The American College of Cardiology and the American Heart Association Task Force on Clinical Practice guidelines revised the criteria for diagnosis of hypertension in adults in 2017, recommending a downward shift in hypertension classification criteria.1 Adults who previously would have been diagnosed with prehypertension are now divided into two categories: elevated blood pressure (BP) (systolic BP 120–129 mm Hg and diastolic BP less than 80 mm Hg) or stage 1 hypertension (systolic BP 130–139 mm Hg or diastolic BP 80–89 mm Hg). Blood pressure higher than this range is now considered stage 2 hypertension (systolic BP 140 mm Hg or higher or diastolic BP 90 mm Hg or higher). This new classification of BP was supported by evidence that modest elevations in BP among adult men and nonpregnant adult women increase risk for cardiovascular disease and was designed to encourage clinicians to counsel and intervene early in the life course to improve cardiovascular health.2 Although the evidence supporting the 2017 guidelines was primarily derived from older adult populations, recent evidence suggests that young men and women with elevated BP or stage 1 hypertension by the 2017 American College of Cardiology and American Heart Association guidelines have a higher risk of subsequent cardiovascular events than normotensive young adults.3
The implications of these new criteria for reproductive-age women are unclear. The prevalence of hypertension in young adult women (20–44 years old) increased from 10% to 19% with application of the current hypertension guidelines compared with the former criteria.1 Therefore, more women will enter pregnancy with a diagnosis of preexisting hypertension. It is well established that pregnant women with what is now defined as stage 2 hypertension have higher rates of maternal, fetal, and neonatal complications than normotensive women, including preeclampsia, cesarean delivery, postpartum hemorrhage, hypertension-induced end-organ damage, gestational diabetes, placental abruption, fetal growth restriction, and perinatal mortality.4,5 Moreover, women with pre-existing hypertension and those who develop preeclampsia have an increased risk of future cardiovascular disease.6–10 What is unknown is whether newly pregnant women with elevated BP or stage 1 hypertension also have increased risks of preeclampsia and maternal or neonatal morbidity. Neither the 2017 American College of Cardiology and American Heart Association guidelines nor recent recommendations from the American College of Obstetricians and Gynecologists11 provide guidance regarding how women with early pregnancy elevated BP or stage 1 hypertension should be managed owing to the lack of evidence.
We aimed to investigate whether women with elevated BP or stage 1 hypertension in early pregnancy exhibit an increased risk for preeclampsia and adverse maternal or neonatal outcomes compared with normotensive women. We also investigated whether the relationship between early pregnancy BP and preeclampsia risk was modified by race. The primary outcome was preeclampsia, and secondary outcomes included severe maternal morbidity, placental abruption, gestational diabetes, and a neonatal morbidity composite score. We hypothesized that there will be an increasing, stepwise association between 2017 American College of Cardiology and American Heart Association BP groups and risk, such that women with elevated BP, stage 1 hypertension, and stage 2 hypertension will have increasing risks of preeclampsia, maternal morbidity, and neonatal morbidity.
We conducted a clinical cohort study using data collected from the Magee Obstetric Maternal & Infant database. Established in 1995, data are aggregated from prenatal and delivery health records for women who give birth at Magee-Womens Hospital in Pittsburgh, Pennsylvania. State-level birth certificate data are also available for each patient in the database. The Magee Obstetric Maternal & Infant database is regularly reviewed by an honest broker for quality control by comparison with patient charts and examination of frequencies for outliers. The study was approved by the University of Pittsburgh Institutional Review Board and supported by grants from the Richard King Mellon Foundation, ID8069, Magee Obstetric Maternal & Infant database; the American Heart Association Go Red for Women Strategic Focused Research Network, Contract 1SFRN27810001; and the National Institutes of Health/University of Pittsburgh Clinical and Translational Science Institute, 5UL1TR001857-04. The funding sources had no role in the design of the study; the collection, analysis, and interpretation of the data, nor the decision to approve publication of the finished manuscript.
The current study included women who delivered a singleton neonate at or after 20 weeks of gestation at Magee-Womens Hospital between January 1, 2015, and June 30, 2018, and who attended at least two prenatal appointments before 20 weeks of gestation (N=18,162). Blood pressure elevations recorded before 20 weeks of gestation are considered by obstetric guidelines to characterize chronic (preexisting) hypertension,5,11 and we required at least two early pregnancy visits to minimize the influence of a single spurious clinic BP measurement. Women were excluded if they had missing BP measurements at prenatal visits, unknown gestational age at delivery, or suspected inaccurate BP measurements (systolic BP less than 70 mm Hg or diastolic BP less than 40 mm Hg). Additionally, only first births were included for women who had more than one delivery within the study period. In general, women who were included in the final cohort and women who were excluded owing to a lack of prenatal record or insufficient BP data had similar baseline characteristics including age, race, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), and frequency of nulliparity; more excluded women were smokers (Appendix 1, available online at http://links.lww.com/AOG/B860).
Blood pressure was measured at the patients' prenatal visits according to the protocol of each individual obstetric practice and was not regulated by a research protocol. Women were classified as having normal BP, elevated BP, stage 1 hypertension, or stage 2 hypertension based on the 2017 American College of Cardiology and American Heart Association guidelines using the average of all available clinic BP measurements before 20 weeks of gestation (2.9±0.9 prenatal visits). The normal BP group determination required women to have both an average systolic BP less than 120 mm Hg and average diastolic BP less than 80 mm Hg in early pregnancy. The elevated BP group included women with average systolic BP between 120 mm Hg and 129 mm Hg and average diastolic BP less than 80 mm Hg. Stage 1 hypertension was identified by an average systolic BP between 130 and 139 mm Hg or an average diastolic BP between 80 and 89 mm Hg. If average systolic BP or diastolic BP exceeded either of the stage 1 hypertension ranges, women were considered to have stage 2 hypertension. Women with chronic (prepregnancy) hypertension identified by using diagnostic codes were grouped into the stage 2 hypertension category, regardless of early pregnancy measurements.
Primary and secondary outcomes were identified using International Classification of Diseases, Ninth and Tenth Revision diagnostic and procedure codes, admitting and discharge data, and other medical record features (Appendix 2, available online at http://links.lww.com/AOG/B860). Preterm preeclampsia was defined as mild or severe preeclampsia; hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; or eclampsia and having delivered before 37 weeks of gestation; women with term preeclampsia delivered at or after 37 weeks. Severe maternal morbidity was defined according to Main et al12 if women met one of three conditions: one of 21 indicators determined by the Centers for Disease Control and Prevention (Appendix 3, available online at http://links.lww.com/AOG/B860),13 admittance to the intensive care unit, or prolonged postpartum length of stay (Appendices 2 and 3, http://links.lww.com/AOG/B860). Prolonged postpartum length of stay was defined as a stay longer than 3 SDs above the mean postpartum length of stay for the study time period, stratified by mode of delivery (mean length-of-stay 1.93±0.73 days for vaginal delivery and 3.11±0.95 days for cesarean delivery). Gestational diabetes was diagnosed according to Carpenter-Coustan criteria (at least two values greater than 95, 180, 155, or 140 mg/dL at fasting, 1, 2, and 3 hours, respectively, after a 100-g glucose load; a 3-hour glucose tolerance test was performed for a 1-hour glucose screening test value greater than 135 mg/dL). The neonatal composite outcome included at least one of the following: intrauterine fetal death after 20 weeks of gestation, neonatal death within 28 days of life, 5-minute Apgar score less than 7, neonatal intensive care unit (NICU) admission, small for gestational age (SGA) according to national birth weight standards,14 or preterm birth (gestational age less than 37 weeks at delivery).
Clinical and demographic characteristics of the analysis cohort are described by mean and SD for continuous variables and by frequency and percentages for categorical variables. Patient characteristics across hypertension groups are compared using analysis of variance for continuous variables and Pearson χ2 or its exact alternative when cell frequencies were small for categorical variables. Incidence of preeclampsia across hypertension groups was compared using logistic regression with pair-wise comparisons conducted using linear contrasts. We reported the results as odds ratios (ORs) and corresponding 95% Cis. We also fit a multivariable logistic regression model with preeclampsia as the binary outcome and hypertension categories, age, race, BMI, smoking status, preexisting diabetes, parity, number of visits before 20 weeks of gestation, gestational age at first prenatal visit, and average time between prenatal visits were covariates. Results from the model are presented as adjusted odds ratio (aOR) and corresponding 95% CI. We have a small proportion (at maximum less than 6%) of participants having missing data on BMI (n=1,073 missing), current smoking (n=1,083 missing), gestational weight gain (n=1,220 missing) and parity (n=752 missing). We do not anticipate that the likelihood of missing these covariates is associated with the outcome. Therefore, a missing at random assumption was reasonable. Likelihood-based methods using all available data such as the logistic regression model used in this paper provide valid estimates.
Considering that the elevated BP and stage 2 hypertensive groups had higher percentages of black women, we also fit the above logistic regression models stratified by race. Incidences of maternal complications (gestational diabetes, placental abruption, severe maternal morbidity) are reported as frequencies and percentages and compared across hypertension categories using Pearson χ2 test or its exact version as appropriate. We then repeated the above modeling strategy for the following: preterm preeclampsia, term eclampsia, severe maternal morbidity, placental abruption, gestational diabetes, and composite neonatal morbidity.
All P-values reported were two sided. The analyses were conducted using SAS 9.4.
There were 30,244 deliveries during the study period. Of these, 12,082 were excluded owing to lack of prenatal record (n=5,570, largely a result of transfers from community hospitals), nonsingleton pregnancy (n=538), fewer than two prenatal visits before 20 weeks of gestation (n=5,323), second delivery within study interval (n=630), and missing or indeterminate BP data (n=21; Fig. 1). The final study population included 18,162 women. To ensure we did not introduce selection bias by excluding women who did not receive prenatal care (based on the lack of prenatal record), we matched the 5,570 women with no prenatal record in our database with their state-level birth record data to ascertain gestational age at initiation of prenatal care. Of those 5,570 women, 4,631 (83.1%) reported initiation of prenatal care at or before 12 weeks of gestation, and therefore we concluded that these women received care outside of the hospital system used for this study. The remaining women reported no prenatal care (n=902; 16.2%) or prenatal care initiated at or after 16 weeks of gestation (n=37; 0.7%).
By the 2017 American College of Cardiology and American Heart Association BP guidelines, 75.2% (n=13,640) of women were categorized with early pregnancy normal BP, 13.9% (n=2,529) with elevated BP, 5.4% (n=988) with stage 1 hypertension, and 5.5% (n=1,005) with stage 2 hypertension. Per the guidelines, women needed to meet only the systolic BP or the diastolic BP criterion for each BP category. For example, 101 of 988 (10%) women met both systolic and diastolic BP criteria for stage 1 hypertension, whereas 216 of 988 (22%) met only the systolic criterion and 670 of 988 (68%) met only the diastolic criterion (Appendix 4, available online at http://links.lww.com/AOG/B860). Most women in the stage 2 hypertension group (836/1,005; 83%) were classified based on diagnostic codes rather than BP criteria (Appendix 4, http://links.lww.com/AOG/B860). No data were available in our data set on antihypertensive medication use.
As severity of BP classification increased (elevated to stage 1 hypertension to stage 2 hypertension), women tended to be older, more obese, and more likely to have preexisting diabetes (Table 1). Women with elevated BP and stage 2 hypertension were more likely to be of black race (Table 1).
A total of 1,249 cases of preeclampsia (6.9%) occurred among our cohort. The incidence of preeclampsia increased in stepwise fashion with increasing BP category from 4.7% in the normal BP group to 7.3% in the elevated BP group, 12.3% in the stage 1 hypertension group, and 30.2% in the stage 2 hypertension group (Fig. 2). Compared with women with normal BP, the odds of preeclampsia increased from 1.59 (95% CI 1.35–1.89) in the elevated BP group to 2.86 (95% CI 2.33–3.52) in the stage 1 hypertension group to 8.77 (95% CI 7.50–10.25) in the stage 2 hypertension group (Table 2). In adjusted analyses accounting for baseline differences among groups in age, race, BMI, smoking status, preexisting diabetes, parity, number of prenatal visits before 20 weeks of gestation, gestational age at first prenatal visit, and average time between visits, the odds of preeclampsia increased from 1.29 (95% CI 1.07–1.56) to 2.35 (95% CI 1.86–2.96) to 6.49 (95% CI 5.34–7.89) among women with elevated BP, stage 1 hypertension, and stage 2 hypertension, respectively, compared with normotensive women (Table 2). Among women with elevated BP, this increase in the odds of preeclampsia was driven by an increase in preterm preeclampsia. Among women with stage 1 and stage 2 hypertension, increased odds of both term and preterm preeclampsia were observed, albeit with a greater increased odds of risk for preterm compared with term preeclampsia (Table 2).
Black race was associated with higher risk of preeclampsia (OR 1.34, 95% CI 1.15–1.57), but there was no statistical evidence of effect modification by race in our overall model or in analyses stratified by gestational age at delivery (P=.56 for multiplicative interaction between race and hypertension in total preeclampsia; P=.25 for preterm preeclampsia; P=.38 for term preeclampsia). When stratified by race, a similar pattern of increasing odds of preeclampsia with higher BP category was seen in both black and white women (Table 2).
To evaluate for other sequelae of elevated BP and hypertension, we determined the incidences of severe maternal morbidity, placental abruption, and gestational diabetes. Although there was a stepwise increase in incidence of severe maternal morbidity with increasing BP category (from 2.6% to 2.9–3.5% to 12.4% among women with normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension, respectively; Table 3), the unadjusted and adjusted odds of severe maternal morbidity were increased only among women with stage 2 hypertension (OR 5.33, 95% CI 4.30–6.61; aOR 2.99, 95% CI 2.26–3.99). Women with elevated BP (OR 1.55, 95% CI 1.32–1.82), stage 1 hypertension (OR 2.32, 95% CI 1.88–2.86), and stage 2 hypertension (OR 2.98, 95% CI 2.46–3.61) had a stepwise increase in the odds of gestational diabetes, compared with normotensive women (Table 3). Accounting for covariates including BMI, the adjusted odds of gestational diabetes were more modestly increased across groups (elevated BP aOR 1.20, 95% CI 1.00–1.45; stage 1 hypertension aOR 1.50, 95% CI 1.18–1.91; stage 2 hypertension aOR 1.65, 95% CI 1.30–2.10). The overall incidence of placental abruption in the total cohort was low (1.4%), and the odds of placental abruption were not increased for any group.
The incidence of neonatal morbidity (a composite of intrauterine fetal death after 20 weeks of gestation, neonatal death within 28 days of life, 5-minute Apgar score less than 7, NICU admission, SGA, and preterm birth) was 22.6% in the normotensive group, 25.7% in the elevated BP group, 24.0% in the stage 1 hypertension group, and 44.4% in the stage 2 hypertension group (Table 3). The rates of NICU admission, 5-minute Apgar score less than 7, SGA, and both spontaneous and indicated preterm birth were each associated with severity of maternal BP group (P<.007, Table 4). In both unadjusted and adjusted analyses, only stage 2 hypertension was associated with increased odds of neonatal morbidity (OR 2.73, 95% CI 2.39–3.11; aOR 2.67, 95% CI 2.28–3.12) (Table 3).
In this large clinical cohort, elevated BP, stage 1 hypertension, and stage 2 hypertension in early pregnancy were associated with an increased risk for preeclampsia, with the severity of hypertension associated with higher risks. The risk of preeclampsia associated with stage 2 hypertension in early pregnancy has been well established, and our study adds to the accumulating evidence that a new population of women—those with systolic BP ranging from 120 to 139 mm Hg and diastolic BP ranging from 80 to 89 mm Hg in early pregnancy—are also at increased risk for preeclampsia. Our findings highlight the importance of early pregnancy BP elevations, which may reflect prepregnancy BP status, and suggest that the revised 2017 American College of Cardiology and American Heart Association hypertension guidelines can identify women early in pregnancy who may benefit from increased surveillance for signs and symptoms of preeclampsia.
Our results are consistent other studies evaluating the 2017 American College of Cardiology and American Heart Association definition of stage 1 hypertension in pregnancy. In two secondary analyses of prophylactic low-dose aspirin trials to reduce risk for preeclampsia conducted in the 1990s, Sutton et al and Hauspurg et al demonstrated increased risk of preeclampsia as well as preterm delivery and gestational diabetes in women newly classified with stage 1 hypertension using the 2017 American College of Cardiology and American Heart Association guideline.15,16 A recent secondary analysis of the NuMoM2b study (Nulliparous Pregnancy Outcome Study: Monitoring Mother-to-Be cohort) also found elevated BP and stage 1 hypertension categorized in first trimester with the 2017 American College of Cardiology and American Heart Association guidelines were associated with an increased risk of preeclampsia.17 Finally, a large retrospective cohort study of low-risk patients from China found increased rates of hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and low birth weight among women with stage 1 hypertension compared with normotensive women in a control group.18 This study categorized women by BP assessed at a single time point before 20 weeks of gestation.
We extend these findings in several ways. Our study examines a large and contemporary clinical cohort in the United States by considering multiple clinical BP measurements, evaluating both term and preterm disease, including nulliparous and parous patients, and evaluating race differences and maternal and neonatal morbidity. We demonstrate that women with elevated BP in early pregnancy have excess preeclampsia risk compared with those with normal BP, and that this association is driven by black women with preterm preeclampsia. Further, as the early pregnancy BP category increases, the risk for gestational diabetes increases in a monotonic fashion.
Our findings may have immediate relevance for primary care providers caring for reproductive age women. Both pharmacologic and nonpharmacologic interventions to lower BP and to address other risk factors for cardiovascular disease, such as obesity, glucose intolerance, and hyperlipidemia, have the potential to improve future maternal and fetal health. Considering that our results demonstrated increased rates of obesity and gestational diabetes among women with elevated BP and stage 1 hypertension, implementing lifestyle interventions to address cardiovascular and metabolic risk factors could be beneficial in affected women.19
Our findings also provoke questions regarding first-time diagnosis of elevated BP or stage 1 hypertension during early pregnancy. How such early pregnancy diagnosis may translate to prenatal management is not yet known, and randomized trials will be required to identify prevention and management strategies among women with these early pregnancy BP elevations. In the meantime, lifestyle modifications such as dietary improvements and exercise programs that improve cardiometabolic health during pregnancy are safe and effective, and may be relevant when BP is elevated.20 During pregnancy, low-dose aspirin is currently the only intervention with demonstrated efficacy for reducing the risk of preterm preeclampsia in high-risk women,21–25 including those entering pregnancy with chronic hypertension.26 Aspirin is a cost-effective intervention27,28 with an excellent risk-benefit profile in pregnancy,21,22,25 and its widespread use for preeclampsia prevention has been advocated.27–29 Thus, it may be reasonable to recommend this low-cost28 medication for the newly identified population of at-risk women, although trials are needed to characterize its efficacy among these women. Medical tests routinely employed in pregnant women with stage 2 hypertension (additional laboratory studies, ultrasound scans, and antenatal fetal surveillance) are of unknown utility in women with lower-range hypertension. Our study did not find higher rates of SGA neonates or adverse neonatal outcomes among women with elevated BP and stage 1 hypertension. Therefore, our data are not sufficient to recommend increased antenatal fetal surveillance for these women. Moreover, limiting increased fetal surveillance would likely help avoid iatrogenic morbidity in this population.
Our study has limitations that should be considered. First, BP measurements in our study were clinical measures collected during the routine care of women at many medical offices. It is likely that many measurements were collected without full adherence to all recommendations regarding BP assessment methodology. This lack of protocol is a limitation but, on balance, does reflect medical practice outside of research protocols. As recommended by the American College of Cardiology and American Heart Association guidelines,1 diagnostic classification was based on the average of at least two measures. The use of routinely measured BP is a pragmatic approach and potentially enhances the generalizability of our findings. Consideration should also be given to the absence of information about antihypertensive medication use in our database. Given that 83% of women in the stage 2 hypertension group had BPs lower than the range of stage 2 hypertension (ie, systolic BP less than 140 mm Hg and diastolic BP less than 90 mm Hg), we speculate that misclassification bias may be modest, because these women were still identified by their diagnostic codes. The lower measured BPs in this group might be a result of a combination of pharmacologic and nonpharmacologic treatment and to the physiologic lowering of BP in early pregnancy. It is notable that despite such a small proportion of women in the stage 2 hypertension group having measured BPs in the stage 2 hypertension range, this group still had the highest risk of preeclampsia and maternal and neonatal morbidity.
Restricting our analysis to women who had at least two prenatal visits before 20 weeks of gestation might introduce selection bias, because women with medical comorbidities might be more likely to establish early prenatal care. Indeed, we noted slightly more prenatal visits before 20 weeks of gestation in the stage 2 hypertension group, and we controlled for the number of prenatal visits in our adjusted analyses. In comparing the baseline characteristics and rate of outcomes between patients included and excluded in our final cohort, we noted many similarities (Appendix 1, http://links.lww.com/AOG/B860), and thus, the influence of selection bias is likely minimal. The data in this study are from a single institution, which might limit generalizability. Yet, Magee-Womens Hospital provides care for a diverse population of both low-risk and high-risk patients from a large geographical area, and providers range from certified nurse midwives to family medicine physicians to general obstetricians and maternal-fetal medicine specialists.
Another limitation is our reliance on diagnostic codes, which may misclassify preeclampsia and other obstetric conditions. We cannot confirm the diagnostic criteria that were used to diagnose preeclampsia in each patient in our cohort. However, use of diagnostic codes is a routine epidemiologic and clinical cohort approach, and data in the Magee Obstetric Maternal & Infant database are regularly evaluated to assure accuracy and completeness. Additionally, a validation study in the subset of women with chronic hypertension with superimposed preeclampsia diagnoses (the subgroup with the most complex medical records) demonstrated that among these 322 women, 95% had a clinical diagnosis of preeclampsia in the medical record. The primary strength of this study is the large, contemporary cohort of women with prenatal, delivery, and neonatal data and our ability to evaluate maternal morbidity.
Application of new BP criteria in early pregnancy may identify women at risk for preeclampsia, particularly preterm preeclampsia, and gestational diabetes. Although the excess risk identified in our study is modest, particularly among women with elevated BP, there is now accumulating observational evidence from both research and clinical cohorts that women with elevated BP and stage 1 hypertension are at increased risk of obstetric and maternal morbidity. The magnitudes of increased risk noted in our study are comparable with those previously reported. Thus, we are assured that the observed associations between early pregnancy BP elevations and adverse outcomes are real and that there is now sufficient observational evidence to consider how to incorporate these lower BP thresholds into obstetric care. For example, newly designed trials of interventions for preeclampsia risk reduction in women with elevated BP and stage 1 hypertension in early pregnancy are warranted. Such trials could drive changes in risk identification, improved prenatal maternal monitoring, and perhaps improved maternal outcomes. Our results are also relevant to general clinicians caring for reproductive age women, as the new BP guidelines may identify risks that could affect future pregnancies. Given the well-described association between hypertensive disorders of pregnancy and future cardiovascular risk, interventions for reproductive-age women may have lifelong and multigenerational cardiovascular benefit.
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