Care prior to and during subsequent pregnancies following stillbirth for improving outcomes

Background: Stillbirth affects at least 2.6 million families worldwide every year and has enduring consequences for parents and health services. Parents entering a subsequent pregnancy following stillbirth face a risk of stillbirth recurrence, alongside increased risks of other adverse pregnancy outcomes and psychosocial challenges. These parents may benefit from a range of interventions to optimise their short- and longer-term medical health and psychosocial well-being. Objectives: To assess the effects of different interventions or models of care prior to and during subsequent pregnancies following stillbirth on maternal, fetal, neonatal and family health outcomes, and health service utilisation. Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 June 2018), along with ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (18 June 2018). Selection criteria: We included randomised controlled trials (RCTs) and quasi-randomised controlled trials (qRCTs). Trials using a cluster-randomised design were eligible for inclusion, but we found no such reports. We included trials published as abstract only, provided sufficient information was available to allow assessment of trial eligibility and risk of bias. We excluded cross-over trials. Data collection and analysis: Two review authors independently assessed trials for eligibility and undertook data extraction and 'Risk of bias' assessments. We extracted data from published reports, or sourced data directly from trialists. We checked the data for accuracy and resolved discrepancies by discussion or correspondence with trialists, or both. We conducted an assessment of the quality of the evidence using the GRADE approach. Main results: We included nine RCTs and one qRCT, and judged them to be at low to moderate risk of bias. Trials were carried out between the years 1964 and 2015 and took place predominantly in high-income countries in Europe. All trials assessed medical interventions; no trials assessed psychosocial interventions or incorporated psychosocial aspects of care. Trials evaluated the use of antiplatelet agents (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH), or both), third-party leukocyte immunisation, intravenous immunoglobulin, and progestogen. Trial participants were women who were either pregnant or attempting to conceive following a pregnancy loss, fetal death, or adverse outcome in a previous pregnancy. We extracted data for 222 women who had experienced a previous stillbirth of 20 weeks' gestation or more from the broader trial data sets, and included them in this review. Our GRADE assessments of the quality of evidence ranged from very low to low, due largely to serious imprecision in effect estimates as a result of small sample sizes, low numbers of events, and wide confidence intervals (CIs) crossing the line of no effect. Most of the analyses in this review were not sufficiently powered to detect differences in the outcomes assessed. The results presented are therefore largely uncertain. Main comparisons LMWH versus no treatment/standard care (three RCTs, 123 women, depending on the outcome) It was uncertain whether LMWH reduced the risk of stillbirth (risk ratio (RR) 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low-quality evidence), adverse perinatal outcome (RR 0.81, 95% CI 0.20 to 3.32; 2 trials; 77 participants; low-quality evidence), adverse maternal psychological effects (RR 1.00, 95% CI 0.07 to 14.90; 1 trial; 40 participants; very low-quality evidence), perinatal mortality (RR 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low-quality evidence), or any preterm birth (< 37 weeks) (RR 1.01, 0.58 to 1.74; 3 trials; 114 participants; low-quality evidence). No neonatal deaths were reported in the trials assessed and no data were available for maternal-infant attachment. There was no clear evidence of a difference between the groups among the remaining secondary outcomes. LDA versus placebo (one RCT, 24 women) It was uncertain whether LDA reduced the risk of stillbirth (RR 0.85, 95% CI 0.06 to 12.01), neonatal death (RR 0.29, 95% CI 0.01 to 6.38), adverse perinatal outcome (RR 0.28, 95% CI 0.03 to 2.34), perinatal mortality, or any preterm birth (< 37 weeks) (both of the latter RR 0.42, 95% CI 0.04 to 4.06; all very low-quality evidence). No data were available for adverse maternal psychological effects or maternal-infant attachment. LDA appeared to be associated with an increase in birthweight (mean difference (MD) 790.00 g, 95% CI 295.03 to 1284.97 g) when compared to placebo, but this result was very unstable due to the extremely small sample size. Whether LDA has any effect on the remaining secondary outcomes was also uncertain. Other comparisons LDA appeared to be associated with an increase in birthweight when compared to LDA + LMWH (MD -650.00 g, 95% CI -1210.33 to -89.67 g; 1 trial; 29 infants), as did third-party leukocyte immunisation when compared to placebo (MD 1195.00 g, 95% CI 273.35 to 2116.65 g; 1 trial, 4 infants), but these results were again very unstable due to extremely small sample sizes. The effects of the interventions on the remaining outcomes were also uncertain. Authors' conclusions: There is insufficient evidence in this review to inform clinical practice about the effectiveness of interventions to improve care prior to and during subsequent pregnancies following a stillbirth. There is a clear and urgent need for well-designed trials addressing this research question. The evaluation of medical interventions such as LDA, in the specific context of stillbirth prevention (and recurrent stillbirth prevention), is warranted. However, appropriate methodologies to evaluate such therapies need to be determined, particularly where clinical equipoise may be lacking. Careful trial design and multicentre collaboration is necessary to carry out trials that would be sufficiently large to detect differences in statistically rare outcomes such as stillbirth and neonatal death. The evaluation of psychosocial interventions addressing maternal-fetal attachment and parental anxiety and depression is also an urgent priority. In a randomised-trial context, such trials may allocate parents to different forms of support, to determine which have the greatest benefit with the least financial cost. Importantly, consistency in nomenclature and in data collection across all future trials (randomised and non-randomised) may be facilitated by a core outcomes data set for stillbirth research. All future trials should assess short- and longer-term psychosocial outcomes for parents and families, alongside economic costs of interventions.