While high-quality Cochrane or other published reviews or meta-analyses were available for many interventions, few of these reviews or their component studies reported stillbirths specifically, and evidence from different studies and different reviews was frequently conflicting. Additionally, comparing findings even for the same intervention was often difficult due to differing study objectives and design issues including study incommensurability, differences in outcome definitions, and differences in allocation technique. Even rigorous intervention trials were usually conducted in tertiary care centres where even controls received ANC, often of better quality than women who do not enroll in such trials; in such trials with appropriate care and monitoring, stillbirths are more rare than in the general population (e.g., use of anti-hypertensive agents in pregnant women with hypertension). This bias limits generalisability of findings and further hinders demonstration of impact attributable to an intervention. To bridge the evidence gap, there is a need for large research trials to report stillbirths–disaggregated from the perinatal mortality composite measure–as an outcome whenever feasible, and for rigorous RCTs in low-resource settings. The recommendation of each intervention for inclusion in programs is given in Table .
Summary of evidence grading for all interventions prior to and during pregnancy to prevent stillbirth and perinatal mortality reviewed in this paper
In many low-/middle-income countries, stillbirths associated with infection comprise a large proportion of stillbirths. Preventing stillbirth associated with maternal infection is appealing because it targets a large proportion of the burden, and interventions and service delivery needs are relatively straightforward, short-term, and noninvasive compared with behavioural, surgical, or nutritional interventions. While the evidence base for prevention of stillbirths with interventions prior to or during pregnancy is limited, evidence strongly supports a benefit of syphilis screening and treatment and malaria prophylaxis in endemic areas, and these interventions should be incorporated into ANC programs where epidemiological evidence indicates women are at risk. Some estimates suggest that better syphilis screening and treatment could prevent as many as half of all stillbirths in areas with high syphilis prevalence [186
]. When women are treated for syphilis successfully, their risk of stillbirth is similar to uninfected women [187
]. The logistical challenges of providing syphilis screening and treatment, particularly at the community level, are many, including training workers to perform a complex test or tests, evaluating ambiguities in diagnosis, preventing test and pharmaceutical supply stock outs, managing the occasional penicillin sensitivity, and ensuring that clients receive both test results and treatment. However, the high rates of ANC attendance (one or more visits) in much of sub-Saharan Africa and South Asia provide a potential infrastructural framework to provide access to this important intervention.
Given the endemicity of malaria in much of sub-Saharan Africa and South Asia, where stillbirth rates are concomitantly high, the three-pronged approach to malaria prevention and treatment advocated by the WHO (ITNs, IPT, and treatment of parasitemia with artemisinin-based therapies) appears prudent, though further research is needed about the safety of artemisinin-based drugs other than artesunate and the impact of timing of dosage on stillbirth rates.
Other interventions, such as anti-helminthic treatment, showed promising impact on stillbirth rates but require more studies to confirm effectiveness. While we recommend the continued practice of PMTCT for HIV, and malaria chemoprophylaxis in women of low parity, these recommendations are based primarily on demonstrated benefit for maternal or other fetal/neonatal outcomes, rather than definitive impact on stillbirths or perinatal mortality.
The area of stillbirth prevention, particularly the development of interventions that address the multifactorial causes of antepartum stillbirths, is a ripe area for new research (Table ). In this review, we found evidence that several interventions brought about reductions in known risk factors for stillbirth, yet failed to bring about statistically significant improvements in stillbirth rates. For example, anti-platelet agents clearly reduced rates of PIH and pre-eclampsia, yet no statistically significant impact on stillbirths was noted. Similarly, antibiotic treatment for PROM was associated with a significant reduction in chorioamnionitis, yet yielded no statistically significant reduction in stillbirth rates. These findings are most likely attributable to studies underpowered to detect impact of the intervention on stillbirth rates, but could also be due to intervention at a point too distal in a multi-causal pathway, a deleterious effect of the intervention itself, including adverse effects of drugs, etc. For these interventions and others (Table ), further research specifically designed to measure stillbirth as an outcome is needed.
Large gaps remain in the basic science of stillbirth causation and many of the maternal conditions and pathologies that lead to stillbirth, including pathophysiological mechanisms involved in pre-eclampsia, autoimmune and inflammatory responses that threaten pregnancy, still-unknown risk factors, and drug safety and efficacy studies. These studies will guide development of appropriate interventions for maternal conditions and infections associated with stillbirth causation.
Evidence for some newly recognised risk factors for stillbirth, such as periodontal disease, suggests the need for large, appropriately designed randomised trials to assess whether effective interventions can be designed to minimise these risks.
Knowledge and evidence gaps in the dynamics and prevention of antepartum stillbirth are numerous and deep. At present, there is no standard international classification system for stillbirth causation, and disagreement persists about the lower benchmarks of birth weight and gestational age used to define stillbirth. These ambiguities complicate measurement of stillbirths, comparison of different studies measuring stillbirth, and tracking trends over time [186
]. Development of practical, standardised templates to assess causes of stillbirth is underway, which, if adopted internationally, will help to more accurately measure the burden of intrapartum versus antepartum stillbirths and their associated causes. These data are crucial to inform the development of appropriate interventions. Meanwhile, the numerous gaps in the growing list of stillbirth risk factors, the pathophysiology of certain maternal infections and conditions, and the many interventions for which there is conflicting evidence of benefit suggest the need for greater investment in large studies powered to measure stillbirth rate reductions. Armed with more definitive knowledge of which interventions are effective and prevent the most stillbirths in particular settings, we can more effectively select and implement these interventions and prevent unnecessary loss of life.
Programmatically, the clearest evidence of impact in stillbirth prevention is adequate prevention and treatment of maternal infections such as syphilis and malaria. Given the enormous human burden of both of these diseases in many countries with the world's highest stillbirth rates, effective prevention and treatment of syphilis and malaria have the potential to greatly reduce global stillbirth rates.
Efforts prior to and during pregnancy to prevent stillbirth will be most effective in conjunction with effective monitoring interventions in pregnancy, prompt recognition and management of high-risk pregnancies and complications, and a system of interlinked facilities capable of prompt referral to ensure that complications are capably managed to prevent unnecessary loss of life for mothers or their babies.