Maternal infection and risk of intrapartum death: a population based observational study in South Asia

Approximately 1.2 million of the world’s annual 3 million stillbirths occur in the intrapartum period, and a further 717,000 of 3.1 million annual neonatal deaths are caused by intrapartum events [1‐4]. Until recently, these neonatal deaths were broadly classified as caused by ‘birth asphyxia’, but recent guidance recommends using the term ‘intrapartum-related neonatal death’, defined as the death of a term infant with neonatal encephalopathy, or who cannot be resuscitated [1]. The burden of morbidity associated with intrapartum-related asphyxial events is also high: according to the World Health Organisation’s global disease burden estimates, ‘birth asphyxia’ was responsible for an estimated 42 million disability adjusted life years (DALYs) in 2004, making it the eighth leading cause of disease for all age groups [5].

Several community-based studies have provided data on intrapartum-related neonatal deaths in developing countries using verbal autopsies [1, 6‐11]. A recent study from Matlab, Bangladesh, showed that intrapartum-related events were responsible for 53% of early neonatal deaths and approximately three percent of late neonatal deaths [7]. In South Asian communities, the intrapartum-related neonatal mortality rate is estimated at between nine and 15 per 1000 live births in the absence of intervention [8].

Previous studies have shown that clinical markers of maternal infection such as pyrexia and chorioamnionitis are significant risk factors for neonatal encephalopathy, low Apgar score and neurological outcomes such as cerebral palsy [12‐15]. In Nepal, a facility-based study found that prolonged rupture of membranes (PROM), meconium stained amniotic fluid and thick meconium were important risk factors for encephalopathy among term newborn infants [16]. A prospective community-based study in rural Nepal also found maternal fever to be a significant risk factor for birth asphyxia [11]. Some studies have suggested that the combination of maternal infection and neonatal encephalopathy increases the likelihood of adverse neurological outcomes including the risk of cerebral palsy [17, 18].

The ‘double hit hypothesis’ is an example of a causal pathway approach to irreversible neonatal brain injury and neonatal death, focusing on perinatal maternal infection and intrapartum events. It hypothesises that the first insult (maternal infection) renders the perinatal brain more vulnerable to the second (asphyxial) insult [17‐19]. Other evidence in support of the double hit hypothesis is based on raised blood levels of pro-inflammatory mediators in term infants who have experienced respiratory arrest and brain injury following intrapartum compromise in association with maternal chorioamnionitis [20‐22].

In this study we aimed to test the hypothesis that intrapartum compromise affecting infants born to mothers with clinical signs of infection immediately prior to, or during delivery, is more likely to result in an early neonatal death compared with compromised infants born to mothers without evidence of infection. This is the first population-based study to investigate the ‘double hit hypothesis’ in a low-resource setting.

We have shown that newborn infants in rural Bangladeshi and Indian who were exposed to signs of maternal infection as indicated by PROM as well as intrapartum asphyxia were at increased risk of early neonatal mortality compared to those who only had signs of asphyxia. Other clinical studies have suggested a similar association, but ours is the first large scale population study to test the hypothesis [17‐22]. A cohort study from a large hospital population in Kathmandu Nepal, demonstrated that antepartum maternal fever was a significant predictor of intrapartum-related neonatal death after adjusting for other factors [16].

Collecting information on complications that occur in the antepartum and delivery periods in rural, low resource settings is wrought with difficulties due to reporting bias, as most deliveries occur in the home without a skilled birth attendant. However, until facility-based deliveries become the norm, surveillance data collected using similar methodology, as in this study, will need to rely on self-reporting by interviews after delivery [32]. Our data relied on a mother’s or close relative’s recall of events in delivery and the antepartum period. There have been attempts to validate such questionnaires in the past, with one study indicating that medically diagnosed conditions occurring during delivery, such as neonatal condition at five minutes, PROM, and maternal fever, are often over-estimated when using questionnaires relying on a women’s recall, especially when this event is rare [33]. In this instance, overestimation of the presence of a complication would lead to underestimation or a diluted estimate for the effect of maternal infection in asphyxiated infants. Recall bias following a neonatal death or significant morbidity could lead to either under- or over-reporting of maternal signs of infection and symptoms of intrapartum asphyxia, and therefore to over or under-estimation of the effect sizes. For instance, if a neonatal death occurs the mother may be searching for explanations as to why this happened, and this may lead to systematic differences in the way these women answered questions compared to women whose newborns survived.

Misclassification bias can occur inadvertently for the indication of maternal infection, as factors such as an incompetent cervix or abnormal presentation of the foetus can induce PROM. Furthermore, after membrane rupture, serious consequences such as prolapsed umbilical cord may increase the risk of intrapartum asphyxia [34]. Similarly, ‘fever’ may indicate a wide range of infectious diseases including influenza, pneumonia, malaria, and typhoid fever, not all of which always affect the fetus [28]. Data was also available on “vaginal smell three days prior to delivery”. In this instance, it was thought the potential for misclassification bias was too great, so this was not assessed further. If maternal signs of infection have been over-estimated due to misclassification bias, assuming the double hit hypothesis holds true, this would under-estimate a positive association of maternal infection for early neonatal death in asphyxiated infants. Additionally, a diagnosis relying on the presence or absence of a symptom has been shown to have a higher sensitivity than a diagnosis that relies on a question indicating the severe end of a normal continuum, such as excessive bleeding [32]. For this reason, we feel that PROM is less subject to recall bias than maternal fever.

Differences were noted in the prevalence of signs of maternal infection and intrapartum asphyxia between Bangladesh and India. In Bangladesh, approximately 5% of newborn infants exhibited signs of intrapartum asphyxia, compared with 2.5% in India. In Bangladesh, higher use of birth attendants trained specifically to recognize signs of birth asphyxia may have made mothers more aware of signs of the event that account for this difference. The combination of maternal fever and intrapartum asphyxia led to higher mortality risk in Bangladesh compared to India, perhaps due to under-reporting of intrapartum asphyxia in India. If this were the case, then our pooled analysis underestimates the true effect of the double hit hypothesis. In India, approximately 4.8% of all newborns were exposed to maternal fever for up to three days prior to delivery compared to 1.7% in Bangladesh, possibly due to the higher incidence of malaria [35]. The percentage of women with PROM (16.6%) observed in Bangladesh was slightly higher than in similar populations elsewhere. Ellis et al. in Nepal found 11% PROM rates in deliveries where infants exhibited signs of intrapartum asphyxia [17]. In a prospective community study assessing risk factors for birth asphyxia in Nepal, 14% of asphyxiated infants had mothers with prolonged rupture of membranes longer than twenty-four hours [11]. There is great variation in the prevalence of reported signs of both intrapartum asphyxia and maternal fever between Bangladesh and India. This variation is potentially due to differences in the way these questions were administered in each country, or could be due to genuine differences in morbidity patterns.

Given the limitations of this analysis due to inherent biases associated with observational data, we used verbal autopsy reports to identify newborns that were likely to have died due to intrapartum asphyxia. Use of the InterVA method ensured that causes of death were standardized between study settings and over time (a significant advantage in the current study) and classification of asphyxia cases based on probabilistic reasoning relating to multiple causes may overcome misclassification bias associated with lay-reports and alternative methods of verbal autopsy interpretation. The verbal autopsy data validated our findings to some extent, in that the risk of an early neonatal death due to intrapartum asphyxia was significantly greater when the neonate was exposed to PROM compared to an unexposed newborn. However, when using maternal fever as the surrogate for maternal infection, there was no significant increased risk of death due to an intrapartum event. The lack of an effect in the exposure of maternal fever could have occurred due to a low sensitivity of this marker of maternal infection and the potential for misclassification bias previously mentioned. However, the fact that the association between PROM and early neonatal death due to intrapartum asphyxia was greater than the association between PROM and an early neonatal death alone, adds weight to the double hit hypothesis.

Our population-based results support, but do not prove, the double-hit hypothesis that an insult such as maternal infection during critical periods of neural development sets up a predisposition toward severe adverse outcomes when exposed to asphyxia [19]. It might be argued that the two events of infection and asphyxia act independently but additively to affect early newborn death rather than through a double-hit interaction. Further studies are needed to understand the biological mechanisms behind the double hit hypothesis in similar low-resource settings, and follow-up to assess the risk of disabilities from a double hit compared with asphyxia alone.

Our findings beg the important policy question whether antibiotic treatment for women with maternal signs of infection should be routinely offered to reduce early neonatal deaths and, possibly, later disability. The use of antibiotics is already advocated for women experiencing preterm premature rupture of membranes [36]. It is also arguable that based on currently available evidence, women who experience prolonged rupture of membranes should be given antibiotics in low-income settings. In addition to treatment women with signs of infection due to bacteria, a recent review of malaria in pregnancy in the Asian context stresses the importance of early detection and treatment of any malaria in pregnancy to prevent the effects of symptomatic disease including stillbirth, intrauterine death, and low birth weight, which as corroborated by a recent hospital study in [37, 38]. There is a surprising lack of trial evidence addressing this question in high-income settings. However benefits are likely to be greater for home births in low-income populations, where the risk of newborn infection is far higher [39]. Trials of antibiotics given to mothers with signs of infection, either in the community or upon arrival at hospital, could assess not only early mortality impact, but also the effect on incidence of neurodevelopmental sequelae.

Our findings support the double hit hypothesis: newborn infants born in rural south Asia showing evidence of intrapartum compromise are more likely to suffer an early neonatal death if the infant’s mother also has evidence of infection. Our finding supports the prompt treatment of mothers exhibiting signs of infection with antibiotics, and raises the question of antibiotic treatment for pregnant women suffering pre-labour rupture of membranes. Benefits are likely to be greater for low-income home births.