Authors: Helen Woolcock (1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York), Natalia Parra (1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York), Yijia Zhang (1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York), Uma M. Reddy (1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York), Natalie A. Bello (2Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California), Eliza Miller (3Department of Neurology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York), Whitney A. Booker (1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York)
Categories: Article, blood pressure, chronic hypertension, adverse pregnancy outcomes, preeclampsia, hypertension, American College of Cardiology, American Heart Association
Source: American journal of perinatology
Doi: 10.1055/a-2298-5347
Authors: Helen Woolcock, Natalia Parra, Yijia Zhang, Uma M. Reddy, Natalie A. Bello, Eliza Miller, Whitney A. Booker
The American College of Obstetrics threshold for hypertension (≥140/90 mm Hg) differs from those of the American College of Cardiology (ACC) and the American Heart Association (AHA). It is unknown if ACC/AHA hypertension levels are associated with adverse pregnancy outcomes (APOs) after 20 weeks gestation. The purpose of this study is to analyze APOs in women with blood pressure (BP) in the elevated or stage 1 range after 20 weeks gestation.
This was a secondary analysis of the nuMoM2b prospective cohort study of 10,038 nulliparous, singleton pregnancies between 2010 and 2014. BP was measured at three visits during the pregnancy using a standard protocol. Women without medical comorbidities, with normal BP by ACC/AHA guidelines (systolic BP [SBP] < 120 and diastolic BP [DBP] < 80 mm Hg) up to 22 weeks, were included. Exposure was BP between 22 and 29 weeks normal (SBP < 120 and DBP < 80 mm Hg), elevated (SBP: 120–129 and DBP < 80 mm Hg), and stage 1 (SBP: 130–139 or DBP: 80–89 mm Hg). The primary outcome was hypertensive disorder of pregnancy (HDP) at delivery. Secondary outcomes included fetal growth restriction (FGR), placental abruption, preterm delivery, and cesarean delivery. Multivariable-adjusted odds ratio (aORs) and 95% confidence intervals (CIs) were estimated using logistic regression models.
Of 4,460 patients that met inclusion criteria, 3,832 (85.9%) had BP in the normal range, 408 (9.1%) in elevated, and 220 (4.9%) in stage 1 range between 22 and 29 weeks. The likelihood of HDP was significantly higher in women with elevated BP (aOR 1.71, 95%CI: 1.18,2.48), and stage 1 BP (aOR: 2.79, 95%CI: 1.84,4.23) compared to normal BP (p< 0.001). Stage 1 BP had twice odds of FGR (aOR: 2.33, 95%CI: 1.22,4.47) and elevated BP had three times odds of placental abruption (aOR: 3.03; 95%CI: 1.24,7.39).
Elevated or stage 1 BP >20 weeks of pregnancy are associated with HDP, FGR, and placental abruption.
According to the American College of Obstetricians and Gynecologists (ACOG), the current standard diagnostic criteria for hypertension during pregnancy includes a systolic blood (pressure (SBP) of ≥140mm Hg, a diastolic blood pressure (DBP) of ≥90 mm Hg, or both.^1^ In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) recommended lowering blood pressure (BP) thresholds to redefine chronic hypertension in nonpregnant adults. “Elevated BP” is now defined as SBP 120–129mm Hg and DBP < 80 mm Hg and “stage 1 hypertension” is defined as SBP 130–139mm Hg or DBP 80–89mm Hg.^2^ These recommendations were modified based on the findings of an increased risk of cardiovascular morbidity and mortality seen in adults at lower BP thresholds.^3^ As a result, these new guidelines have increased the prevalence of hypertension in women of reproductive age and the prevalence of any hypertensive disorder of pregnancy (HDP).^4,5^
Chronic hypertension in pregnancy has previously been defined as hypertension diagnosed before pregnancy or before 20 weeks gestation.^1^The prevalence of chronic hypertension in pregnancy, using ACOG diagnostic criteria, in the US was reported to be 2.21% in 2019 and continues to increase.^6^ In comparison to normotensive pregnant individuals, those with chronic hypertension have increased maternal mortality and are at an increased risk for adverse pregnancy outcomes (APOs) including preeclampsia, placental abruption, fetal growth restriction (FGR) and perinatal mortality.^7–9^ Previous studies have investigated whether lower BP thresholds to define chronic hypertension in pregnancy are associated with adverse maternal and neonatal outcomes. These studies consistently found that patients with elevated or stage 1 range BP prior to 20 weeks gestation are at an increased risk of adverse maternal and neonatal outcomes.^10–14^
Few studies have assessed maternal and fetal outcomes in patients with hypertension diagnosed after 20 weeks gestation. BP during pregnancy is dynamic and typically reaches a nadir at 20 weeks gestation, then increases until delivery.^15^ However, it is unknown whether the absence of this mid-trimester drop in BP, or an increase in BP levels to the elevated and stage 1 range after 20 weeks gestation, place women at an increased risk for APOs.^16–20^
We aimed to determine whether previously normotensive women who developed elevated or stage 1 range BP after 20 weeks gestation have an increased risk of APOs including HDP, FGR, placental abruption, cesarean section, and preterm delivery.
This was a secondary analysis of data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b), a prospective cohort study designed to identify factors that contribute to preterm birth and other APOs.^21^ The nuMoM2b study took place from October 2010 to September 2013, and included 10,038 first-time pregnant women from one of eight academic medical centers in the United States (Case Western Reserve University, Columbia University, Indiana University, University of Pittsburgh, Northwestern University, University of California Irvine, University of Pennsylvania and University of Utah). NuMoM2b study methods have been previously described and published.^21^ Briefly, eligible women had a viable singleton pregnancy less than 14 weeks gestation that was confirmed by ultrasound. Women with a prior pregnancy of more than 20 weeks gestation were excluded. Additional exclusion criteria included maternal age younger than 13 years, history of three or more spontaneous abortions, current pregnancy complicated by a fatal fetal malformation, known fetal aneuploidy, assisted reproduction with a donor oocyte, multifetal reduction or plans to terminate the pregnancy. Four study visits were scheduled throughout the participant’s visit 1 (6 weeks-13 weeks and 6 days), visit 2 (16 weeks-21 weeks and 6 days), visit 3 (22 weeks-29 weeks and 6 days), visit 4 (time of birth). BP was measured with an aneroid sphygmomanometer at each of the visits by trained and credentialed staff, following a common protocol and manual of operations.^21,22^ Participants were allowed 10 minutes to rest in a comfortable position prior to the BP measurement. Study personnel measured the arm circumference to select an appropriate cuff size from multiple options available. Arm length was also measured to identify the midpoint on the dorsal aspect of the arm for cuff placement. Study subjects were instructed to sit with legs uncrossed in a chair with appropriate arm support, such that the cubital fossa was resting at heart level (at the 4^th^ intercostal space). BP was measured three times and the average of the second and third measurements was used for all analyses.
For this analysis, we excluded women with medical conditions that are independently associated with risk for APOs at delivery. These included all of the following medical hypertension at visit 1 or 2, asthma, seizures, pre-gestational diabetes, structural or valvular heart disease, coronary artery disease, cardiac arrythmias, kidney disease, sickle cell, lupus, rheumatoid arthritis, or hyperthyroidism. The final cohort included all subjects whose BP was normal by ACC/AHA definitions during visit 1 and visit 2, up to 21 weeks, 6 days gestation (►Figure 1). Exposure groups were then defined by the visit 3 BP (which were measured between 22 and 29 weeks gestation) with readings in visit 3 as being 1) normal (SBP < 120 mm Hg and DBP <80 mm Hg), 2) elevated (SBP 120–129 mm Hg and DBP <80 mm Hg) or 3) stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg). The primary outcome was a diagnosis of HDP that was diagnosed any time after visit 3 until delivery hospitalization. HDP included gestational hypertension and preeclampsia with and without severe features. HDP were defined and diagnosed according to American College of Gynecology and Obstetrics (ACOG) guidelines.^23^ Secondary outcomes included FGR (defined as an estimated fetal weight that is less than the 10th percentile for gestational age^24^), placental abruption, preterm birth (defined as delivery between 20 weeks 0 days gestation and 36 weeks 6 days gestation^25^) and cesarean delivery. Diagnoses and outcomes were adjudicated from medical record abstraction by investigators trained in Maternal Fetal Medicine or Obstetrics and Gynecology. Written informed consent was collected from each participant in the nuMoM2b study at the time of study enrollment. Approval for this analysis was obtained from the institutional review board at Columbia University.
Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Bivariate tests of association between hypertensive groups and maternal characteristics were employed, using chi-square for categorical variables and ANOVA for continuous variables. To evaluate the relationship between BP status with adverse outcomes such as HDP, FGR, placental abruption, preterm delivery, and cesarean delivery, we employed multivariable logistic regression analysis.
Covariates were selected as factors that are associated with an increased risk of APOs. Covariates include maternal age, pre-pregnancy body mass index (BMI), race, and ethnicity. Maternal age was categorized as <35 and ≥35 years because advanced maternal age is associated with an increased risk of HDP and other APOs.^26,27^ Pre-pregnancy BMI was calculated from weight recorded at the first study visit, given that this measurement is a valid surrogate for prepregnancy BMI.^28^ Finally, self-identified race and ethnicity were included as covariates because of the evident racial disparities in which there is an increased risk of morbidity and mortality associated with APOs, particularly in non-Hispanic Black women.^29–31^ Results are reported as unadjusted (OR) and adjusted odds ratios (aOR) with corresponding 95% confidence intervals (CI). A significance level of p < .05 was used to determine statistical significance.
Of the 10,038 subjects in the original nuMoM2b cohort, 4,460 met our study inclusion criteria (►Figure 1). Of these, 3,832 (85.9%) had BP in the normal range, 408 (9.1%) in the elevated BP range, and 220 (4.9%) in the stage 1 hypertension range within visit 3 (22–29 weeks gestation). Demographics and characteristics of the study population are shown in ►Table 1. Age and gestational diabetes were similar whereas maternal race or ethnicity and BMI differed across exposure more self-identified White and fewer self-identified Hispanic participants had elevated or stage 1 BP range (p = 0.009), and there was a higher proportion of overweight and obesity in the groups with elevated and stage 1 BP range (p < 0.001).
The proportion of participants with any HDP at delivery was significantly higher in women with BP at 22–29 weeks gestational age in the elevated BP range (9.5%) and stage 1 group (14.9%) compared to those in the normal range (5.0%, p < 0.001) (►Table 2, ►Figure 2). The odds of any HDP at delivery was higher in subjects with elevated BP (OR 2.01; 95% CI 1.40, 2.90) and stage 1 BP (OR 3.35; 95% CI 2.24, 5.01) compared with normal range BP (►Table 3). After adjusting for maternal age, pre-pregnancy BMI, race, and ethnicity, the risk of HDP remained elevated for both elevated BP (aOR 1.71; 95% CI 1.18, 2.48) and stage 1 BP (aOR 2.79; 95% CI 1.84, 4.23) (►Table 3). As seen in ►Table 3, the adjusted odds of preeclampsia remained significantly higher in the elevated BP group only (aOR 2.37; 95% CI 1.07, 5.22) although the direction of the effect was similar for the stage 1 BP group (aOR 1.87, 95% CI 0.76, 4.63).
The proportion of participants with placental abruption was also significantly higher in the elevated and stage 1 groups [0.6% in the normotensive group, 1.8% in the elevated BP, and 1.4% in the stage 1 BP group (p =0.012)] (►Table 2, ►Figure 2). There was a significantly increased odds of placental abruption in the elevated BP group (aOR 3.03; 95% CI 1.24, 7.39) (►Table 3). Similarly, the proportion of participants with FGR was significantly different between normotensive patients and patients with elevated and stage 1 BPs [(2.6% in the normotensive group, 1.0% in elevated group and 5.1% in the stage 1 group (p = 0.009)]. The adjusted odds of FGR were significantly higher in the stage 1 BP group (aOR 2.33; 1.22, 4.47) (►Table 3).
In this secondary analysis of a large prospective cohort study of 4,460 nulliparous women, we found that previously normotensive pregnant women with elevated BP between 22 to 29 weeks gestation have about 2 times higher odds of developing HDP at delivery and those with stage 1 BP between 22 to 29 weeks gestation have almost 3 times higher odds of developing HDP at delivery, compared to normotensive patients. In addition, we found a threefold increased odds of placental abruption in women with elevated BP and a doubled increased odds of FGR in women with stage 1 range BP.
Our data indicate that there is an increased odds of having a diagnosis of HDP at delivery in patients with elevated or stage 1 range BP between 22 to 29 weeks gestation, compared with women who are normotensive at that time. These results align with those of a retrospective cohort study of 2,090 that found that pregnant patients with new-onset BP elevations of SBP 130–139 or DBP 80–89 mm Hg after 20 weeks gestation are at more than double the risk for developing an HDP at admission or during delivery relative to “normotensive” patients, defined as having a maximum BP < 130/80 after 20 weeks gestation (aRR 2.41; 95% CI 2.02, 2.85).^16^ Similarly, another retrospective cohort study of 377 found that patients with prehypertension (BP of 120–139 SBP or 80–89 DBP mm Hg) were at an increased risk for pregnancy related hypertension (gestational hypertension, severe gestational hypertension, preeclampsia or preeclampsia with severe features) compared to normotensive patients (OR 4.3; 95% CI 1.2, 15.46).^32^ However, these studies used different binarized thresholds to define “normotensive” and failed to elucidate the risks between the three groups of normotensive, elevated, and stage 1 BP as defined by the ACC/AHA.
Our study highlights that the risk of HDP extends to those with elevated BP, a range that would typically be defined as normal by current obstetric standards. To our knowledge, no study has compared HDP outcomes between these three groups. Within the various HDP outcomes, we found that there is over double the odds of preeclampsia even in the elevated BP group, compared to the normotensive group. It has been shown that women with gestational hypertension according to ACOG criteria who were reclassified as having chronic hypertension under the ACC/AHA criteria threshold of SBP ≥ 130 and/or DBP ≥ 80 mm Hg had the highest rate of preeclampsia, compared to women who were always normotensive.^5^ However, our study findings suggest that this risk is still prevalent in normotensive patients who develop hypertension by ACC/AHA criteria only after 20 weeks gestation. This aligns with the findings of a large retrospective cohort study, which found over double the risk of preeclampsia in patients with elevated BP after 20 weeks gestation in comparison to normotensive patients.^33^ On a physiological level, these findings of increased HDP risk in patients with elevated BP after 20 weeks gestation suggest that vascular remodeling and endothelial dysfunction may be occurring in these patients as compared to their normotensive equivalents.^34,35^
Our data also demonstrated that women with elevated BP between 22–29 weeks gestation had a threefold increased risk of placental abruption. Placental abruption is a highly morbid event associated with stillbirth, neonatal death, and maternal mortality.^36^ It is also highly associated with chronic hypertension and preeclampsia.^37^ One recent study found a strong association between placental abruption and hypertension (defined as ≥ 140/90 mm Hg) in pregnant women after 20 weeks gestation. ^38^ Our findings suggest that even mild BP elevations after 20 weeks gestation may severely impact maternal and neonatal morbidity and mortality. However, there is much unknown about the association between placental abruption and hypertension, as defined by the ACC/AHA, after 20 weeks gestation.
Hypertension is also highly associated with small for gestational age neonates.^39^ We found that pregnant patients with stage 1 range BP between 22 to 29 weeks gestation had over double the increased risk of FGR. Abnormal perfusion of the placenta is a possible mechanism to explain this increased risk of growth restriction, particularly in those with preeclampsia, given that this disorder is thought to be partly due to abnormal placentation.^40^ Our findings support the available literature that stage 1 range BP are associated with decreased fetal growth; however, the effects of elevated BP on fetal growth are not fully known.^18,41,42^ Additionally, our data demonstrated that BP in the elevated range are not associated with FGR. This aligns with a large retrospective cohort study in China which found no significantly increased risk of FGR in patients with new-onset elevated BP after 20 weeks gestation (defined as SBP 120–129 mm Hg and DBP < 80 mm Hg).^17^ Further studies are needed to better understand the pathophysiology of de novo second trimester elevated BPs and if targeting a therapeutic BP to the range of 120–129 mm Hg affects fetal growth.
While guidelines for treatment of hypertension in non-pregnant adults are well established, uncertainty remains regarding treatment of hypertension during pregnancy.^1,2,43,44^ The recent multicenter randomized CHAP (Chronic Hypertension and Pregnancy) trial found that targeting a BP of less than 140 and/or 90 mm Hg (rather than treating once patients reach SBP of 160 or DBP of 105 mm Hg) in chronically hypertensive women resulted in improved pregnancy outcomes, including decreased risk of preeclampsia with severe features, preterm birth, placental abruption, or fetal or neonatal death. Interestingly, they also reported no increased risk of neonates with small-for-gestational-age birth weights.^45^ In response, the Society for Maternal-Fetal Medicine and ACOG recommended a threshold of 140 SBP or 90 DBP mm Hg for initiation or titration of medical therapy for chronic hypertension in pregnancy.^46^ Of note, these recommendations apply to chronically hypertensive pregnant patients (diagnosed prior to 20 weeks gestation), while our study focuses on hypertension after 20 weeks gestation. With our findings of increased risk of APOs at time of delivery in women who have no history of chronic hypertension and are normotensive prior to 20 weeks gestation, a better understanding is needed of whether there is a need to treat mid-trimester elevated and/or stage 1 range BP to avoid such complications.
The rationale behind lowering the threshold for treatment of hypertension in pregnancy is to mitigate the risks associated with such high BP readings. At the same time, we also inherently lower the diagnostic threshold for the definitions of chronic and gestational hypertension. A recent meta-analysis investigated the strength of association between BP groups as defined by the ACC/AHA and adverse outcomes, as well as the diagnostic value of these BP cutoffs.^47^ They included 12 studies in their analysis and, while they concluded that BP cutoffs lower than SBP 140 and/or DBP 90 mm Hg after 20 weeks gestation would not assist clinicians in identifying women and neonates at risk, their data showed that, in fact, they had small to moderate increases in the likelihood of adverse outcomes such as preeclampsia, eclampsia, stroke, maternal death, and stillbirth. This indicates that there continues to be an increased risk and likelihood of many adverse maternal and neonatal outcomes in BP ranges lower than the established 140/90 mm Hg.
Strengths of our study include its prospective study design and diverse group of participants, with a larger percentage of Hispanic participants than other studies.^16–18,20,33^ Our pregnancy outcomes were adjudicated, which provided us with reliable outcome data. Furthermore, we stratified patients according to the current ACC/AHA guidelines, unlike most studies that defined normotensive as any BP under 130 mm Hg SBP or 80 mm Hg DBP. Of the other studies that assessed maternal and fetal outcomes in patients with hypertension after 20 weeks gestation, over half based their findings on a single BP measurement and a third used non-standardized BP measurements.^47^ This contrasts with our study, as we utilized a standardized BP measurement protocol to record BP from three different visits. Furthermore, the visit 3 BP used to group subjects into their respective BP categories was not a single BP reading, but the average of the last two BP readings taken at the visit, out of three.
Our study is limited in that we were unable to determine baseline nonpregnant BP for the study participants, as prepregnancy BP was not a part of the study design. As such, we only included participants who had been previously normotensive (BP less than SBP 120 / DBP 80 mm Hg) in visit studies 1 and 2 prior to 22 weeks gestation. Our study was also under-powered for certain outcome groups, such as FGR and placental abruption. It is also possible that this prospective cohort study suffered from selection bias patients who were more likely to return to their visits may have been healthier or had higher health literacy levels. Finally, unmeasured confounders may have introduced bias.
In conclusion, in women with no history of hypertension and who begin pregnancy with normal BP, a slight increase in SBP and DBP in the second half of pregnancy confers an increased risk for maternal and neonatal complications. Using the ACC/AHA criteria for defining hypertension, our data demonstrated that previously normotensive women who then developed elevated and/or stage 1 range BP between 22 and 29 weeks of pregnancy had a significantly increased odds of HDP, FGR, and placental abruption. Our findings suggest that lower diagnostic and treatment BP thresholds might be warranted in pregnant patients. Future studies should continue to investigate optimal BP based on maternal and neonatal outcomes and whether treatment at lower BP thresholds would improve maternal and neonatal outcomes.