Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

Abstract

Background: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors.

Objective: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality.

Study design: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21^st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions.

Results: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios.

Conclusion: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Keywords: SARS-CoV 2; aspirin; cohort; gestational hypertension; hypertension; hypertensive disorders in pregnancy; infection; morbidity; mortality; obesity; overweight; preeclampsia; pregnancy; preterm birth; proteinuria; relative risk; renal disease; risk ratio; small for gestational age.

Figure 1

Kaplan-Meier curves For gestational age at diagnosis of COVID-19, stratified by preeclampsia status during pregnancy. Blue represents no preeclampsia; red represents preeclampsia. Cox model hazard ratio, 1.49 (95% CI, 1.12–1.97). One woman was diagnosed with COVID-19 at ≤13 weeks’ gestation; 34 were diagnosed from >13 to ≤26 weeks’ gestation; 636 were diagnosed at >26 weeks’ gestation; for 35 women the information about the gestational age at diagnosis was not available. Papageorghiou et al. Preeclampsia and COVID-19. Am J Obstet Gynecol 2021.

Figure 2

Kaplan-Meier curves A, For gestational age at delivery, stratified by preeclampsia and COVID-19 diagnosis and (B) for gestational age at spontaneous birth, treating medically-indicated births as censored; the spontaneous preterm birth rate was 4.4%. Blue represents no preeclampsia and no COVID-19 diagnosis; red represents no preeclampsia with a COVID-19 diagnosis; green represents preeclampsia without a COVID-19 diagnosis; orange represents preeclampsia with a COVID-19 diagnosis. Papageorghiou et al. Preeclampsia and COVID-19. Am J Obstet Gynecol 2021.

Supplemental Figure

Kaplan-Meier curves For gestational age at delivery, stratified by gestational hypertension (GH) and COVID-19 diagnosis. The blue curve indicates no GH, no COVID-19 diagnosis; the red curve indicates no GH with COVID-19 diagnosis; the green curve indicates GH, no COVID-19 diagnosis; and the orange curve indicates GH with COVID-19 diagnosis. Papageorghiou et al. Preeclampsia and COVID-19. Am J Obstet Gynecol 2021.