Hypertensive disorders occur in approximately 12–22% of all pregnancies and are associated with significant maternal and neonatal morbidity and mortality.1–3 Pregnancy-associated hypertension includes a spectrum of clinical presentations from mild to severe disease and classification is dependent on the severity of hypertension, presence of clinical signs and symptoms, proteinuria, and other laboratory abnormalities.1,3
Laboratory assessment has become routine practice in the evaluation of pregnancy-associated hypertension. The cost of this surveillance can be considerable and it leads to increased interventions such as hospital admission and labor induction.4 In a study of 442 women with severe preeclampsia, approximately 20% were reported to develop laboratory abnormalities including hemolysis, elevated liver enzymes, and low platelet count.5 Severe preeclampsia with hemolysis, elevated liver enzymes, low platelet count, and elevated creatinine or multiple abnormalities is associated with a significant increase in adverse maternal and perinatal morbidity.5–8 However, there are limited contemporary data from well-defined populations regarding the yield of these laboratory evaluations and the associated pregnancy outcomes.
Our objective was to estimate the frequency of laboratory abnormalities in women with pregnancy-associated hypertension and to assess the relationship with adverse perinatal outcomes.
MATERIALS AND METHODS
This study is a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network multicenter randomized, double-blinded trial of low risk nulliparous women assigned to daily vitamin C and E supplementation or matching placebo to prevent pregnancy-associated hypertension.9 Women with singleton pregnancies between 9 0/7 and 16 6/7 weeks of gestation at the time of randomization were followed until delivery. Gestational age was based on a previously described algorithm10 using the date of the last menstrual period (if reliable) and results of the earliest ultrasound examination. Exclusion criteria included medical comorbidity (including preexisting hypertension) and known fetal anomalies, which have been described previously.9 All data were collected by certified research personnel and uploaded to a database managed by an independent data coordinating center. The study was approved by the institutional review board at each clinical site and the data coordinating center.
This secondary analysis included women who developed confirmed new-onset hypertension (including gestational hypertension and preeclampsia) per the study protocol. Pregnancy-associated hypertension was confirmed by central review of deidentified medical records using a standardized protocol by three reviewers not associated with the clinical site of origin. Mild pregnancy-associated hypertension was defined as blood pressure (BP) of 140–159 mm Hg systolic or 90–109 mm Hg diastolic on two occasions 2–240 hours apart. Severe pregnancy-associated hypertension was defined as systolic BP of 160 mm Hg or higher or diastolic of 110 mm Hg or higher on two occasions, 2–240 hours apart, or a single occurrence treated with antihypertensives, or any BP elevation associated with severe clinical signs or symptoms of end-organ dysfunction. Severe clinical signs and symptoms were defined as one or more of the following: headache, epigastric pain, blurred vision, pulmonary edema (confirmed by radiography), eclampsia, or oliguria (less than 500 mL in a 24-hour urine sample).
Laboratory abnormalities in the context of pregnancy-associated hypertension were defined as one or more of the following with the worst result recorded (eg, lowest platelet count, highest aspartate aminotransferase, etc): thrombocytopenia (platelet count less than 100,000/mm3), elevated liver enzyme levels (aspartate aminotransferase 100 units/L or greater), elevated serum creatinine level (1.5 mg/dL or greater [132.6 micromoles/L]), or evidence of hemolysis (either a lactate dehydrogenase level 600 units/L or greater or a total bilirubin level 1.2 mg/dL or greater, or a peripheral blood smear showing nucleated red cells, schistocytes, or an elevated reticulocyte count).9 An aspartate aminotransferase 100 units/L or greater (rather than twice the upper limit of normal) was chosen as the threshold because the values were obtained clinically at each center and the upper limit varied among the centers. The aspartate aminotransferase value of 100 units/L is approximately twice the upper limit of normal at the participating centers. All chart-reviewed laboratory values were included from 20 weeks of gestation through discharge after delivery. The laboratory data were based on clinical routine at each center and were run in each center's laboratory. In general, all patients with suspected pregnancy-associated hypertension would undergo laboratory evaluation as part of the workup.
For this analysis, the severity of pregnancy-associated hypertension was categorized into four groups: Category I—mild pregnancy-associated hypertension alone in the absence of laboratory abnormalities or severe clinical signs or symptoms, Category II—mild pregnancy-associated hypertension with laboratory abnormalities, Category III—severe hypertension or any BP elevation associated with severe clinical signs or symptoms with normal laboratory values, and Category IV—severe hypertension or any BP elevation associated with severe clinical signs or symptoms and laboratory abnormalities.
The main prespecified outcomes of interest were 1) the frequency of laboratory abnormalities overall and stratified by category of pregnancy-associated hypertension based on severity of BP and presence of clinical signs; and 2) adverse perinatal outcomes across the four predefined categories of pregnancy-associated hypertension. The prespecified adverse outcomes examined included a primary composite neonatal morbidity (one or more of respiratory distress syndrome, sepsis, necrotizing enterocolitis, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, or Apgar score 3 or less at 5 minutes), overall and indicated preterm birth (delivery either before 37 weeks of gestation or before 32 weeks of gestation), placental abruption, small for gestational age (SGA) birth weight less than the fifth percentile,11 fetal or neonatal death (20 weeks or gestation or greater), neonatal intensive care unit (NICU) admission, neonatal length of stay, and maternal length of stay. Neonatal outcomes were defined according to the criteria in the original trial protocol.9
Continuous variables were compared with the use of the Wilcoxon rank-sum test (two groups) or Kruskal–Wallis test (three groups) and categorical variables with the use of the χ2 or Fisher's exact tests as appropriate. Frequency of laboratory abnormalities across pregnancy-associated hypertension categories was assessed using the Cochran-Armitage trend test. Univariable analyses were performed and logistic regression was used for multivariable analysis of binary outcomes and included significant covariates (maternal age, race, body mass index [BMI, calculated as weight (kg)/[height (m)]2] at enrollment, smoking, education level [total years of schooling completed for a maximum of 16 years], and family history of preeclampsia) as well as treatment group (vitamins C and E compared with placebo) to compare pregnancy-associated hypertension groups relative to the mild pregnancy-associated hypertension group. Exact logistic regression was performed as appropriate. Attempts were made to normalize the continuous outcomes; however, as a result of the skewness of the data, this was not possible and adjusted means are not presented. Observations with missing data were excluded from the analysis. For all outcomes, nominal P values of <.05 were considered to indicate statistical significance; no adjustments were made for multiple comparisons. Analyses were performed using SAS software.
A total of 10,154 women were randomized in the original trial and outcome data were available for 9,969 women. For this secondary analysis, 2,779 (27.9%) women developed pregnancy-associated hypertension. Twenty-seven women had neonates with major malformations and were excluded, leaving 2,752 women for analysis. In those who developed pregnancy-associated hypertension, the frequency of laboratory abnormalities was 7.3% overall (95% confidence interval [CI] 6.3–8.3%) and the frequency increased with increasing severity of pregnancy-associated hypertension: mild hypertension alone (4.9%, 95% CI 3.9–6.0%), severe hypertension alone (8.9%, 95% CI 4.8–13.1%), and mild or severe hypertension with severe clinical signs (12.2%, 95% CI 9.9–14.5%) (P for trend <.001) (Table 1). The frequency of laboratory abnormalities in women without pregnancy-associated hypertension was 0.4%.
Baseline maternal characteristics of women in each of the four pregnancy-associated hypertension categories are presented in Table 2. The groups differed by age, baseline BMI, race, smoking status, family history of preeclampsia, and education level. Women with laboratory abnormalities (groups II and IV) when compared with the those without abnormalities were significantly more likely to be older, Caucasian or Hispanic, nonsmokers, have a higher education level, and lower BMI (data not shown).
The incidence of the adverse perinatal outcomes in each pregnancy-associated hypertension category is presented in Table 3 with the results comparing each category of pregnancy-associated hypertension relative to the mild pregnancy-associated hypertension category after adjusting for maternal age, race, baseline BMI, smoking, treatment group (vitamins C and E compared with placebo), education level, and family history of preeclampsia. Mean gestational age at delivery decreased with increasing severity of pregnancy-associated hypertension. Compared with the mild pregnancy-associated hypertension category (I), there were no increases in the rates of the composite neonatal morbidity, preterm birth at less than 32 weeks of gestation, indicated preterm birth at less than 37 or less than 32 weeks of gestation, fetal or neonatal death, SGA, or NICU admission in those with mild pregnancy-associated hypertension plus laboratory abnormalities (Category II), whereas there were increases in the rate of abruption (adjusted odds ratio [OR] 7.1 [1.9–27.5]) and overall preterm birth at less than 37 weeks of gestation (adjusted OR 2.1 [1.1–4.0]). In those with severe pregnancy-associated hypertension (Category III), the incidence of the composite neonatal morbidity (adjusted OR 2.0 [1.4–2.9]), overall and indicated preterm birth at less than 37 (adjusted OR 3.6 [2.8–4.6] and adjusted OR 8.5 [5.9–12.3]) and less than 32 weeks of gestation (adjusted OR 3.8 [1.8–8.1] and adjusted OR 11.3 [3.3–38.7]), SGA (adjusted OR 1.5 [1.1–2.0]), and NICU admission (adjusted OR 1.9 [1.5–2.3]) were increased compared with mild pregnancy-associated hypertension (Category I). With the exception of SGA, the incidence and adjusted odds of adverse outcomes increased further with severe pregnancy-associated hypertension in the presence of laboratory abnormalities (Category IV) when compared with mild pregnancy-associated hypertension alone (Category I): composite neonatal morbidity (adjusted OR 4.8 [2.6–9.1]), overall preterm birth at less than 37 weeks (adjusted OR 7.8 [5.0–12.1]) and less than 32 weeks (adjusted OR 24.7 [9.9–61.8]) of gestation, indicated preterm birth at less than 37 weeks (adjusted OR 20.1 [12–33.9]) and less than 32 weeks (adjusted OR 82.1 [21.9–307.7]) of gestation, cesarean delivery (adjusted OR 2.1 [1.4–3.0]), and NICU admission (adjusted OR 3.9 [2.5–5.9]). There was no significant difference in fetal or neonatal death 20 weeks or greater among any of the pregnancy-associated hypertension categories regardless of laboratory abnormalities. Neonatal and maternal length of stay were longer in pregnancy-associated hypertension Categories II–IV when compared with those having mild pregnancy-associated hypertension alone (Category I) (P<.001); however, the median lengths of stay were 2–3 days for all groups. The risk of cesarean delivery differed by pregnancy-associated hypertension category: 29.2%, 45.5%, 35.5%, and 45.1% for Categories I–IV, respectively (P<.001); categories with laboratory abnormalities were at higher risk of cesarean delivery.
In additional multivariable analyses that added gestational age at delivery to the model, there was no longer an increase in the adjusted odds of the composite neonatal morbidity (Categories III and IV), SGA (Category III), or NICU admission (Category III) compared with mild pregnancy-associated hypertension alone (Category I). However, in women with severe pregnancy-associated hypertension and laboratory abnormalities (Category IV), the increase in NICU admission persisted after adjustment for gestational age (adjusted OR 1.8 [1.1–3.0]). When we considered a creatinine level of 1.2 mg/dL or more to be abnormal, the results for the composite neonatal outcome were materially unchanged: adjusted OR (95% CI) was 2.0 (0.8–4.8) for group II compared with I, 1.9 (1.3–2.8) for group III compared with I, and 4.8 (2.7–8.8) for group IV compared with I.
Analyses were performed to determine if outcomes were worse in women with severe pregnancy-associated hypertension or any hypertension with severe clinical signs and laboratory abnormalities (Category IV) compared with those having severe pregnancy-associated hypertension or any hypertension with severe clinical signs without abnormal laboratory values (Category III). As shown in Table 4, laboratory abnormalities were associated with an increase in the odds of the neonatal composite (adjusted OR 2.5 [1.3–4.9]), preterm birth at less than 37 (adjusted OR 2.2 [1.4–3.4]) and less than 32 (adjusted OR 6.1 [2.7–14.0]) weeks of gestation, indicated preterm birth at less than 37 (adjusted OR 2.4 [1.5–3.8]) and less than 32 (adjusted OR 6.7 [2.9–15.8]) weeks of gestation, and NICU admission (adjusted OR 2.0 [1.3–3.2]) by twofold or greater.
An additional analysis was performed to determine the association between the number of laboratory abnormalities and the composite outcome. Of the 201 women with laboratory abnormalities, 163 had one abnormal, 24 had two abnormal, and 14 had three or more abnormal results. For the neonatal composite, there was a significant increasing trend (4.4%, 8.6%, 8.7%, and 28.6% for zero, one, two, and three or more laboratory abnormalities, respectively; P for trend <.001).
Although proteinuria was not required or used to define the category of pregnancy-associated hypertension, the frequency of proteinuria (defined as a 24-hour urine protein of 300 mg/24 hours or 2+ on dipstick [in the absence of urinary tract infection] or protein–creatinine ratio of 0.35) increased across pregnancy-associated hypertension categories: 16.0%, 25.0%, 41.6%, and 56.6% for Categories I–IV, respectively (P for trend <.001).
This study demonstrates that abnormal laboratory results occur in 7.3% of otherwise healthy nulliparous women whose pregnancies are complicated by pregnancy-associated hypertension and that the frequency increases from 5% to 12% with increasing severity of BP and presence of severe symptoms. Overall, the incidence of laboratory abnormalities in our study is lower than what has been reported in the literature.4,5,12 The incidence of hemolysis, elevated liver enzymes, low platelet count and elevated creatinine or multiple abnormalities among women with severe preeclampsia has been reported to be as high as 20%; however, this likely reflects the high-risk patient population examined compared with our general population of nulliparous women at otherwise low risk, including those who developed less severe as well as severe pregnancy-associated hypertension.5,12 Few studies have examined laboratory abnormalities in the broad group of women with pregnancy-associated hypertension. The low prevalence of laboratory abnormalities in patients without pregnancy-associated hypertension almost certainly represents an underestimate because these women did not undergo routine clinical screening.
The presence of abnormal laboratory values was associated with an increased risk of selected adverse outcomes, which increased with the number of abnormal laboratory values. Although the increase in adverse outcomes may be a direct consequence of a higher degree of disease severity associated with abnormal laboratory values, the decision to deliver early after observing an abnormal laboratory finding is likely also a contributing factor. Laboratory abnormalities in women with pregnancy-associated hypertension are considered a marker of disease severity and an important factor in the clinical decision to deliver preterm. This is supported by the lack of association of most pregnancy-associated hypertension categories with perinatal outcomes observed in the additional analyses adjusting for gestational age. However, this is not meant to imply that laboratory testing results should not be factored into the decision to deliver, a question that cannot be addressed using our data.
The results of this study are consistent with the available literature in that adverse neonatal outcomes are relatively low in women with mild pregnancy-associated hypertension (gestational hypertension or preeclampsia),3,6,12–15 whereas those who develop severe pregnancy-associated hypertension including hemolysis, elevated liver enzymes, low platelet count, and elevated creatinine or multiple abnormalities have higher rates of preterm birth, maternal and neonatal morbidity, and mortality.7,8,14–16 Our study is unique in that we are able to quantify the prevalence of laboratory abnormalities in women with varying severity of pregnancy-associated hypertension including those with otherwise mild disease.
We found a sevenfold increase in the incidence of placental abruption in those women with mild pregnancy-associated hypertension and abnormal laboratory values compared with those with mild pregnancy-associated hypertension and normal laboratory values, which was not seen with increasing severity of pregnancy-associated hypertension. This observation may be because patients with abruption are more likely to have less severe BP elevation as a result of the bleeding associated with abruption.
Traditionally, a diagnosis of preeclampsia is made in the setting of new-onset hypertension after 20 weeks of gestation associated with proteinuria.1,3 The literature suggests that laboratory abnormalities (hemolysis, elevated liver enzymes, low platelet count, and elevated creatinine or multiple abnormalities) may occur in the absence of proteinuria in approximately 10–15% of women.13,17 Therefore, proteinuria was not required or used to define the category of pregnancy-associated hypertension. This is consistent with the recent guidelines released from the American College of Obstetricians and Gynecologists' (the College) Task Force in that proteinuria is no longer required to make a diagnosis of preeclampsia if other systemic findings are present.18
In this secondary analysis, we used the terminology of pregnancy-associated hypertension to coincide with that of the primary trial. However, the defined BP categories can be extrapolated to the new College classification of hypertensive disorders in pregnancy.18 Category I (mild pregnancy-associated hypertension alone) corresponds to BP in the setting of either gestational hypertension or preeclampsia with nonsevere features; Category II (mild pregnancy-associated hypertension+abnormal laboratory values) corresponds to a subgroup of preeclampsia with severe features regardless of proteinuria given the abnormal laboratory values. Category III (severe hypertension or any BP elevation associated with severe clinical signs with normal laboratory values) corresponds to either preeclampsia with severe features or severe gestational hypertension. Category IV (severe hypertension or any BP elevation associated with severe clinical signs with laboratory abnormalities) also corresponds to a subgroup of preeclampsia with severe features given abnormal laboratory values.
The strengths of our study include the relatively large proportion of women with pregnancy-associated hypertension, central validation of key outcomes, and data abstraction by trained and certified research staff—factors that minimize bias. Limitations include the relatively small number of women with laboratory abnormalities reducing our ability to fully evaluate less frequent outcomes and delineate differences between pregnancy-associated hypertension Categories I and II. Factors such as use of corticosteroids or magnesium sulfate could have resulted in additional confounding with regard to neonatal outcomes; however, these data were not available. Those with laboratory abnormalities were delivered earlier and, therefore, might have been more likely to receive corticosteroids biasing the results toward the null. Also, because only nulliparous women were enrolled in the study, generalizability of our findings to parous women is uncertain. Furthermore, we have not addressed whether the relationship with adverse outcomes is modified by the presence or absence of proteinuria (and the definition of proteinuria differs slightly from the recent College Task Force document)18—we focused on hypertension, which is essential for the diagnosis of pregnancy-associated hypertension. Finally, when multiple comparisons are conducted, the likelihood of chance findings increases. Given that we prespecified the composite as the primary outcome of interest for this analysis, and secondary findings are consistent, this is less of a concern.
In conclusion, women with pregnancy-associated hypertension have a relatively low incidence of laboratory abnormalities. This is useful contemporary information for counseling women with the condition regarding laboratory abnormalities. In women with mild pregnancy-associated hypertension and no signs or symptoms of severity, routine laboratory evaluation may not be beneficial or cost-effective given the low frequency of laboratory abnormalities. Studies comparing outcomes with and without (or masked) routine laboratory assessment are needed to further clarify this question.
1. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;99:159–67.
2. Cunningham G, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams obstetrics. 23rd ed. New York (NY): McGraw Hill; 2010.
3. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.
4. Bailey DJ, Walton SM. Routine investigations might be useful in pre-eclampsia, but not in gestational hypertension. Aust N Z J Obstet Gynaecol 2005;45:144–7.
5. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169:1000–6.
6. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 2003;102:181–92.
7. Cavkaytar S, Ugurlu EN, Karaer A, Tapisiz OL, Danisman N. Are clinical symptoms more predictive than laboratory parameters for adverse maternal outcome in HELLP syndrome? Acta Obstet Gynecol Scand 2007;86:648–51.
8. Haddad B, Barton JR, Livingston JC, Chahine R, Sibai BM. Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 2000;183:444–8.
9. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al.. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 2010;362:1282–91.
10. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al.. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 2000;342:534–40.
11. Alexander GR, Himes JH, Kaufman RB, Kogan M. A United States reference for fetal growth. Obstet Gynecol 1996;87:163–8.
12. Audibert F, Friedman S, Frangieh A, Sibai B. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1996;175:460–4.
13. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.
14. Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB, et al.. Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group. Obstet Gynecol 2000;95:24–8.
15. Buchbinder A, Sibai B, Caritis S, Macpherson C, Hauth J, Lindheimer MD, et al.. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol 2002;186:66–71.
16. Abramovici D, Friedman S, Mercer B, Audibert F, Kao L, Sibai B. Neonatal outcome in severe preeclampsia at 24 to 36 weeks' gestation: does the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome matter? Am J Obstet Gynecol 1999;180:221–5.
17. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 2004;103:981–91.
18. American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122–31.