The Contribution of Hypertensive Disorders of Pregnancy to Neonatal Unit Admissions and Iatrogenic Preterm Delivery at < 34+0 Weeks' Gestation in the UK: A Population-Based Study Using the National Neonatal Research Database.

OBJECTIVES: The objectives of this study were to (i) quantify the contribution of maternal hypertensive disorders of pregnancy (HDP) to iatrogenic preterm birth (PTB) and neonatal unit (NNU) admissions < 34+0 weeks and (ii) describe short-term population-level outcomes for HDP infants, exploring ethnic disparities and comparing outcomes by HDP exposure. DESIGN: Retrospective population-based study using the National Neonatal Research Database. SETTING: England and Wales. POPULATION: Infants born < 34+0 weeks and admitted to NNU 2012-2020. METHODS: Descriptive statistics, linear and logistic regression models to compare outcomes between groups. MAIN OUTCOME MEASURES: Survival to discharge with/without comorbidity. RESULTS: 122 228 infants met inclusion criteria. Where collected, 49 839/114 164 (43.7%, 95% CI 43.4%-43.9%) of infants had an iatrogenic PTB. HDP was recorded in 16 510/122 228 (13.5%) of all infants and 13 560/49 839 (27.2%) of iatrogenic PTBs. HDP and/or foetal growth restriction (FGR) were recorded in 24 124/49 839 (48.4%) of iatrogenic PTBs. Singleton HDP infants < 10th BWC had ≥ 90% survival to discharge from 28 weeks' gestation, versus from 26 weeks' gestation for those born ≥ 10th BWC. In extreme preterm HDP infants (< 27 weeks), 27.3% of infants < 10th BWC died compared to 15.2% of those ≥ 10th BWC. Survival without comorbidity was ≥ 90% from 32 weeks' gestation in HDP infants across BWC. CONCLUSIONS: These contemporaneous population-level data show that almost one in two PTB < 34+0 weeks' gestation are iatrogenic, with HDP and/or FGR being the major contributors to iatrogenic prematurity. This has substantial implications for strategies to reduce preterm birth in the UK and internationally. The data further inform antenatal and at-birth counselling of HDP-exposed infants.

The contribution of hypertensive disorders of pregnancy to late preterm and term admissions to neonatal units in the UK 2012-2020 and opportunities to avoid admission: A population-based study using the National Neonatal Research Database.

OBJECTIVE: To quantify maternal hypertensive disorder of pregnancy (HDP) prevalence in late preterm and term infants admitted to neonatal units (NNU) and assess opportunities to avoid admissions. DESIGN: A retrospective population-based study using the National Neonatal Research Database. SETTING: England and Wales. POPULATION: Infants born ≥34 weeks' gestation admitted to NNU between 2012 and 2020. METHODS: Outcomes in HDP infants are compared with non-HDP infants using regression models. MAIN OUTCOME MEASURES: Hypertensive disorder of pregnancy, primary reason for admission, clinical diagnoses and resource use. RESULTS: 16 059/136 220 (11.8%) of late preterm (34+0 to 36+6 weeks' gestation) and 14 885/284 646 (5.2%) of term (≥37 weeks' gestation) admitted infants were exposed to maternal HDP. The most common primary reasons for HDP infant admission were respiratory disease (28.3%), prematurity (22.7%) and hypoglycaemia (16.4%). HDP infants were more likely to be admitted with primary hypoglycaemia than were non-HDP infants (odds ratio [OR] 2.1, 95% confidence interval [CI] 2.0-2.2, P < 0.0001). 64.5% of HDP infants received i.v. dextrose. 35.7% received mechanical or non-invasive ventilation. 8260/30 944 (26.7%) of HDP infants received intervention for hypoglycaemia alone (i.v. dextrose) with no other major intervention (respiratory support, parenteral nutrition, central line, arterial line or blood transfusion). CONCLUSIONS: The burden of maternal HDP on late preterm and term admissions to NNU is high, with hypoglycaemia and respiratory disease being the main drivers for admission. Over one in four were admitted solely for management of hypoglycaemia. Further research should determine whether maternal antihypertensive agent choice or postnatal pathways may reduce NNU admission.

Placental growth factor for the prognosis of women with preeclampsia (fullPIERS model extension): context matters.

BACKGROUND: The fullPIERS risk prediction model was developed to identify which women admitted with confirmed diagnosis of preeclampsia are at highest risk of developing serious maternal complications. The model discriminates well between women who develop (vs. those who do not) adverse maternal outcomes. It has been externally validated in several populations. We assessed whether placental growth factor (PlGF), a biomarker associated with preeclampsia risk, adds incremental value to the fullPIERS model. METHODS: Using a cohort of women admitted into tertiary hospitals in well-resourced settings (the USA and Canada), between May 2010 to February 2012, we evaluated the incremental value of PlGF added to fullPIERS for prediction of adverse maternal outcomes within 48 h after admission with confirmed preeclampsia. The discriminatory performance of PlGF and the fullPIERS model were assessed in this cohort using the area under the receiver's operating characteristic curve (AUROC) while the extended model (fullPIERS +PlGF) was assessed based on net reclassification index (NRI) and integrated discrimination improvement (IDI) performances. RESULTS: In a cohort of 541 women delivered shortly (< 1 week) after presentation, 8.1% experienced an adverse maternal outcome within 48 h of admission. Prediction of adverse maternal outcomes was not improved by addition of PlGF to fullPIERS (NRI: -8.7, IDI - 0.06). Discriminatory performance (AUROC) was 0.67 [95%CI: 0.59-0.75] for fullPIERS only and 0.67 [95%CI: 0.58-0.76]) for fullPIERS extended with PlGF, a performance worse than previously documented in fullPIERS external validation studies (AUROC > 0.75). CONCLUSIONS: While fullPIERS model performance may have been affected by differences in healthcare context between this study cohort and the model development and validation cohorts, future studies are required to confirm whether PlGF adds incremental benefit to the fullPIERS model for prediction of adverse maternal outcomes in preeclampsia in settings where expectant management is practiced.

Pharmacotherapeutic options for the treatment of hypertension in pregnancy.

INTRODUCTION: Hypertensive disorders of pregnancy affect approximately one in 10 pregnancies and are associated with increased risk of adverse fetal, neonatal and maternal outcomes. There is strong evidence that effective treatment of hypertension (blood pressure ≥ 140/90 mmHg), and enhanced monitoring throughout pregnancy reduces these risks. AREAS COVERED: This article provides a contemporaneous review of treatment of hypertension in pregnancy with antihypertensive agents. We completed a systematic search and review of all meta-analyses and systematic reviews of studies comparing antihypertensives for treatment of pregnancy hypertension in the last five years. We provide a clinically focused summary of when to treat hypertension in pregnancy and which antihypertensive agents can be offered. Special scenarios reviewed include treatment-resistant hypertension and pre-pregnancy antihypertensive optimization. EXPERT OPINION: Several antihypertensives are considered safe and are known to be effective for treatment of hypertension in pregnancy. Given the current uncertainty as to which antihypertensive(s) are superior for treatment of hypertension in pregnancy, women should be counselled and offered a range of antihypertensive options in keeping with evidence on clinical effectiveness, local context and availability of antihypertensive(s), potential side effect profile, and women's preference. Further research is required to help guide clinical decision making, and move toward personalized treatment.

Association of genetic ancestry with pre-eclampsia in multi-ethnic cohorts of pregnant women.

OBJECTIVES: Maternal self-reported ethnicity is recognised as a risk factor for pre-eclampsia in clinical screening tools and models. This study investigated whether ethnicity is acting as a proxy for genetic variants in this context. STUDY DESIGN: A total of 436 women from multi-ethnic backgrounds recruited to two UK observational pregnancy hypertension cohort studies were genotyped. Genetically-computed individual ancestry estimates were calculated for each individual through comparison to the multi-ethnic 1000 Genomes reference panel genotypes. Regression models for pre-eclampsia using clinical risk factors including self-reported ethnicity with and without ancestry estimates were built and compared using Likelihood Ratio Tests (LRT). MAIN OUTCOME MEASURES: Pre-eclampsia (early- and late-onset). RESULTS: In these multi-ethnic cohorts (mean age 34.9 years; 41.3 % White, 34.2 % Black, 13.1 % Asian ethnic backgrounds; 82.6 % chronic hypertension), discrepancies between self-reported ethnicity and genetically-computed individual ancestry estimates were present in all ethnic groups, particularly minority groups. Genetically-computed pan-African ancestry percentage was associated with early-onset (< 34 weeks) pre-eclampsia in adjusted models (aOR 100 % vs 0 % African ancestry: 3.81, 95 % CI 1.04-14.14, p-value 0.044) independently of self-reported ethnicity and established clinical risk factors. Addition of genetically-computed African ancestry to a clinical risk factor model including self-reported ethnicity, improved model fit (Likelihood ratio test p-value 0.023). CONCLUSIONS: Self-reported maternal ethnicity is an imperfect proxy for genetically-computed individual ancestry estimates, particularly in ethnic minority groups. Genetically-computed African ancestry percentage was associated with early-onset pre-eclampsia independently of self-reported maternal ethnicity. Well-powered studies in multi-ethnic cohorts are required to delineate the genetic contribution to pre-eclampsia.

Inclusion of people with multiple long-term conditions in pregnancy research: patient, public and stakeholder involvement and engagement in a randomised controlled trial.

BACKGROUND: Both pregnant women and those with multiple long-term conditions are under-served groups in clinical research. Informing and improving research through patient and public involvement, including pregnant women with two or more long-term health conditions, is critical to increasing their inclusion in maternity research. Giant PANDA is a randomised controlled trial, evaluating the effect of a treatment initiation strategy with nifedipine versus labetalol on severe maternal hypertension and a composite outcome of fetal/neonatal death, or neonatal unit admission. We aimed to undertake a mixed methods study-within-a-project within the Giant PANDA trial to understand barriers and facilitators to participation, understand and optimise current representativeness of clinical trial delivery of those with multiple long-term conditions and co-create a checklist to support their inclusion in pregnancy research. METHODS: We undertook online workshops with women with lived experience and hybrid workshops with healthcare professionals who look after women with multiple long-term conditions. A site audit of Giant PANDA sites provided insights into research delivery capacity and health system set-up, and how this influences inclusion. An extension to the Giant PANDA screening log captured data on multiple long-term conditions enabling analysis of the impact of these health conditions on women's inclusion in the trial. We co-created a checklist of recommendations for those designing and recruiting to similar clinical trials. RESULTS: Five key recommendations were identified including a need to (1) involve women with multiple long-term conditions as partners in maternity research and (2) minimise barriers that stop them from taking part through (3) designing and delivering research that is flexible in time and place (4) consider research as part of care for everyone, including those with multiple long-term conditions and (5) measure and report inclusion of those with two or more health conditions in maternity research. Multiple long-term conditions were not a barrier to recruitment or randomisation in the Giant PANDA trial. CONCLUSION: Women with multiple long-term conditions would like opportunities to find out about and participate in research which accounts for their needs. Our checklist aims to support those designing and delivering maternity research to optimise inclusion of individuals with multiple-long term conditions. TRIAL REGISTRATION: Giant PANDA: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616.

Pregnant women with two or more long-term health problems may be less likely to be included in research. Including them in research is important to ensure we give the best care. Giant PANDA is a study comparing two medicines (nifedipine or labetalol) to manage high blood pressure in pregnancy. As part of the study, we looked at the number of women with two or more long-term health conditions included. We talked to women with experience of two or more long-term health conditions in pregnancy, and healthcare staff who look after these women. Finally, we looked at how maternity research is set up in Giant PANDA study sites. We found that women with two or more health conditions were taking part in the Giant PANDA study. Women with two or more long-term conditions would like the choice to be included in research which considers their needs. This includes being involved in the planning and ongoing support for studies. Research needs to be part of routine care, flexible, and not time consuming to help those with two or more health conditions take part. Our findings have been used to make a checklist to help plan and support studies for women and birthing people with two or more long-term health conditions.

Rule-in and rule-out of pre-eclampsia using DELFIA Xpress PlGF 1-2-3 and sFlt-1: PlGF ratio.

OBJECTIVES: The objective of this study was to explore and validate thresholds for Placental growth factor (PlGF) and soluble fms-like tyrosine-kinase 1 (s-Flt-1) (as s-Flt-1: PlGF ratio), to rule-in and rule-out disease in women with suspected pre-eclampsia, using DELFIA® Xpress PlGF1-2-3 and sFlt-1 assays. STUDY DESIGN: 369 samples from women with suspected or confirmed pre-eclampsia were analysed from a prospective cohort study. MAIN OUTCOME MEASURES: Serum PlGF and sFlt-1: PlGF were quantified using DELFIA® Xpress PlGF1-2-3 and DELFIA® Xpress sFlt-1 tests. Performances were evaluated at established and exploratory thresholds. Low PlGF concentration and sFlt-1: PlGF AUROC were compared. RESULTS: PlGF 1-2-3 concentration thresholds were confirmed to have high performance for rule-in (<50 pg/ml) and rule-out (≥150 pg/ml) pre-eclampsia within seven days (20-33+6 Weeks <50 pg/ml: Negative predictive value (NPV) 90.7% (95% CI 83.9, 95.3); ≥150 pg/ml: NPV 94.8% (95% CI 88.4, 98.3)) and 28 days (20-33+6 Weeks <50 pg/ml: Negative predictive value (NPV) 83.9% (95% CI 76.0, 90.0); ≥150 pg/ml: NPV 92.8% (95% CI 85.7, 97.0)). Optimal sFlt-1: PlGF thresholds for rule-in were ≥ 70 before 34 weeks and ≥ 90 after 34 weeks, and <50 to rule-out pre-eclampsia. Low PlGF alone had comparable performance to sFlt-1: PlGF, but test performance for both was reduced in women with Kidney Disease. CONCLUSIONS: DELFIA® Xpress PlGF1-2-3 and sFlt-1 assays for pre-eclampsia rule-in and rule-out have comparable performance to other established assays, and could be an alternative for clinical use. Performance was not enhanced by use of sFlt-1: PlGF ratio, suggesting that PlGF alone could provide a cheaper alternative to dual biomarker testing.

Renal biopsy findings during and after pregnancy.

BACKGROUND: Chronic kidney disease is estimated to affect up to 6% of women of reproductive age. Maternity care represents an opportunity for early diagnosis but there is limited understanding of chronic kidney disease aetiology occurring in or revealed by pregnancy. METHODS: A retrospective evaluation of renal biopsies during and after pregnancy between 2000 and 2015 was undertaken. A large academic health centre pathology database was searched for free text pregnancy-related terms, restricted to typology code 71000 (kidney). Indications and findings of postpartum renal biopsies were reviewed. RESULTS: Sixty-three renal biopsy reports were identified. Of 45 biopsies performed postpartum, 34 (75.6%) investigated persistent postpartum proteinuria. 20/34 (70.6%) of these biopsies yielded a primary renal disease, and 6/34 (17.6%) women had progressed to end stage renal disease at latest follow-up. CONCLUSION: Renal biopsy findings of women investigated for persistent postpartum proteinuria revealed a high incidence of histological diagnosis of de novo renal disease.

Detection of additional abnormalities or co-morbidities in women with suspected intrahepatic cholestasis of pregnancy.

BACKGROUND: Current guidelines recommend viral, autoimmune, coagulation and liver ultrasound testing in intrahepatic cholestasis of pregnancy to exclude alternative diagnoses. METHODS: Electronic health records were searched for investigations and diagnoses in women with raised bile acid concentrations (>10 µmol/L) between January 2016 and December 2017 at two UK maternity units. RESULTS: Five hundred and thirty-one women had a raised bile acid concentration (median (IQR): 18 (13-32 µmol/L)) at a median gestation of 35.1 (IQR 31.8-37.0) weeks. Out of 531 women, 250 (47.1%) had full virology, autoimmune and ultrasound tests, and 348 (65.5%) had coagulation performed. Positive hepatitis B and C results were previously known. No new Epstein-Barr virus, cytomegalovirus or hepatitis A diagnoses were made. There were 11 positive autoimmune results, but no new diagnoses. No woman had an unexplained prolonged prothrombin time. No ultrasound liver (n = 38) or gallbladder (n = 85) abnormalities were of acute clinical significance. CONCLUSION: Intrahepatic cholestasis of pregnancy investigations provided no new diagnoses that influenced clinical management during pregnancy.

Acute kidney injury in pregnancy including renal disease diagnosed in pregnancy.

Pregnancy-related acute kidney injury (AKI) is a rare but serious complication in high-income settings and remains an important cause of maternal and foetal morbidity and mortality in low- and middle-income settings. Hypertensive disorders of pregnancy are the leading cause of pregnancy-related AKI worldwide. In this article, we outline the epidemiology, aetiology, recognition, investigation and management of pregnancy-related AKI. Difficulties in the definition of AKI, approaches to determine the cause of AKI in diagnostically challenging circumstances and diagnosis of new renal disease in pregnancy are discussed.

Markers of maternal cardiac dysfunction in pre-eclampsia and superimposed pre-eclampsia.

AUTHORS: Frances Conti-Ramsden MBBS Academic Clinical Fellow1, Carolyn Gill PhD BRC Research Assistant1, Paul T Seed MSc CStat Senior Lecturer in Medical Statistics1, Kate Bramham PhD Clinical Senior Lecturer in Nephrology2, Lucy C Chappell PhD NIHR Research Professor in Obstetrics1, Fergus P McCarthy PhD Clinical Senior Lecturer in Obstetrics and Gynaecology1,3. OBJECTIVES: To determine whether glycogen phosphorylase isoenzyme B (GPBB) and/or brain natriuretic peptide (BNP) concentrations are elevated in pre-eclampsia and superimposed pre-eclampsia (SPE), demonstrating cardiac ischaemia and strain. STUDY DESIGN: A nested case-control study was performed using samples and clinical data available from a prospective pregnancy cohort. Four groups were selected: healthy pregnant controls (n = 21), pre-eclampsia (n = 19), pre-existing chronic hypertension (CHT) and/or chronic kidney disease (CKD) without (n = 20) or with superimposed pre-eclampsia (SPE) (n = 19). Plasma samples were taken at time of disease or the third trimester in controls. MAIN OUTCOME MEASURES: Plasma concentrations of GPBB and BNP. RESULTS: There was no significant difference in GPBB plasma concentrations between controls and pre-eclampsia (geometric mean (GM) [95% CI]: 4.74 [2.54-8.84]ng/mL vs 5.01 [2.58-9.74]ng/mL, p = 0.90)), or between CHT and/or CKD and SPE (GM [95% CI]: 9.49 [4.93-18.25]ng/mL vs 10.24 [5.27-19.92]ng/mL, p = 0.87). BNP plasma concentrations were significantly raised in women with pre-eclampsia compared to controls (GM [95% CI]: 31.83 [20.18-50.22]pg/mL vs 11.33 [7.34-17.51]pg/mL, p = 0.001). Women with CKD, but not CHT, who developed SPE had elevated BNP concentrations. There were no significant differences in BNP concentration between women with comorbidity (CHT and/or CKD) and controls. CONCLUSIONS: GPBB has a limited role as a biomarker in hypertensive disorders of pregnancy. BNP concentrations were elevated in pre-eclampsia compared to controls. This suggests cardiac strain at the time of pre-eclampsia. Further studies are needed to examine whether BNP can identify women at increased risk of cardiovascular disease.

Pregnancy-Related Acute Kidney Injury in Preeclampsia: Risk Factors and Renal Outcomes.

Preeclampsia is a common cause of acute kidney injury (AKI) in low- and middle-income countries, but AKI incidence in preeclampsia, its risk factors, and renal outcomes are unknown. A prospective observational multicenter study of women admitted with preeclampsia in South Africa was conducted. Creatinine concentrations were extracted from national laboratory databases for women with maximum creatinine of ≥90 µmol/L (≥1.02 mg/dL). Renal injury and recovery were defined by Kidney Disease Improving Global Outcomes creatinine criteria. Predefined risk factors, maternal outcomes, and neonatal outcomes were compared between AKI stages. Of 1547 women admitted with preeclampsia 237 (15.3%) met AKI criteria: 6.9% (n=107) stage 1, 4.3% (n=67) stage 2, and 4.1% (n=63) stage 3. There was a higher risk of maternal death (n=7; relative risk, 4.3; 95% CI, 1.6-11.4) and stillbirth (n=80; relative risk, 2.2; 95% CI, 1.8-2.8) in women with AKI compared with those without. Perinatal mortality was also increased (89 of 240; 37.1%). Hypertension in a previous pregnancy was the strongest predictor of AKI stage 2 or 3 (odds ratio, 2.24; 95% CI, 1.21-4.17). Renal recovery rate reduced with increasing AKI stage. A third of surviving women (76 of 230 [33.0%]) had not recovered baseline renal function by discharge. Approximately half (39 of 76; 51.3%) of these women had no further creatinine testing post-discharge. In summary, AKI was common in women with preeclampsia and had high rates of associated maternal and perinatal mortality. Only two-thirds of women had confirmed renal recovery. History of a previous hypertensive pregnancy was an important risk factor.

Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia.

The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped into three datasets for assessing the primary external, and temporal validity, and broader transportability of the model. The predicted risks of developing an adverse maternal outcome were calculated using the model equation and model performance was evaluated based on discrimination, calibration, and stratification. Our study included a total of 2429 women, with an adverse maternal outcome rate of 6.7%, 6.6%, and 7.0% in the primary external, temporal, and combined (broader) validation cohorts, respectively. The model had good discrimination in all datasets: 0.81 (95%CI 0.75-0.86), 0.82 (95%CI 0.76-0.87), and 0.75 (95%CI 0.71-0.80) for the primary external, temporal, and broader validation datasets, respectively. Calibration was best for the temporal cohort but poor in the broader validation dataset. The likelihood ratios estimated to rule in adverse maternal outcomes were high at a cut-off of ≥30% in all datasets. The fullPIERS model is temporally and externally valid and will be useful in the management of women with pre-eclampsia in high income settings although model recalibration is required to improve performance, specifically in the broader healthcare settings.

Maternal and perinatal adverse outcomes in women with pre-eclampsia cared for at facility-level in South Africa: a prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy contribute to 14% of all maternal deaths, the majority of which occur in low- and middle-income countries. The aim of the study was to describe the maternal and perinatal clinical outcomes of women with pre-eclampsia living in middle- and low-income countries. METHODS: The study was a prospective observational study of women with pre-eclampsia (n = 1547, 42 twin pregnancies) at three South African tertiary facilities. Using stepwise logistic regression model area under the receiver operating characteristic curve (AUROC) values, the association between maternal baseline and admission characteristics and risk of adverse outcomes was evaluated. Main outcome measures were eclampsia, kidney injury and perinatal death. RESULTS: In 1547 women with pre-eclampsia, 16 (1%) died, 147 (9.5%) had eclampsia, four (0.3%) had a stroke and 272 (17.6%) had kidney injury. Of the 1589 births, there were 332 (21.0%) perinatal deaths; of these, 281 (84.5%) were stillbirths. Of 1308 live births, 913 (70.0%) delivered <37 completed weeks and 544 (41.7%) delivered <34 weeks' gestation. Young maternal age (AUROC = 0.76, 95% confidence interval (CI) = 0.71-0.80) and low Body Mass Index BMI (AUROC 0.65, 95% CI = 0.59-0.69) were significant predictors of eclampsia. Highest systolic blood pressure had the strongest association with kidney injury, (AUROC = 0.64, 95% CI = 0.60-0.68). Early gestation at admission was most strongly associated with perinatal death (AUROC = 0.81, 95% CI = 0.77-0.84). CONCLUSIONS: The incidence of pre-eclampsia complications, perinatal death and preterm delivery in women referred to tertiary care in South Africa was much higher than reported in other low- and middle-income studies and despite access to tertiary care interventions. Teenage mothers and those with low BMI were at highest risk of eclampsia. This information could be used to inform guidelines, the research agenda and policy.

Impact of Antihypertensive Treatment on Maternal and Perinatal Outcomes in Pregnancy Complicated by Chronic Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic hypertension complicates around 3% of all pregnancies. There is evidence that treating severe hypertension reduces maternal morbidity. This study aimed to systematically review randomized controlled trials of antihypertensive agents treating chronic hypertension in pregnancy to determine the effect of this intervention. METHODS AND RESULTS: Medline (via OVID), Embase (via OVID) and the Cochrane Trials Register were searched from their earliest entries until November 30, 2016. All randomized controlled trials evaluating antihypertensive treatments for chronic hypertension in pregnancy were included. Data were extracted and analyzed in Stata (version 14.1). Fifteen randomized controlled trials (1166 women) were identified for meta-analysis. A clinically important reduction in the incidence of severe hypertension was seen with antihypertensive treatment versus no antihypertensive treatment/placebo (5 studies, 446 women; risk ratio 0.33, 95%CI 0.19-0.56; I2 0.0%). There was no difference in the incidence of superimposed pre-eclampsia (7 studies, 727 women; risk ratio 0.74, 95%CI 0.49-1.11; I2 28.1%), stillbirth/neonatal death (4 studies, 667 women; risk ratio 0.37, 95%CI 0.11-1.26; I2 0.0%), birth weight (7 studies, 802 women; weighted mean difference -60 g, 95%CI -200 to 80 g; I2 0.0%), or small for gestational age (4 studies, 369 women; risk ratio 1.01, 95%CI 0.53-1.94; I2 0.0%) with antihypertensive treatment versus no treatment/placebo. CONCLUSIONS: Antihypertensive treatment reduces the risk of severe hypertension in pregnant women with chronic hypertension. A considerable paucity of data exists to guide choice of antihypertensive agent. Adequately powered head-to-head randomized controlled trials of commonly used antihypertensive agents are required to inform prescribing.