of antepartum SMM (52.1%), followed by exacerbation of chronic somatic conditions, psychiatric disorders (de novo or decompensation of a chronic psychiatric condition), and obstetric haemorrhage, each accounting for 8.7% to 9.6% of the cases (Table 1).

TABLE 1. Causes of antepartum severe maternal morbidity Causes* Women with antepartum SMM (N = 601) n % Any severe pregnancy-related hypertensive disorder 313 52.1 Severe preeclampsia 272 45.3 Eclampsia 24 4.0 HELLP associated with splenic rupture or hematoma 79 13.1 Exacerbation of a chronic somatic diseasea 58 9.6 Hematologic disease 14 2.3 Nephropathy 8 1.3 Cardiopathy 7 1.1 Diabetes 5 0.8 Chronic infection 5 0.8 Neurologic disease 5 0.8 Other 14 2.3 Psychiatric disorder 52 8.7 De novo 30 5.0 Exacerbation of chronic disease 22 3.7 Severe antepartum obstetrical haemorrhage 52 8.7 Severe hepatic disease 33 5.5 Sepsis 24 4.0 Stroke 14 2.3 Pulmonary embolism 11 1.8 Otherc 47 7.8

Characteristics of cases and controls are presented in Table 2. In the multivariable analysis with imputed data, risk factors for antepartum SMM were maternal age ≥35 years, higher pre-pregnancy BMI, maternal birth in sub-Saharan Africa, pre-existing medical condition, nulliparity, prior pregnancy-related hypertensive disorders, multiple pregnancy and irregular prenatal care (Table 3). The same risk factors were found for antepartum SMM due to pregnancy-related hypertensive disorders (Table S3).

TABLE 2. Characteristics of cases and controls

Women with antepartum SMM

N = 601

Controls

N = 3651

n % n % Maternal age (years) <35 426 70.9 2915 79.9 35–39 130 21.6 599 16.4 ≥40 45 7.5 137 3.7 Pre-pregnancy BMI (per 5 kg/m2) 25.6 6.2 23,9 5.0 Maternal place of birth France or other European country 369 70.3 2419 79.0 North Africa 71 13.5 353 11.5 Sub-Saharan Africa 69 13.1 172 5.6 Othera 16 3.0 119 3.9 Living alone 41 7.5 135 4.0 Pre-existing medical conditionb 127 21.7 274 7.5 Nulliparous 301 50.9 1517 41.8 Previous pregnanciesc Prior pregnancy-related-hypertensive disorder 66 23.9c 102 4.8c Prior caesarean 87 31.4c 441 21.2c In vitro fertilisation 30 5.1 76 2.1 Multiple pregnancy 47 8.0 59 1.6 Irregular prenatal follow-up 40 8.4 151 4.6 TABLE 3. Risk factors for antepartum severe maternal morbidity Unadjusted OR (95% CI) Adjusted OR (95% CI) Maternal age (years) <35 1.00 (Reference) 1.00 (Reference) 35–39 1.49 (1.20,1.84) 1.55 (1.22,1.97) ≥40 2.25 (1.58,3.19) 2.01 (1.35,3.00) Pre-pregnancy BMI (/5 kg/m2) 1.29 (1.20,1.40) 1.24 (1.14,1.36) Maternal place of birth France or other European country 1.00 (Reference) 1.00 (Reference) North Africa 1.27 (0.96,1.68) 1.30 (0.97,1.73) Sub-Saharan Africa 2.43 (1.81,3.26) 1.80 (1.29,2.53) Othera 0.89 (0.51,1.57) 0.90 (0.49,1.62) Living alone 1.88 (1.30,2.71) 1.34 (0.89,2.01) Pre-existing medical conditionb 3.31 (2.62,4.17) 2.56 (1.99,3.30) Nulliparous 1.49 (1.25,1.77) 2.26 (1.83,2.80) Previous pregnanciesc Prior pregnancy-related-hypertensive disorder 4.47 (3.23,6.17) 4.94 (3.36,7.26) Prior caesarean 1.26 (0.99,1.63) 1.01 (0.73,1.38) In vitro fertilisation 2.51 (1.64,3.87) 1.34 (0.81,2.22) Multiple pregnancy 5.20 (3.51,7.72) 5.79 (3.75,7.26) Irregular prenatal follow-up 1.72 (1.22,2.44) 1.86 (1.27,2.72) Note Bivariate and multivariable logistic regression models with multiple imputation, including all variables listed in the table except prior postpartum haemorrhage. Abbbreviations: 95% CI, 95% confidence interval; aOR, adjusted odds ratio; BMI, body mass index.

Compared with controls, women with antepartum SMM gave birth significantly more frequently by emergency caesarean (69.4% vs. 13.6%) and with general anaesthesia (29.7% vs. 1.2%), as well as before 37 weeks (73.0% vs. 7.3%) and before 32 weeks (50.3% vs. 1.4%). The proportion of induced preterm delivery among infants born to mothers with antepartum SMM was also higher than among controls (93.3% vs. 49.6%) (Table 4).

TABLE 4. Delivery characteristics and neonatal outcomes among women with antepartum severe maternal morbidity and controls

Women with antepartum SMM

N = 601

Controls

N = 3651

n % n % Delivery mode Vaginal delivery 131 22.7 2906 79.6 Caesarean during labour 48 8.3 357 9.8 Caesarean before labour 399 69.0 386 10.6 Emergency caesarean 353 88.5 139 36.0 General anaesthesia for delivery 171 29.7 43 1.2 Gestational age at birth (weeks) 22–27 84 14.6 26 0.7 28–31 206 35.7 26 0.7 32–36 131 22.7 214 5.9 37–42 156 27.0 3382 92.7 Induced preterm delivery 393 93.3 132 49.6 Status at birtha Alive 562 90.5 3680 99.2 Intrapartum death 10 1.6 4 0.1 Intrauterine foetal death 49 7.9 25 0.7 Birthweight (mean, SD), gb 1889.7 1025.0 3265.8 580.3 <1500 264 46.2 55 1.5 1500–2499 134 23.4 207 5.7 ≥2500 174 30.4 3385 92.8 Apgar <7 at 5 min a,c, a,c 92 16.4 52 1.4 Arterial umbilical pH <7.0a,c, a,c 22 3.9 13 0.3 Neonatal ICU transfera,c, a,c 376 66.9 187 5.1 Neonatal death <7 daysa,c, a,c 17 3.0 3 0.1

Adverse neonatal outcomes occurred more frequently among women with antepartum SMM than controls, with higher rates of stillbirths (9.6% vs. 0.8%); among live births, higher rates of transfer to the NICU (65.4% vs. 4.8%) and of neonatal mortality within the first 7 days of life (2.7% vs. 0.1%) were also seen among SMM cases than controls. Gestational age at occurrence of the morbid event and at delivery differed according to the cause of SMM. In women with antepartum SMM due to pregnancy-related hypertensive disorders, both morbid event and delivery occurred before 32 weeks in more than 80% of the women. In contrast, among women with antepartum SMM from psychiatric disorders, the morbid event occurred before 28 weeks in 50% of women, but 80% of them gave birth after 37 weeks (Table 5).

TABLE 5. Gestational age at the occurrence of the morbid event and at delivery in women with antepartum severe maternal morbidity, overall and by causes Gestational age (weeks) Antepartum SMM overall (n = 601) Antepartum SMM from pregnancy-related hypertensive disorder (n = 313) Antepartum SMM from exacerbation of chronic somatic disease (n = 58)

Antepartum SMM from psychiatric disorder

(n = 52)

Antepartum SMM from obstetrical haemorrhage (n = 52) SMM event Delivery

SMM

event

Delivery

SMM

event

Delivery

SMM

event

Delivery

SMM

event

Delivery n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) 22–27 147 (25.1) 84 (14.6) 80 (25.7) 73 (23.5) 14 (24.1) 3 (5.5) 20 (47.6) 0 (0.0) 8 (16.7) 7 (13.7) 28–31 234 (40.0) 206 (35.7) 173 (55.6) 176 (56.6) 17 (29.3) 8 (14.5) 3 (7.1) 0 (0.0) 13 (25.5) 11 (21.6) 32–36 148 (25.3) 131 (22.7) 43 (13.8) 45 (14.5) 19 (32.8) 24 (43.6) 16 (38.1) 8 (19.1) 16 (31.4) 18 (35.3) 37–42 56 (9.6) 156 (27.0)