Objective
To study the association of prepregnancy blood pressure, lipids, and glucose with length of pregnancy, and to assess whether the association between preterm delivery and later maternal cardiovascular disease may be due to common risk factors.
Study Design
Prospective study linking information of 3506 women in the HUNT Study with 4990 singleton births recorded in the Medical Birth Registry of Norway.
Results
Unfavorable prepregnancy levels of triglycerides, cholesterol, high-density lipoprotein-cholesterol, and glucose were associated with increased risk of preterm birth and shorter gestational length. Triglycerides above 1.6 mmol/L were associated with 60% higher risk of preterm birth (odds ratio, 1.6, 95% confidence interval, 1.0–2.5), compared with triglycerides below 0.7 mmol/L. Blood pressure was positively associated with risk of preterm birth and shorter gestational length, but these associations were substantially attenuated after adjustment for hypertensive disorders in pregnancy.
Conclusion
Women with unfavorable cardiovascular risk factors before conception have excess risk of preterm birth.
Preterm delivery has been related to increased risk of maternal cardiovascular disease and mortality later in life, but the underlying mechanisms are poorly understood. Possibly, preterm births and cardiovascular diseases share common causes or underlying risk factors, such as high blood pressure, dyslipidemia, or insulin resistance.
Pregnancies are metabolically stressful, and often characterized by up-regulation of inflammatory markers, gestational hyperlipidemia, and insulin resistance. If the mother has a predisposition to cardiovascular disease, reduced ability to adapt appropriately to the vascular and metabolic changes may increase the risk for preeclampsia or intrauterine growth restriction (IUGR). Women with these conditions tend to have high blood pressure before pregnancy, and in women with preeclampsia prepregnancy, serum lipids also tend to be unfavorable. In the long-term, there is increasing evidence that women with preeclampsia or IUGR are at increased risk for cardiovascular disease. With this background, it seems plausible that prepregnancy unfavorable cardiovascular risk factors may be associated with the risk of preterm birth.
Recently, one study has assessed the association of plasma lipids measured before conception and the risk of preterm birth, indicating that both low and high levels of total cholesterol were related to preterm birth. In the current study, we linked data from a large population-based study with data from the Medical Birth Registry of Norway to assess whether body mass index (BMI), plasma lipids, glucoses, and blood pressure measured before conception are associated with the length of pregnancy.
Materials and Methods
Data from the second wave of a Norwegian population study (the HUNT Study) were linked to data from the Medical Birth Registry of Norway. The HUNT Study has been described elsewhere, but briefly, all residents of Nord Trøndelag County in Norway 20 years and older were invited to participate in the second wave between 1995 and 1997. A total of 34,882 women (75%) accepted the invitation and attended a clinical examination that included standardized measurements of height, weight, waist circumference, blood pressure, and nonfasting measurements of serum lipids and glucose. In addition, medical history related to diabetes and cardiovascular disease, and information on smoking habits, socioeconomic position, and educational attainment were collected using comprehensive self-administered questionnaires.
Since 1967, there has been compulsory notification of all deliveries after 16 weeks of gestation to the Medical Birth Registry of Norway. Midwives or doctors at the delivery units fill in a standardized form that includes information related to maternal health before and during pregnancy, complications during pregnancy and at birth, and comprehensive information on the newborn.
In total, 4189 women who participated in the second wave of the HUNT Study were registered with at least 1 birth (gestational age >22 weeks or birthweight above 500 g) in the Medical Birth Registry of Norway from 1995 to 2005. We excluded 598 women who were either pregnant at baseline or delivered within 9 months after participating in the study, and 62 women with multiple births and 23 women who had not attended the clinical examination, were also excluded. Thus, a total of 3506 women with 4990 singleton births were included in the analyses.
Study variables
Clinical examinations were conducted by specially trained nurses or technicians. Blood pressure was measured using an automatic oscillometric method (Dina map 845 XT; Criticon, Tampa, FL) after a minimum of 2 minutes rest in the sitting position. Three consecutive standardized blood pressure measurements were recorded at 1-minute intervals, and the mean of the second and third reading was used in this study. Cuff size was adjusted according to the measured arm circumference.
Venous blood sampling was performed non-fasting at attendance and time (hours) since last meal was recorded. Serum concentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides were determined using a Hitachi 911 Auto analyzer (Hitachi, Mito, Japan), and applying reagents from Boehringer Mannheim (Mannheim, Germany). Total serum cholesterol and HDL-cholesterol were measured after precipitation with phosphor tungsten and magnesium ions, and triglycerides were measured with an enzymatic calorimetric method. Glucose was measured using an enzymatic hexokinase method. Day-to-day coefficients of variation were 1.3-1.9% for total cholesterol, 2.4% for HDL-cholesterol, 0.7-1.3% for triglycerides, and 1.3-2.0% for glucose.
Waist circumference was measured horizontally at the height of the umbilicus. BMI was calculated as body weight (in kilograms) divided by the squared value of height (in meters). On the basis of self-report, the participants were classified as current, former, or never smokers.
Estimated gestational age at delivery was determined by the last menstrual period (LMP) until 1998, and since then, it was based on an ultrasound examination in the second trimester. Births up to 36 completed weeks or 259 days were defined as preterm and births at 37 weeks or later were defined as term deliveries. Nearly 80% of the deliveries had estimates of gestational age based on ultrasound scans. In addition, we had access to LMP dating for more than 97% of the deliveries. Gestational age was assessed both as a dichotomous variable (term/preterm) and as a continuous variable. Whereas the categorization into term/preterm is of clinical value, the use of gestational age as a continuous variable avoids loss of information and may also indicate biologically relevant differences.
Statistical analysis
Logistic regression analysis was used to estimate crude and adjusted associations of cardiovascular risk factors with the risk of a preterm birth. We used linear regression analysis to estimate crude and adjusted associations of maternal prepregnancy cardiovascular risk factors with mean gestational age at delivery. To account for deliveries by the same woman, we used the cluster option with robust standard errors in STATA (StataCorp, College Station, TX) to obtain variance estimates with adjustment for within-cluster correlation. Quintiles were chosen to handle all the variables in the same manner, and evaluate variations over a wide biologic range, and simultaneously secure sufficient statistical power in each category. Quintiles were constructed using the percentile function in STATA. Tests for trend across quintiles were performed by scoring the 5 categories (quintiles) from 1 to 5, and including the scores as a continuous variable in the models. In the multivariable analyses, we adjusted for the time interval from baseline measurements at the HUNT Study until birth, maternal age (continuous), parity (nullipara, para 1, para 2+), smoking status (never, former, or current smoking), educational level (<9 years, 9-12 years, 12-14 years, and >14 years), and whether the women received social security benefits. In additional analyses, we also adjusted for history of hypertensive disorders in pregnancy (preeclampsia, gestational hypertension, or chronic hypertension), and in the analyses of lipids and glucoses, we also adjusted for time since last meal.
STATA version 10.0 for Windows was used for the statistical analyses.
Results
Sociodemographic characteristics of the 3506 women in the study are shown in Table 1 and characteristics of the 4990 births that took place after the baseline measurements until 2005 are described in Table 2 . On average, 4 years had passed from baseline until the first subsequent delivery. Six percent of these deliveries were preterm and about one third of the preterm births occurred before the 34 gestational week ( Table 2 ). Unfortunately, medical indications for preterm births were not available, except for preterm prelabor rupture of membranes (PPROM), which constituted about 13% of the preterm births. Overall, 7% of all births, and 26% of preterm births, were complicated by hypertensive disorders in pregnancy (preeclampsia, gestational, or chronic hypertension). About 3.5% (n = 116) of the parous women had experienced preeclampsia in a previous birth before being included in this study (not tabulated).
| Variable | Study population, n = 3506 women |
|---|---|
| Mean age, y (SD) | 26.3 (4.4) |
| Smoking, n (%) a | |
| Never | 2136 (61) |
| Former | 422 (12) |
| Current | 938 (27) |
| Education, n (%) b | |
| <9 y | 198 (6) |
| 9–12 y | 931 (27) |
| 12–14 y | 1942 (55) |
| >14 y | 395 (11) |
| Receives Social Security c benefits, n (%) d | |
| No | 2818 (80) |
| Yes | 654 (19) |
| Mean BMI, kg/m 2 (SD) d | 24.4 (3.9) |
a Missing information on smoking in 10 women;
b Missing information on education in 40 women;
c Missing information on Social Security benefits in 34 women;
| Variable | n = 4990 births |
|---|---|
| Mean maternal age, y | 30.3 (4.1) |
| Parity, n (%) | |
| 0 | 1444 (29) |
| 1 | 1852 (37) |
| 2 | 1694 (34) |
| Gestational age, n (%) | |
| <34 wk | 87 (2) |
| 34-37wk | 185 (4) |
| >37 wk | 4718 (94) |
| Mean birthweight, g (SD) | 3634 (616.4) |
| Mean gestational age, d (SD) | 279.0 (14.5) |
| Deliveries with preeclampsia, n (%) | |
| No | 4809 (96) |
| Yes | 181 (4) |
| Deliveries with gestational or chronic hypertension, n (%) | |
| No | 4838 (97) |
| Yes | 152 (3) |
| Deliveries with cesarean section, n (%) | |
| No | 4183 (84) |
| Yes | 807 (16) |
| Induction of labor, n (%) | |
| No | 4311 (86) |
| Yes | 679 (14) |
In the crude analysis, there was a positive association of prepregnancy systolic blood pressure with the risk of preterm birth ( Table 3 ). The odds ratio (OR) for women with baseline systolic blood pressure above 131 mm Hg was 1.7 (95% confidence interval [CI], 1.1–2.5), compared with women with systolic blood pressure below 112 mm Hg ( Table 3 ). After adjustment for age at delivery, time interval from baseline measurements until delivery, education, parity, smoking status, and socioeconomic position, the positive association persisted. However, after additional adjustment for hypertensive disorders in pregnancy (preeclampsia, gestational, or chronic hypertension) the association was fully attenuated (OR, 1.2; 95% CI, 0.8–1.9), and similar attenuations were found when excluding women with hypertensive disorders in pregnancy. The results for prepregnancy diastolic blood pressure were similar to those for systolic pressure (results not shown). We found no association of maternal BMI with the risk of preterm birth. However, we found positive associations with preterm birth related to prepregnancy serum levels of unfavorable cholesterol, triglycerides, HDL-cholesterol, and glucose ( Figure ; Table 3 ). The crude and adjusted analyses showed nearly identical results, and associations were only modestly attenuated after additional adjustment for hypertensive disorders in pregnancy.
| In quintiles | Cases/noncases a | Crude estimate | Adjusted estimate b | P for trend | Adjusted estimate c | P for trend | |||
|---|---|---|---|---|---|---|---|---|---|
| Mean | 95% CI | Mean | 95% CI | Mean | 95% CI | ||||
| Systolic blood pressure, mm Hg | |||||||||
| 89–111 | 46/1013 | 1.0 | ref | 1.0 | ref | .03 | 1.0 | ref | .6 |
| 112–117 | 51/940 | 1.2 | 0.8–1.8 | 1.2 | 0.8–1.9 | 1.1 | 0.7–1.7 | ||
| 118–123 | 59/987 | 1.3 | 0.9–2.0 | 1.3 | 0.9–2.0 | 1.2 | 0.8–1.8 | ||
| 124–130 | 49/884 | 1.2 | 0.8–1.9 | 1.2 | 0.8–1.8 | 1.0 | 0.6–1.6 | ||
| 131–168 | 67/889 | 1.7 | 1.1–2.5 | 1.6 | 1.0–2.5 | 1.2 | 0.8–1.9 | ||
| Maternal BMI, kg/m 2 d (in quintiles) | |||||||||
| 16.2–21.2 | 55/938 | 1.0 | ref | 1.0 | ref | .7 | 1.0 | ref | > .99 |
| 21.3–22.8 | 46/964 | 0.8 | 0.5–1.2 | 0.8 | 0.5–1.2 | 0.8 | 0.5–1.2 | ||
| 22.9–24.5 | 56/947 | 1.0 | 0.7–1.5 | 1.0 | 0.7–1.5 | 1.0 | 0.6–1.5 | ||
| 24.6–26.8 | 56/931 | 1.0 | 0.7–1.5 | 0.9 | 0.6–1.3 | 0.9 | 0.6–1.3 | ||
| 26.9–45.0 | 58/922 | 1.1 | 0.7–1.6 | 1.1 | 0.8–1.5 | 0.9 | 0.6–1.3 | ||
| Cholesterol, d mmol/L | |||||||||
| 2.1–4.1 | 51/964 | 1.0 | ref | 1.0 | ref | .02 | 1.0 | ref | .09 |
| 4.2–4.6 | 45/1047 | 0.8 | 0.5–1.2 | 0.8 | 0.5–1.2 | 0.8 | 0.5–1.3 | ||
| 4.7–5.0 | 47/903 | 1.0 | 0.6–1.5 | 0.9 | 0.6–1.5 | 0.9 | 0.6–1.4 | ||
| 5.1–5.6 | 59/959 | 1.2 | 0.8–1.7 | 1.1 | 0.7–1.7 | 1.1 | 0.7–1.6 | ||
| 5.7–9.9 | 69/833 | 1.6 | 1.1–2.3 | 1.5 | 1.0–2.2 | 1.3 | 0.9–2.0 | ||
| Triglycerides, d mmol/L | |||||||||
| 0.2–0.6 | 37/961 | 1.0 | ref | 1.0 | ref | .008 | 1.0 | ref | .04 |
| 0.7–0.9 | 49/960 | 1.3 | 0.8–2.1 | 1.4 | 0.8–2.2 | 1.3 | 0.8–2.1 | ||
| 1.0–1.1 | 61/936 | 1.7 | 1.1–2.6 | 1.7 | 1.1–2.7 | 1.6 | 1.0–2.5 | ||
| 1.2–1.5 | 69/933 | 1.9 | 1.2–3.0 | 2.0 | 1.3–3.1 | 2.1 | 1.3–3.2 | ||
| 1.6–9.5 | 55/916 | 1.6 | 1.0–2.5 | 1.6 | 1.0–2.5 | 1.3 | 0.8–2.2 | ||
| HDL-cholesterol, d mmol/L | |||||||||
| 0.6–1.2 | 85/1145 | 1.6 | 1.0–2.5 | 1.6 | 1.0–2.5 | .04 | 1.4 | 0.9–2.2 | .11 |
| 1.3–1.4 | 63/1107 | 1.2 | 0.8–2.0 | 1.3 | 0.8–2.0 | 1.2 | 0.7–1.9 | ||
| 1.5–1.6 | 29/575 | 1.1 | 0.6–1.9 | 1.1 | 0.6–2.0 | 1.0 | 0.6–1.8 | ||
| 1.7–1.8 | 64/1227 | 1.1 | 0.7–1.8 | 1.2 | 0.7–1.9 | 1.1 | 0.7–1.8 | ||
| 1.9–3.1 | 30/652 | 1.0 | ref | 1.0 | ref | 1.0 | ref | ||
| Glucose, d mmol/L | |||||||||
| 1.0–4.4 | 56/1153 | 1.0 | ref | 1.0 | ref | .07 | 1.0 | ref | .12 |
| 4.5–4.7 | 56/1016 | 1.2 | 0.8–1.7 | 1.1 | 0.7–1.6 | 1.0 | 0.7–1.5 | ||
| 4.8–4.9 | 43/712 | 1.3 | 0.8–1.9 | 1.1 | 0.7–1.7 | 1.1 | 0.7–1.6 | ||
| 5.0–5.3 | 58/968 | 1.3 | 0.8–1.9 | 1.2 | 0.8–1.8 | 1.2 | 0.8–1.8 | ||
| 5.4–11.5 | 58/857 | 1.4 | 0.9–2.1 | 1.4 | 0.9–2.1 | 1.4 | 0.9–2.1 | ||
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