Research letterTesting the broad definition of pre-eclampsia: should chronic hypertension with fetal growth restriction be included?AuthorsPeter von Dadelszen 1Terry Lee 2Joel Singer 2Laura A Magee 1For the CHIPS Study GroupAffiliationsDepartment of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, London, UKSchool of Population and Public Health, University of British Columbia, Vancouver, BC, CanadaCorresponding author:Professor Laura Magee, 6th Floor, Addison House, Guy’s Campus, Great Maze Pond, London SE1 1UL, UK; email: laura.a.magee@kcl.ac.ukIntroductionHistorically, pre-eclampsia was defined as proteinuric gestational hypertension or that superimposed on chronic hypertension. The 2021 International Society for the Study of Hypertension in Pregnancy (ISSHP) guidelines updated the broad definition of pre-eclampsia (1). One controversy has been whether women with chronic hypertension whose pregnancies are complicated by fetal growth restriction (FGR) fulfil a clinically-relevant definition of pre-eclampsia, or whether FGR is solely a complication of chronic hypertension and not a useful criterion. Therefore, we examined Control of Hypertension in Pregnancy Study (CHIPS) trial data (2) to determine whether or not including pregnant women living with chronic hypertension whose pregnancies are complicated by small-for-gestational age (SGA) infants are at increased risks of adverse perinatal and, in particular, maternal events, compared with women with chronic hypertension who give birth to babies with birthweights at or above the 10th percentile for gestational age.MethodsThis was a secondary analysis limited to those women with chronic hypertension who participated in the international CHIPS trial (2). Women were included if they had non-severe, non-proteinuric pre-existing/chronic hypertension; a diastolic blood pressure (dBP) of 90 to 105 mmHg if they were not receiving antihypertensive therapy, or 85 to 105 mmHg if they were receiving such treatment; and a live singleton fetus at 14+0 weeks to 33+6 weeks of gestation (determined in most cases by early pregnancy ultrasound examination). Chronic hypertension was defined as dBP ≥90 mmHg before pregnancy or at randomised to ‘tight’ (target diastolic BP = 85 mmHg) vs less tight’ (target dBP = 100 mmHg) control. To be conservative, infants who were SGA, defined as birthweight <10th percentile for sex and gestational age (3), were selected as a surrogate for FGR, recognising that ≈50% of SGA infants are growth-restricted due to placental dysfunction (4). We compared the rates of the CHIPS trial outcomes between women who gave birth to infants who were SGA, compared with those with birthweights ≥10th percentile, using logistic regression. A p<0.05 was considered statistical significance (SAS 9.4, SAS Institute Inc., Cary, NC).Results987 women participated in the CHIPS trial, of whom 727 women had chronic hypertension and known birthweights and gestational age at birth; 122/727 (16.8%) gave birth to SGA infants (Table). Recruited women were generally in their 30s, parous, and recruited during the second trimester. Women who gave birth to SGA infants were slightly older, less frequently overweight or obese, and more frequently randomised to ‘tight’ control (Table). Women with chronic hypertension complicated by SGA (vs those without SGA) more frequently experienced episodes of severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg), new proteinuria (≥300 mg/24h; protein-to-creatinine ratio ≥30 mg/mL; ≥ ++ dipstick proteinuria), pre-eclampsia (defined as either proteinuric hypertension or chronic hypertension with symptoms, signs, and/or abnormal laboratory tests of pre-eclampsia), preterm birth (<34+0 weeks or stillbirth specifically), receipt of high-level neonatal care ≥48 hours, or pregnancy loss or receipt of high-level neonatal care ≥48 hours; however, symptoms of pre-eclampsia and serious maternal complications did not differ (Table).ConclusionsThe data from this secondary analysis of the CHIPS trial support the inclusion of FGR as a diagnostic criterion for pre-eclampsia in women whose pregnancies are complicated by chronic hypertension (1), as such women were more likely to experience episodes of severe maternal hypertension and to evolve into pre-eclampsia, as defined contemporaneously. Severe maternal hypertension, especially severe systolic hypertension, is a surrogate for stroke risk (5). That adverse perinatal events were more common in women who gave birth to SGA infants was unsurprising.References1. Magee LA, Brown MA, Hall DR, Gupte S, Hennessy A, Karumanchi SA, et al. The hypertensive disorders of pregnancy: the 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis and management recommendations for international practice. Pregnancy Hypertens. 2022;27:148-69.2. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med. 2015;372(5):407-17.3. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001;108(2):E35.4. Benton SJ, McCowan LM, Heazell AE, Grynspan D, Hutcheon JA, Senger C, et al. Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction. Placenta. 2016;42:1-8.5. Martin JN, Jr., Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol. 2005;105(2):246-54.Table: Characteristics and effect of small-for-gestational birthweight on outcomes in pregnant women with chronic hypertension (n (%) or mean (standard deviation))