Objective
We sought to compare the risk of giving birth to large-for-gestational-age (LGA) infants in women with and without preeclampsia, after adjustment for obesity and glucose intolerance.
Study Design
We conducted secondary analysis of a prospective database of pregnant women with and without preeclampsia who delivered infants from 1998 through 2006 at Massachusetts General Hospital (n = 17,465).
Results
The risk of LGA was similar in women with and without preeclampsia (odds ratio, 0.81; 95% confidence interval, 0.59–1.14). After adjustment for body mass index, glucose intolerance, and other factors, the risk of LGA was significantly lower in women with preeclampsia compared to those without preeclampsia (odds ratio, 0.69; 95% confidence interval, 0.49–0.96). Stratified analysis in groups with a higher risk of LGA revealed that preeclampsia has a similar effect on the risk of LGA regardless of maternal obesity, glucose intolerance, parity, and race.
Conclusion
Preeclampsia appears to be characterized by reduced, and not increased, fetal growth.
Preeclampsia is a systemic syndrome unique to pregnancy, characterized clinically by new-onset hypertension and proteinuria >20 weeks of gestation. An important initiating event in the pathogenesis of preeclampsia is thought to be abnormal placentation with shallow invasion of the placental cytotrophoblast and consequent compromised placental perfusion. This altered placentation is thought to lead to placental ischemia and hypoxia, triggering the release of circulating factors that lead to systemic endothelial dysfunction. If placental ischemia is a critical pathogenic factor in preeclampsia, one would expect this disorder to be associated with reduced fetal growth. Consistent with this, the risk of fetal growth restriction and small size for gestational age among infants born to women with preeclampsia is reported to be 2-5 times the risk among infants born to women without preeclampsia. Recently, however, several epidemiologic studies have reported an association between large-for-gestational-age (LGA) infants and preeclampsia. These studies challenge experimental and human data suggesting that placental hypoperfusion and ischemia are important to the pathogenesis of preeclampsia. In fact, in light of these reports, some have suggested that preeclampsia may be 2 diseases with 2 different biological processes, 1 that results in reduced fetal growth, and 1 that results in increased fetal growth. Clarity on this matter is needed to guide clinicians caring for women with preeclampsia, and importantly directing future clinical and experimental research in preeclampsia.
Obesity and glucose intolerance are some of the most common risk factors for both preeclampsia and LGA infants. Infant birthweight is strongly associated with maternal prepregnancy body mass index, independent of gestational weight gain, and among obese women the risk of preeclampsia is elevated by 2- to 3-fold. Similarly, maternal glucose intolerance is linearly associated with LGA infants and outcomes related to infant size, including birth injury and cesarean delivery. Glucose intolerance also increases the risk for preeclampsia; in fact, treatment of gestational diabetes mellitus with diet or insulin decreases the risk of preeclampsia by half. While some studies reporting an excess risk of LGA infants in preeclampsia excluded women with pregestational diabetes mellitus from their analyses, it appears that none have adjusted for body mass index or controlled for more subtle variation in glucose intolerance. In addition, other factors such as smoking, which is directly associated with small-for-gestational-age infants and less frequent in women with preeclampsia, may have falsely inflated the rate of LGA infants in preeclampsia (ie, not smoking increases the risk for both preeclampsia and LGA).
The Massachusetts General Hospital (MGH) birth database includes detailed information on all women who enrolled in prenatal care at MGH and affiliated health centers from 1998 through 2006. We hypothesized that the reported excess risk of LGA infants in preeclampsia could be accounted for by confounding by obesity, glucose intolerance, and other factors associated with preeclampsia and fetal growth. We sought to test this hypothesis in our cohort by comparing the risk of delivering an LGA infant in women with and without preeclampsia after adjustment for possible confounding factors.
Materials and Methods
Subjects and data collection
We performed a study of pregnancies in the MGH obstetric service birth database from Sept. 1, 1998, through Dec. 31, 2006. This database contains clinical information on all women who enroll in prenatal care at MGH or one of its affiliated health care centers. The MGH obstetrics service provides community-based obstetrics care for women from the metropolitan Boston area and high-risk obstetrics care for women referred from throughout New England. This cohort represents a population of women from varied ethnic and socioeconomic backgrounds with 38% of patients being ethnic minorities. Clinical information such as medical histories, prenatal blood pressures, and delivery information are entered into the database prospectively.
For this study we included all singleton pregnancies in women who enrolled in prenatal care during the study period (1998 through 2006, n = 22,980). The database contains information downloaded from the obstetrical electronic medical record that was entered prospectively during the incident pregnancy. These data include maternal age, body mass index, race, and smoking status at the first prenatal visit. They also include information on blood pressure, results of urine dipstick testing throughout pregnancy, and the results of a 50-g, 1-hour oral glucose loading test (GLT) performed routinely at 24-28 weeks of gestation to screen for gestational diabetes mellitus and from a 100-g, 3-hour oral glucose tolerance test performed if the GLT result was abnormal (≥140 mg/dL). Finally the database contains data from the delivery including infant birthweight, and maternal and infant complications. We excluded pregnancies with missing blood pressure data from the first prenatal visit (n = 3124), missing height or weight data (n = 2135) from the first prenatal visit, or missing birthweight data at delivery (n = 90). We also excluded women who did not have a recorded GLT result, as they may have had pregestational diabetes (n = 166). This left 17,465 pregnancies for analysis.
Ascertainment of exposures and outcomes
The diagnosis of preeclampsia was based on blood pressures and spot urine protein measurements made at prenatal visits. In women who were normotensive at their first prenatal visit (blood pressure <140/90 mm Hg), gestational hypertension was defined as blood pressure ≥140/90 mm Hg >20 weeks of gestation. In women who were hypertensive at their first prenatal visit (blood pressure ≥140/90 mm Hg) gestational hypertension was defined by the presence of a rise in systolic blood pressure >30 mm Hg or a rise in diastolic blood pressure >15 mm Hg >20 weeks of gestation. Cases of preeclampsia were women with gestational hypertension and >2+ proteinuria >20 weeks of gestation (n = 386) or gestational hypertension and >1+ proteinuria >20 weeks of gestation with confirmation of the diagnosis in the electronic delivery record (n = 102). Obesity was defined as body mass index ≥30 kg/m 2 at the first prenatal visit. Nulliparity was defined as never having had a live birth >20 weeks of gestation. Gestational diabetes was defined as ≥2 abnormal values on a glucose tolerance test by Carpenter-Coustan criteria. LGA was defined as the 90th percentile for completed week of gestation based on national standards from Oken et al. Small for gestational age was defined as the 10th percentile for completed week of gestational age based on the same national standards.
Statistical analysis
Characteristics of women with and without preeclampsia were compared using Mann-Whitney U tests and χ 2 tests as appropriate. Univariate and multivariate logistic regression models were used to compare the odds of delivering an LGA infant in women with and without preeclampsia both before and after stratification for obesity, gestational diabetes, and parity. Multivariate logistic regression models included variables associated with preeclampsia and size for gestational age. To test the robustness of our results, we conducted additional analyses in the group of pregnancies in which the mother was normotensive at the first prenatal visit, the group of pregnancies that resulted in term deliveries, and after eliminating repeat pregnancies in the same woman from our data set. All statistical analyses were conducted using software (STATA 11; Stata Corp, College Station, TX).
Results
At the first prenatal visit, women who subsequently developed preeclampsia (n = 474, 2.8%) had similar ages and gestational ages, but higher average body mass index and blood pressure compared with those who did not go on to develop preeclampsia ( Table 1 ). Women who subsequently developed preeclampsia were more likely to be obese, nulliparous, and Hispanic than women who did not subsequently develop preeclampsia. Women who subsequently developed preeclampsia were less likely to have smoked, but this did not reach statistical significance. Women who developed preeclampsia had higher GLT results and a higher rate of gestational diabetes mellitus. Infants of women with preeclampsia were delivered earlier, and likely as a consequence, had a smaller mean birthweight and were admitted to the neonatal intensive care unit more often than infants born to mothers without preeclampsia. Pregnancies complicated by preeclampsia resulted in delivery of small-for-gestational-age infants more often than in pregnancies not complicated by preeclampsia (15.9% vs 7.3%, P < .0001) ( Table 1 ). LGA infants were slightly less common in pregnancies complicated by preeclampsia compared with those that were not, but this did not reach statistical significance (8.4% vs 10.1%, P = .230) ( Table 1 ).
