Pre-eclampsia A risk factor for pre-term birth, low birth weight and neonatal mortality Tabassum Firoz MD MSc FRCPC University of British Columbia Department of Medicine

Objectives Outline the pathophysiology of pre-eclampsia and its natural history Describe the epidemiology of perinatal morbidity and mortality related to pre-eclampsia Highlight the gaps and identify potential areas for research and action

Pathophysiology of Pre-eclampsia Review the spectrum of HDP and highlight that pre-eclampsia is the most severe form HDP-related mortality and morbidity are due in large part, but not entirely, to pre-eclampsia. L.A. Magee et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 105–145

Pre-eclampsia and Feto-placental Implications Adverse conditions Severe complications Non-reassuring fetal heart rate IUGR Oligohydramnios Absent or reversed end-diastolic flow by Doppler velocimetry Abruption with evidence of maternal or fetal compromise Reverse ductus venosus A wave Stillbirth Adverse conditions increase the risk of severe complications Severe complications warrant delivery L.A. Magee et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 105–145

Natural History of Pre-eclampsia 2 RCTs (133 women) show that expectant care of severe pre-eclampsia was associated with a mean pregnancy prolongation of 2.0 weeks [1.4, 2.6] 1 A 2009 systematic review found that expectant care of severe preeclampsia <34 weeks (39 cohorts, 4,650 women) was associated with pregnancy prolongation of 7-14 days2 1Obstet Gynecol 1990;76:1070-5; AJOG 1994;171:818-822 2Hypertens Pregnancy 2009;28(312-47.

Pre-eclampsia and Perinatal Outcomes IUGR Low birth weight Spontaneous Pre-term Birth Neonatal death Fetal outcomes tend to cluster around the diagnosis of pre-eclampsia whether defined traditionally (as gestational hypertension and proteinuria) or broadly (as gestational hypertension with end-organ dysfunction) In a secondary analysis of the WHO Multi-country survey, hypertension showed a higher prevalence of spontaneous and provider-initiated preterm delivery. Pre-eclampsia (AOR 1.25, 95% CI 1.05–1.49) increased odds of spPTB A 2012 systematic review and The EMIP study corroborates a recent upward trend in national and global preterm rates   Provider Initiated Pre-term Birth Stillbirth

Provider Initiated Pre-term Birth Hypertension is the leading cause of provider-initiated preterm delivery1,2 EMIP3: Hypertensive disorders (pre-eclampsia 58.2%, chronic hypertension 15.3%, gestational hypertension 12.9%, and HELLP syndrome 9.4%) were the most common indications of provider initiated pre term delivery WHO Multi-Country Survey2: pre-eclampsia (18.2% vs 2.6%, p < 0.001) was higher in women with provider initiated pre-term birth2 1 BJOG 121 Suppl: 101–9 14% of provider initiated PTB were not medically indicated. The proportion of piPTB deliveries that did not have a medical indication was generally less than 10% of all piPTBs, however facilities in Sri Lanka (23.8%), China (22.3%) and India (16.2%) had the highest proportion of non-medically indicated piPTBs Pre-eclampsia rates were highest in Africa and Asia Only about one-quarter of pi-PTB due to maternal conditions were supported by maternal exams/tests, highlighting the importance of evidence-based decisions EMIP study: regardless of gestational age 2 BMC Pregnancy and Childbirth 2014, 14:56 3 PLoS ONE 11(2): e0148244

Geography of Pre-eclampsia related Pre-term Birth Pre-eclampsia rates vary nationally, regionally and globally Hypertensive disorders were associated with both spontaneous and indicated preterm birth in all Human Development Index groups The risk of preterm delivery caused by these complications did not decrease despite higher levels of country development Sub-Saharan Africa and South Asia – where most pre-term occurs but also the regions where the most live births occur the proportion of preterm births that were provider initiated increased as HDI increased, with the percentage being 20% in low HDI countries and 40% in high HDI countries. Chronic hypertension (AOR, 2.28; 95% CI, 1.94; 2.68) and pre-eclampsia/eclampsia (AOR, 5.03; 95% CI, 4.72; 5.37) on preterm birth were similar among all four HDI subgroups. BJOG 2014 Mar;121 Suppl 1:101-9

Pre-eclampsia and Perinatal Death 9-20% of perinatal deaths are reported to be a direct result of the hypertensive disorders of pregnancy1 Adverse perinatal outcomes, including stillbirth, are modified by gestational age with the risk of perinatal death being highest at earlier gestational ages1,2,3 Risks of stillbirth and early neonatal death lower in spontaneous preterm deliveries compared with provider-initiated deliveries 4 1FIGO Textbook of the Hypertensive Disorders of Pregnancy 2BMC Pregnancy and Childbirth 2014, 14:56 3PLoS ONE 11(2): e0148244 4 BJOG 2014 Mar;121 Suppl 1:101-9 First point: in several large multi-country cohort studies In the Nationwide Inpatient Sample study of all deliveries reported in the USA, 7.5% of all stillbirths deaths were in association with pre-eclampsia In the Norwegian Medical Birth Registry (1999 to 2008), the RR of fetal death among women with pre-eclampsia was 86 (95% CI 46-142) at 26 weeks gestation, 7.3 (95% CI 3.3-1.0) at 34 weeks and 3.0 at 38 weeks Last point: Brazilian Multicentre Study on Pre-term Birth

Chronic Hypertension and Adverse Perinatal Outcomes Prevalence of chronic hypertension in pregnant women is unknown; WHO systematic review underway. Population based studies lacking and most studies are from HICs In the Brazilian multi-centre study on pre-term birth, other hypertensive disorders (chronic hypertension and gestational hypertension), maternal morbidities (chronic diabetes, cardiac disease and systemic lupus erythematosus) and vaginal bleeding during pregnancy also showed higher risks for pi- PTB. Bramham et al. BMJ 2014;348:g2301

Summary Pre-eclampsia is associated a number of adverse perinatal outcomes Pre-eclampsia is associated with both spontaneous and provider initiated pre-term birth The spectrum of the hypertensive disorders of pregnancy, particularly chronic hypertension, should be considered for pre-term birth, low birth weight and neonatal mortality

Discussion: Gaps Regional variations: pre-eclampsia prevalene and rates of provider initiated pre-term delivery Provider initiated pre-term delivery: exploration of reasons for delivery Severe hypertension: optimal and timely management Chronic hypertension: pre conception counseling Pre-eclampsia risk modification and surveillance Guidelines and protocol- standardization so that there is uniformity in indications for delivery Lack of provider knowledge esp around management of severe hypertension and eclampsia