Objective
We sought to explore to what extent the presence of cardiometabolic and cardiovascular risk constitutions differ between pregnancies complicated by small-for-gestational-age (SGA) infancy, preeclampsia (PE), or a combination of both.
Study Design
We conducted a cohort study in women after pregnancies complicated by placental syndrome with fetal manifestations (SGA infancy [n = 113]), maternal manifestations (PE [n = 729]), or both (n = 461). Independent sample t test was used to compare cardiometabolic and cardiovascular risk factors between groups. Logistic regression was used to calculate odds ratios and adjusted odds ratios of the prevalence of the metabolic syndrome and its constituents between groups. Adjustments were made for maternal age, parity, smoking, interval between delivery and measurements, and intrauterine fetal demise.
Results
The metabolic syndrome was present in 7.5% of women who delivered SGA infants, 15.6% of former PE women, and 19.8% of women after pregnancy complicated by both SGA and PE. Hypertension was observed in 25% of former PE women and 15% of women with solely SGA. Women who delivered a SGA infant had lower global vascular compliance compared to former PE women without SGA.
Conclusion
Cardiometabolic risk factors consistent with metabolic syndrome relate to the maternal rather than to the fetal presentation of placental syndrome. Nonetheless, highest incidence of metabolic syndrome was observed in women with both PE and SGA. PE relates to chronic hypertension, whereas increased arterial stiffness seems to be associated with women who deliver a SGA infant.
Preeclampsia (PE) and small-for-gestational-age (SGA) infancy are common pregnancy-specific diseases referred to as placental syndrome with maternal and fetal clinical manifestations, respectively. They are thought to originate from shallow first-trimester trophoblast invasion, placental damage, and ultimately dysfunction. Both diseases are major causes of maternal and perinatal mortality and morbidity and are characterized by maternal oxidative stress, vascular endothelial excitation, and up-regulation of inflammatory state. Placental syndromes seem to be superimposed upon preexisting maternal conditions that are capable of jeopardizing placental and vascular function. Nonetheless, the clinical presentation of both disease entities of the placental syndrome is completely different. PE is clinically diagnosed as de novo hypertension with co-occurrence of proteinuria developing >20th week of gestation, whereas SGA is defined as a neonate whose weight in reference to a certain population is lower than expected for the gestational age at birth. Although PE is often associated with SGA, SGA can, on the one hand, occur in the absence of maternal features while, on the other hand, PE can also occur without SGA.
Women with a history of PE have a 2- to 7-fold increased risk for developing cardiovascular disease (CVD) later in life compared to women with a history of uncomplicated pregnancies. Women who gave birth to a SGA infant are, independent of PE, also at increased risk for developing CVD, although to a lesser extent. It has been suggested that the increased risk of CVD after placental syndromes comes from cardiovascular and cardiometabolic risk factors that were already present before pregnancy, suggesting that these women are already destined to develop vascular disease. Therefore the American Heart Association suggests including the obstetric history in determining the gender-specific risk of later CVD in women. The metabolic syndrome, an independent risk factor for CVD, tends to be more often present in women after PE rather than after sole SGA. Nonetheless, it may be that the concurrent presence of both SGA and PE relates to the highest risk on cardiovascular jeopardy.
In this study, we tested the hypothesis that combined fetal-maternal presentation of placental syndrome relates strongest to the presence of maternal cardiometabolic and cardiovascular risk factors.
Materials and Methods
In this cohort study, we selected women with pregnancy complicated by maternal (PE) and/or fetal (SGA infancy) presentation of placental syndrome from 1996 through 2010 that have had our standardized structured cardiovascular and cardiometabolic analysis at least 4 months postpartum. For the study, we only evaluated women with singleton pregnancies giving birth at gestational age of >22 weeks, without chromosomal abnormalities. In all, 1303 women fulfilled our inclusion criteria. These women had gone through the postpartum cardiovascular assessment with a median postgestation until evaluation interval of 9 months. The protocol for this retrospective cohort study was approved by the medical ethical committee of the Radboud University Medical Center (the Committee on Research Involving Human Subjects 2007/252) and the medical ethical committee board of Maastricht University Medical Center (medical ethical committee 0-4-049).
PE was defined based on the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria as de novo hypertension with a systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg in 2 repeated measurements (at least 6 hours apart) and the co-occurrence of proteinuria (≥0.3 g/24 h or ≥2+ on dipstick analysis) occurring >20 weeks of gestation in previously normotensive women or when proteinuria developed >20 weeks of gestation in women with preexisting hypertension. SGA infant was defined as a fetal birthweight <10th percentile according to the Dutch reference standard.
The postpartum screening was performed in 1 run and started at 8:00 AM after an overnight fast. Women were asked to refrain from drinking or eating 10 hours prior to measurements. None of the participants used oral contraceptives or was breast-feeding. Clinical data on obstetric history, medical history, and use of medication were collected from medical files and by self-report.
Height, weight, and BP were measured by an experienced and specialized nurse. Body mass index was calculated by weight (kg) divided by the height (m 2 ).
After 5 minutes of rest, arterial BP was measured on the right upper arm by a semiautomatic oscillometric device (Dinamap Vital Signs Monitor 1846; Critikon, Tampa, FL). The median value of 11 measurements in a period of 30 minutes was used.
Urine was collected in the 24 hours preceding the measurements. The 24-hour urine sample was assayed for albumin, protein, and creatinine output to calculate (micro)albuminuria corrected for creatinine output (g/mol creatinine) and total protein level (g/24 h).
Glucose, insulin, hemoglobin (Hb)A1c, high-density lipoprotein cholesterol, and triglycerides were collected from fasting blood samples. The homeostasis model assessment (insulin [mU/L] × glucose [mmol/L]/22.5) was used to estimate the degree of insulin resistance (HOMA-ir). HbA1c was expressed as HbA1c [mol]/Hb [mol] × 100%.
Metabolic syndrome was diagnosed based on the World Health Organization criteria as follows: the presence of hyperinsulinemia (fasting insulin ≥9.2 mU/L, fasting blood glucose ≥6.1 mmol/L, or HOMA-ir ≥2.2) along with ≥2 of the following: (1) body mass index ≥30 kg/m 2 , (2) dyslipidemia (triglycerides ≥1.69 mmol/L or high-density lipoprotein cholesterol ≤0.9 mmol/L), (3) hypertension: systolic BP ≥140 mm Hg and/or diastolic BP ≥85 mm Hg or the use of antihypertensive medication, and (4) microalbuminuria (≥2.5 g/mol creatinine) or proteinuria (≥0.30 g/24 h).
Chronic hypertension was categorized in 2 groups: (1) women on antihypertensive medication, and (2) women not using antihypertensive medication but with elevated BP (systolic BP ≥140 mm Hg and/or diastolic ≥90 mm Hg) during evaluation. Prehypertension was defined as a systolic BP between 120-139 mm Hg and/or diastolic BP between 80-89 mm Hg in women who did not use antihypertensive medication.
Echocardiography was performed using a cross-sectional phased-array oscillometric device (Agilent Sonos 5500; Philips Medical System, Eindhoven, The Netherlands; and Hewlett-Packard Sonos 2000 and 2500; Hewlett-Packard Company, Palo Alto, CA). We estimated the mean aortic velocity time integral by averaging the outer edge tracings of 5 consecutive continuous wave Doppler registrations of the left ventricular outflow tract velocity. By taking the product of velocity time integral and the midsystolic cross-sectional area at the level of the left ventricular outflow tract in the parasternal long-axis view, we obtained stroke volume (mL). Heart rate (beats/min) was obtained by taking the reciprocal of the mean of 5 consecutive R-R intervals on the electrocardiogram multiplied by 60. Cardiac output (L/min) was obtained by multiplying stroke volume with heart rate. The assessments were performed offline using EchoPAC PC SW, version 6.1.2; Vingmed Ultrasound, Horten, Norway and Excelera; Philips, The Netherlands. Total peripheral resistance was calculated by dividing mean arterial pressure × 80 by cardiac output (stroke volume × heart rate). An estimate for arterial compliance (mL/mm Hg) was made by dividing the stroke volume by brachial artery pulse pressure.
Statistical analysis
The independent t test was used to analyze continuous data and these variables are presented as mean with SD. Not normally distributed data were analyzed nonparametrically using the Mann-Whitney U test and depicted as median with interquartile range. Categorical data were compared by the χ 2 (if at least 5 cases were present in each group) and presented as percentage. Logistic regression was used to calculate odds ratios (ORs). With multivariate regression analysis adjusted OR (aOR) were calculated. We corrected for maternal age (continuous), smoking (yes/no), primiparity (yes/no), interval between delivery and measurements, and intrauterine fetal demise. A 2-sided P value < .05 was considered statistically significant. In multiple comparisons we conducted Bonferroni adjustment to correct for the increased risk of a type 1 error. Consequently, a P value < .017 was considered statistically significant. All analyses were performed using SPSS Statistics 20 (IBM Corp, Armonk, NY).
Results
We included all participants with a history of a pregnancy complicated by SGA infancy (n = 113), PE (n = 729), or both (n = 461).
Demographic and obstetric characteristics are presented in Table 1 . Women in the PE group were more often primiparous and had a larger interval between delivery and measurements compared to SGA and SGA + PE groups. Women with solely SGA and SGA + PE were more likely to smoke at the time of assessment. In the SGA + PE group >70% of women delivered <34 weeks, which was higher compared to both other groups. The percentage of pregnancies resulting in intrauterine fetal demise was different between all groups and related mostly to the presence of SGA (26.8%, 12.1%, and 2.6% in the SGA, SGA + PE, and PE groups, respectively). Nearly 12% of women in the PE groups had preexisting hypertension, about twice that of solely SGA.
| Characteristic | SGA (n = 113) | PE (n = 729) | SGA + PE (n = 461) | P value | ||
|---|---|---|---|---|---|---|
| PE vs SGA | SGA + PE vs SGA | SGA + PE vs PE | ||||
| Maternal age, y | 31.4 (4.5) | 31.8 (4.2) | 31.2 (4.4) | .373 | .646 | .020 |
| BMI, kg/m 2 | 25.3 (7.0) | 25.5 (5.1) | 25.9 (5.5) | .775 | .347 | .178 |
| Smoking, % | 20.4 | 10.3 a | 17.8 b | .002 c | .527 | < .001 c |
| Primiparous, % | 72.6 | 83.8 a | 75.9 b | .004 c | .459 | .001 c |
| GA at delivery, wk | 32.6 (5.1) | 34.0 (3.6) a | 31.5 (4.1) b | .004 c | .048 | < .001 c |
| GA at delivery <34 wk, % | 57.5 | 46.4 | 70.9 a,b | .027 | .006 c | < .001 c |
| Fetal birthweight, g | 1258 (781) | 2118 (862) a | 1210 (630) b | < .001 c | .544 | < .001 c |
| Birthweight percentile <3, % | 57 (50.4) | 0.0 (0) | 105 (22.8) | < .001 c | < .001 c | < .001 c |
| Birthweight percentile 3–4, % | 19 (16.8) | 0.0 (0) | 91 (19,7) | < .001 c | .509 | < .001 c |
| Birthweight percentile 5–9, % | 37 (32.7) | 0.0 (0) | 265 (57.5) | < .001 c | < .001 c | < .001 c |
| IUFD, % | 26.8 | 2.6 a | 12.1 a,b | < .001 c | < .001 c | < .001 c |
| Interval between delivery and measurements, mo | 7.0 (5.0–20.5) | 10.0 (7.0–19.0) a | 9.0 (6.0–18.0) b | .010 c | .316 | .006 c |
| Preexisting hypertension, % | 6.2 | 11.8 | 11.9 | .079 | .083 | .965 |
| Antihypertensive medication, % | 8.0 | 15.2 | 13.5 | .043 | .118 | .406 |
a Significant difference ( P ≤ .017) compared to SGA group
b Significant difference ( P ≤ .017) compared to PE group
Cardiometabolic and cardiovascular variables of groups are presented in Table 2 . We did not observe a significant difference in glucose levels and in HbA1c and lipid profiles between groups. However, insulin levels and HOMA-ir indicating insulin resistance were higher in former PE women compared to women who solely delivered a SGA infant. Systolic BP and diastolic BP were higher in former PE women compared to those with an obstetric history of solely SGA. Moreover, diastolic (but not systolic) BP was also modestly higher in the PE group compared to the SGA + PE group. The prevalence of prehypertension seemed lower in the SGA group (24.8%) compared to the PE group (33.2%, P = .091) and the SGA + PE group (35.6%, P = .040) but did not reach the statistical significance threshold accounting for Bonferroni correction. Cardiac output and total peripheral vascular resistance did not differ between groups. Global vascular compliance was lower in PE + SGA group compared to the PE group ( P = .012).
| Variable | SGA (n = 113) | PE (n = 729) | SGA + PE (n = 461) | P value | ||
|---|---|---|---|---|---|---|
| PE vs SGA | SGA + PE vs SGA | SGA + PE vs PE | ||||
| Metabolic | ||||||
| Glucose, mmol/L | 4.9 (0.7) | 5.1 (1.1) | 5.1 (0.6) | .077 | .106 | .170 |
| Insulin, mU/L | 9.9 (5.5) | 11.2 (7.1) a | 11.8 (6.8) a | .017 b | .006 b | .151 |
| HOMA-ir | 2.2 (1.2) | 2.6 (1.9) a | 2.7 (1.8) a | .004 b | < .001 b | .293 |
| HbA1c, % | 5.3 (0.4) | 5.3 (0.5) | 5.3 (0.5) | .597 | .109 | .098 |
| Triglycerides, mmol/L | 1.0 (0.6) | 1.1 (0.9) | 1.1 (0.7) | .108 | .052 | .994 |
| HDL, mmol/L | 1.3 (0.3) | 1.3 (0.8) | 1.3 (0.3) | .971 | .825 | .782 |
| Hemodynamic | ||||||
| Systolic BP, mm Hg | 117 (13) | 120 (14) | 121 (16) a | .034 | .001 b | .057 |
| Antihypertensives + | 128 (15) | 129 (16) | 133 (21) | .838 | .508 | .175 |
| Antihypertensives – | 116 (12) | 118 (13) | 120 (14) a | .134 | .010 b | .062 |
| Diastolic BP, mm Hg | 70 (9) | 73 (10) a | 74 (11) a | .002 b | < .001 b | .424 |
| Antihypertensives + | 78 (9) | 79 (11) | 82 (13) | .802 | .410 | .152 |
| Antihypertensives – | 69 (9) | 72 (10) a | 72 (10) a | .007 b | .006 b | .605 |
| Prehypertension, % | 24.8 | 33.2 | 35.6 | .091 | .040 | .448 |
| Cardiac output, L/min | 5.2 (1.3) | 5.3 (1.2) | 5.3 (1.2) | .327 | .425 | .767 |
| TPVR, dynes × s/cm 5 | 1407 (353) | 1407 (327) | 1425 (344) | .998 | .627 | .372 |
| GVC, mL/mm Hg | 1.65 (0.42) | 1.71 (0.45) | 1.65 (0.45) c | .175 | .909 | .012 b |
a Significant difference ( P ≤ .017) compared to SGA group
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