Objective
Because obesity is a risk factor for placental dysfunction, we hypothesized that maternal body mass index (BMI) would be associated with alterations in serum angiogenic markers.
Study Design
We included 2399 singleton pregnancies with and without placental dysfunction in a prospective longitudinal cohort study of angiogenic markers. We modeled the relationship between categorical and continuous BMI, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) over gestation, stratified by pregnancy outcome.
Results
In women with normal pregnancies, a higher BMI was associated with lower sFlt-1 values across gestation ( P < .0001), lower PlGF in the second and third trimesters ( P < .0001), and lower rate of change in PlGF ( P < .0001). Similar relationships were seen between maternal BMI, sFlt-1 ( P < .0001), and PlGF ( P = .0005) in women with clinically evident placental dysfunction.
Conclusion
The sFlt-1 value is inversely associated with maternal BMI. The pattern of change in PlGF is also dependent on maternal BMI, indicating that obese women may have abnormalities in angiogenesis near term.
Nearly 25% of women have a body mass index (BMI) in the obese range (≥30 kg/m 2 ) prior to pregnancy. Maternal obesity is associated with abnormal placental function clinically apparent as preeclampsia, clinically unrecognized intrauterine growth restriction, placental abruption, and potentially stillbirth. The mechanisms underlying the association between maternal obesity and ischemic placental disease are not well understood; however, there is a large body of literature on nonpregnant individuals to support that obesity, like preeclampsia, is a state of systemic inflammation characterized by endothelial dysfunction and abnormalities in angiogenesis. When taken together, these associations suggest the possibility that maternal obesity is associated with endothelial damage leading to abnormal placental function.
An evolving literature has linked the development of placental dysfunction with the expression of abnormal quantities of placental angiogenic proteins. In animal models, abnormal uteroplacental blood flow is associated with an increase in the antiangiogenic protein, soluble fms-like tyrosine kinase-1 (sFlt-1), which binds and antagonizes both placental growth factor (PlGF) and vascular endothelial growth factor. Although the analyses were limited by sample size, observational data from the Calcium for Preeclampsia Prevention trial suggested that the ratio of sFlt-1 to PlGF increases several weeks before the onset of clinical disease in women destined to develop preeclampsia.
In vitro, the adipokine visfatin alters the expression of vascular endothelial growth factor, providing a potential link between obesity and altered angiogenesis at the maternal-fetal interface. In vivo data connecting maternal obesity with altered placental angiogenesis are limited, however. Although some have attempted to examine the associations between maternal obesity and alterations of serum angiogenic markers in preeclamptic pregnancies, their conclusions are limited by small sample size, homogenous population, and a narrow range of maternal BMI. Furthermore, factors affecting angiogenic markers in normal pregnancies are not well understood.
We hypothesize that maternal obesity is associated with abnormalities in placental angiogenesis. We therefore investigated the effect of maternal BMI on serum angiogenic markers in normal pregnancies and those affected by clinical placental dysfunction.
Materials and Methods
Study population
This study is a secondary analysis of data from a prospective longitudinal cohort study designed to evaluate the utility of sFlt-1 and PlGF as markers for the diagnosis of preeclampsia. Women were recruited from 3 urban academic medical centers in Boston, MA, and Philadelphia, PA, from 2006 to 2008. Participants were eligible for enrollment if the estimated gestational age was 15 weeks or less, they were at least 18 years old, and they were able to provide informed consent and had no more than 3 fetuses. For this analysis, we excluded women missing first-trimester BMI (n = 41) as well as those who did not have serum samples at 3 or more study visits (n = 53). Of the remaining 2544 women, we excluded 143 with multiple gestations and 2 with stillbirths, leaving 2399 participants in the final analysis.
We considered women with preeclampsia, placental abruption, or delivery of a small-for-gestational-age infant to have clinical placental dysfunction. Preeclampsia was defined as systolic blood pressure elevation of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg after 20 weeks’ gestation, in association with proteinuria, either spot urine protein/creatinine ratio of greater than 0.20 or at least 300 mg or 24 hours ; each case was reviewed by a consensus committee of site primary investigators (K.-H.L., S.I.P., or T.F.M.). The diagnosis of placental abruption was based on clinician diagnosis at the time of delivery and was abstracted from the medical record by trained reviewers. We defined small for gestational age as a birthweight less than the 10th percentile (z-score less than –1.28) by published sex-specific growth curves.
Exposure assessment
Maternal BMI was calculated using weight and height measured in the first trimester. We defined normal weight as a BMI less than 25 kg/m 2 , overweight as a BMI 25 to less than 30 kg/m 2 , and obesity as a BMI of 30 kg/m 2 or greater.
Outcome assessment
Serum samples were collected at 4 study visits (<15 weeks, 16-20 weeks, 24-28 weeks, and 34-38 weeks) and stored at –80°C. sFlt-1 and PlGF were assayed at each time point using the Architect immunoassay (Abbott Diagnostics, Abbott Park, IL). All included participants had at least 3 specimens. We analyzed the data in both a cross-sectional and longitudinal fashion using all available specimens at each gestational age interval.
Covariates
Demographic (including maternal age, race, and ethnicity) and historical information (including pregnancy history, smoking status, use of assisted reproduction, a history of diabetes, and a history of hypertension) was collected by a participant questionnaire at the study enrollment. Medical records were abstracted by trained reviewers to obtain relevant pregnancy outcomes.
Statistical analysis
We compared baseline sociodemographics and prevalence of selected pregnancy characteristics by BMI category using analysis of variance (ANOVA) for continuous variables, and Mantel-Hanzel χ 2 tests for categorical variables. Statistical testing of angiogenic markers was performed after logarithmic transformation. For cross-sectional analyses, we compared sFlt-1 and PlGF by BMI category at each time point using ANOVA in women with and without ischemic placental disease. The pattern of change in sFlt-1 and PlGF was each modeled as a function of baseline BMI as a continuous variable using mixed linear models to adjust for significant confounders including maternal age, race, smoking, parity, gestational or pregestational diabetes, and chronic hypertension in women with and without placental dysfunction. All analyses were performed with SAS version 9.2 (SAS Institute Inc, Cary, NC).
The study was approved by the institutional review boards at Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and the Hospital of the University of Pennsylvania.
Results
Baseline characteristics
We included 2399 participants in our analysis. The majority (n = 1292, 53.9%) were normal weight, whereas 584 (24.3%) were overweight, and 523 (21.8%) were obese. Overweight and obese women were more likely to be African American or Hispanic than normal-weight women ( Table 1 ). Overweight and obese women were more likely than normal-weight women to have a diagnosis of chronic hypertension, preexisting diabetes, or gestational diabetes (all P < .0001). Of the participants, 321 had clinically evident placental dysfunction including 182 women with preeclampsia. Fewer normal-weight women (n = 137, 10.6%) developed clinical placental disease than overweight (n = 77, 13.2%) or obese (n = 107, 20.5%) women ( P < .0001) ( Table 1 ).
| Characteristic | First trimester BMI, kg/m 2 | Total (n = 2399) | P value | ||
|---|---|---|---|---|---|
| <25 (n = 1292) | 25 to <30 (n = 584) | ≥30 (n = 523) | |||
| Age, mean (SD) | 31.3 (5.4) | 30.9 (6.2) | 30.4 (5.7) | 31.0 (5.7) | .005 |
| Race/ethnicity | < .0001 | ||||
| Caucasian, n, % | 865 (67.0%) | 319 (54.6%) | 220 (42.1%) | 1404 (58.5%) | |
| African American, n, % | 172 (13.3%) | 146 (25.0%) | 214 (40.9%) | 532 (22.2%) | |
| Hispanic, n, % | 98 (7.6%) | 61 (10.5%) | 69 (13.2%) | 228 (9.5%) | |
| Asian, n, % | 110 (8.5%) | 31 (5.3%) | 6 (1.2%) | 147 (6.1%) | |
| Other or missing, n, % | 47 (3.6%) | 27 (4.6%) | 14 (2.7%) | 88 (3.7%) | |
| BMI at baseline, kg/m 2 , mean (SD) | 22.0 (1.9) | 27.1 (1.4) | 35.9 (5.7) | 26.3 (6.3) | < .0001 |
| Nulliparous, n, % | 424 (32.8%) | 156 (26.7%) | 105 (20.1%) | 685 (28.6%) | < .0001 |
| Current smoker, n, % | 31 (2.4%) | 17 (2.9%) | 28 (5.4%) | 76 (3.2%) | .005 |
| History of diabetes, n, % | 15 (1.2%) | 7 (1.2%) | 25 (4.8%) | 47 (2.0%) | < .0001 |
| History of hypertension, n, % | 24 (1.9%) | 24 (4.1%) | 52 (9.9%) | 100 (4.2%) | < .0001 |
| Gestational diabetes, n, % | 35 (2.7%) | 20 (3.4%) | 51 (9.8%) | 106 (4.4%) | < .0001 |
| GA at delivery, mean (SD) | 39.0 (1.7) | 38.9 (1.8) | 38.6 (2.1) | 38.9 (1.8) | .004 |
| Birthweight, g, mean (SD) | 3278 (520) | 3311 (532) | 3301 (635) | 3292 (550) | .12 |
| Placental ischemic disease, n, % a | 137 (10.6%) | 77 (13.2%) | 107 (20.5%) | 321 (13.4%) | < .0001 |
| SGA, n, % | 89 (6.9%) | 34 (5.8%) | 37 (7.1%) | 161 (6.7%) | .63 |
| Preeclampsia, n, % | 51 (4.0%) | 45 (7.7%) | 86 (16.4%) | 182 (7.6%) | < .0001 |
| Abruption, n, % b | 7 (0.5%) | 6 (1.0%) | 2 (0.4%) | 15 (0.6%) | .34 |
a Patient may have more than 1 of SGA, preeclampsia, and abruption
Normal pregnancies
Among women with normal pregnancy outcomes, the maternal BMI category was inversely associated with sFlt-1 at each time point in pregnancy ( P < .0001). When compared with values in normal-weight women, the median sFlt-1 concentration was approximately 10% lower in overweight women and 20% lower in obese women ( Table 2 ). The concentration of sFlt-1 increased over gestation for all participants, and although baseline values differed by BMI category, the pattern of change was similar, regardless of BMI category ( Figure 1 ). In a linear longitudinal regression accounting for change over time, each unit BMI increase was associated with a 2% decrease in the geometric mean sFlt-1 value ( P < .0001), and adjustment for covariates including age, race, parity, and comorbidities did not modify this relationship ( Table 3 ).
| Variable | First-trimester BMI, kg/m 2 | Total | P value a | ||
|---|---|---|---|---|---|
| <25 | 25 to <30 | ≥30 | |||
| Normal pregnancies, n (%) | 1155 (55.6) | 507 (24.4) | 416 (20.0) | 2078 | |
| sFlt, pg/mL, median (IQR) | |||||
| <15 wks | 5.4 (3.7–7.7) | 5.0 (3.5–7.2) | 4.1 (2.6–5.9) | 5.0 (3.4–7.3) | < .0001 |
| 16-20 wks | 6.5 (4.4–9.8) | 6.0 (4.0–8.7) | 5.2 (3.5–7.3) | 6.0 (4.0–7.0) | < .0001 |
| 24-28 wks | 6.2 (4.1–9.8) | 5.6 (3.8–8.1) | 4.6 (3.2–7.4) | 5.8 (3.8–8.7) | < .0001 |
| 34-38 wks | 10.4 (7.0–15.6) | 9.3 (6.7–13.8) | 8.4 (5.9–11.9) | 9.6 (6.6–14.3) | < .0001 |
| PlGF, ng/mL, median (IQR) | |||||
| <15 weeks | 20.3 (14.5–31.4) | 21.9 (14.8–32.3) | 20.7 (14.9–31.4) | 20.7 (14.6–31.7) | .28 |
| 16-20 wks | 146.6 (103.4–197.5) | 127.1 (93.4–184.1) | 122.9 (88.8–169.7) | 136.3 (97.2–191.4) | < .0001 |
| 24-28 wks | 495.8 (330.5–713.0) | 431.2 (279.8–630.0) | 378.8 (258.8–552.6) | 452.9 (304.4–663.4) | < .0001 |
| 34-38 wks | 410.6 (177.1–785.4) | 355.7 (175.0–658.9) | 350.9 (187.8–678.4) | 377.7 (177.6–740.5) | .16 |
| Pregnancies with ischemic placental disease, n (%) | 137 (42.7) | 77 (24.0) | 107 (33.3) | 321 | |
| sFlt in pg/mL, median (IQR) | |||||
| <15 wks | 4.8 (3.2–7.4) | 4.7 (3.6–7.6) | 3.7 (2.4–5.9) | 4.5 (3.0–6.9) | .0009 |
| 16-20 wks | 6.7 (4.8–10.2) | 6.7 (4.6–9.3) | 4.7 (3.3–8.5) | 6.0 (4.3–9.3) | .01 |
| 24-28 wks | 7.8 (4. 9–12.8) | 5.9 (4.2–10.5) | 5.3 (3.5–9.6) | 6.3 (4.2–11.1) | .005 |
| 34-38 wks | 15.6 (8.5–31.9) | 14.1 (9.1–29.0) | 13.1 (9.3–21.0) | 14.6 (9.1–25.6) | .42 |
| PlGF, ng/mL, median (IQR) | |||||
| <15 wks | 20.8 (14.5–31.4) | 22.0 (16.0–40.3) | 20.4 (15.7–31.1) | 20.9 (15.2–32.4) | .30 |
| 16-20 wks | 130.1 (95.7–178.1) | 139.1 (97.9–204.0) | 107.3 (70.3–151.8) | 128.9 (87.1–177.5) | .01 |
| 24-28 wks | 382.3 (247.8–588.9) | 341.4 (224. 8–547.9) | 318.2 (173.9–472.3) | 349.0 (215.3–527.3) | .02 |
| 34-38 wks | 174.4 (78.7–350.1) | 169.0 (108.8–434.3) | 181.5 (78.4–371.8) | 173.7 (81.6–378.8) | .91 |
a P value by analysis of the variance across BMI category (cross-sectional at each point in gestation).
| Angiogenic marker | Predictor | Unadjusted | Adjusted a | ||
|---|---|---|---|---|---|
| Parameter estimate (95% CI) | P value | Parameter estimate (95% CI) | P value | ||
| sFlt-1 | BMI, kg/m 2 | –0.02 (–0.03 to –0.02) | < .0001 | –0.02 (–0.03 to –0.02) | < .0001 |
| Time | 0.13 (0.08–0.18) | < .0001 | 0.13 (0.08–0.18) | < .0001 | |
| BMI∗time | 0.0006 (–0.001 to 0.002) | .52 | 0.0006 (–0.001 to 0.002) | .54 | |
| PlGF | BMI, kg/m 2 | 0.003 (–0.003 to 0.008) | .32 | –0.004 (–0.01 to 0.001) | .12 |
| Time | 1.29 (1.23–1.35) | < .0001 | 1.29 (1.23–1.35) | < .0001 | |
| BMI∗time | –0.006 (–0.008 to –0.004) | < .0001 | –0.006 (–0.008 to –0.004) | < .0001 | |
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