Obstetrics & Gynecology:
Maternal Obesity, Uterine Activity, and the Risk of Spontaneous Preterm Birth
Ehrenberg, Hugh M. MD; Iams, Jay D. MD; Goldenberg, Robert L. MD; Newman, Roger B. MD; Weiner, Steven J. MS; Sibai, Baha M. MD; Caritis, Steve N. MD; Miodovnik, Menachem MD; Dombrowski, Mitchell P. MD; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal–Fetal Medicine Units Network (MFMU)
* For the other members of the NICHD MFMU who participated in this study, see the Appendix online at http://links.lww.com/A617.
From the 1Case Western Reserve University-MetroHealth Medical Center, Cleveland, Ohio; 2Ohio State University, Columbus, Ohio; 3Drexel University, Philadelphia, Pennsylvania; 4Medical University of South Carolina, Charleston, South Carolina; 5George Washington University Biostatistics Center, Washington, DC; 6University of Tennessee, Memphis, Tennessee; 7University of Pittsburgh, Pittsburgh, Pennsylvania; 8University of Cincinnati, Cincinnati, Ohio; and 9Wayne State University, Detroit, Michigan.
Supported by grants from the National Institute of Child Health and Human Development (HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, HD19897, HD36801, and HD40544).
The authors thank Francee Johnson, RN, BSN, for protocol development and coordination between clinical research centers, Elizabeth Thom, PhD, for study design, data management, statistical analysis, and manuscript development, and Brian Mercer, MD, for his assistance and guidance with manuscript preparation.
Presented at the Annual Meeting of the Society for Maternal–Fetal Medicine, San Francisco, California, January 31 to February 2, 2007.
Corresponding author: Hugh M. Ehrenberg, MD, Ohio State University Medical Center, 325 E 12th Street, Columbus, Ohio.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To assess the associations among maternal obesity, uterine contraction frequency, and spontaneous preterm birth in women at risk for spontaneous preterm birth.
METHODS: In a secondary analysis, we analyzed data from 253 women at risk for spontaneous preterm birth (prior spontaneous preterm birth, vaginal bleeding) enrolled in a multicenter observational study of home uterine activity monitoring at 11 centers. All women wore a uterine activity monitor twice daily from 22 weeks through 34 weeks of gestation. Mean and maximal contractions/hour at 22–24, 25–26, 27–28, 29–30, 31–32 weeks, and at or after 33 weeks of gestation were compared between overweight/obese women (a body mass index [BMI] at 22–24 weeks greater than 25 kg/m2) and normal/underweight women (a BMI of 25 kg/m2 or less) at each gestational age interval. Multivariable analysis evaluated the influences of BMI, contractions, fetal fibronectin, and transvaginal cervical length on spontaneous preterm birth before 35 weeks.
RESULTS: Obese/overweight women (n=156) were significantly less likely to experience spontaneous preterm birth before 35 weeks (8.3% compared with 21.7%, P<.01). For each gestational age interval before 32 weeks, obese/overweight women had fewer mean contractions/hour (P<.01 for each) and maximal contractions/hour (P<.01 for each) than normal/underweight women, although their mean cervical lengths (34.3 mm compared with 33.1 mm, P=.25), and fetal fibronectin levels (7.1% compared with 7.2% 50 ng/mL or more, P=.97) were similar at study enrollment. Obese/overweight status was associated with a lower risk of spontaneous preterm birth before 35 weeks after controlling for contraction frequency and other factors evaluated at 22–24 weeks, but not at later periods.
CONCLUSION: Obese/overweight women at risk for spontaneous preterm birth exhibit less uterine activity and less frequent spontaneous preterm birth before 35 weeks of gestation than normal/underweight women.
LEVEL OF EVIDENCE: II
The prevalence of obesity in the United States continues to rise, with 33.1% and 33.2% of adult men and women classified as obese (body mass index [BMI] of 30 kg/m2 or more) in 2003–2004.1 The obstetric population is similarly affected, with 22.4% of women delivering in 2001–2004 conceiving while obese and another 23% being overweight.2
Pregravid body habitus is related to the risk of peripartum complications, including hypertension and preeclampsia, diabetes, macrosomia and labor arrest, as well as cesarean delivery and postoperative complications such as wound disruption and venous thromboembolism.3 Preconceptional body habitus also may influence the timing of parturition. Low pregravid BMI and inadequate weight gain are independent risk factors for preterm birth.4,5 Change in BMI between pregnancies may alter the risk of recurrent preterm birth,6 in that weight loss after a preterm delivery may increase the risk of recurrence. Conversely, the risk of spontaneous preterm birth decreases with increasing maternal BMI.7,8 The mechanisms responsible for reduced spontaneous preterm birth among obese/overweight women are not known. One plausible explanation is a reduction in uterine activity in these women.
The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network (NICHD-MFMU) Home Uterine Activity Monitoring Study (HUAM) was a prospective study that evaluated the association between uterine activity and spontaneous preterm birth.9,10 We postulated that, despite issues thought to exist in the accuracy of monitoring in this population, overweight/obese women would demonstrate less frequent uterine activity remote from delivery than nonoverweight/nonobese women and that this decreased activity would be associated with a lower risk of spontaneous preterm birth. The purpose of this study was to assess the associations among maternal obesity, uterine contraction frequency, and spontaneous preterm birth in at-risk women.
MATERIALS AND METHODS
This is a secondary analysis of data collected in a prospective observational cohort study conducted by the NICHD-MFMU Network. The primary study was conducted at 11 centers between 1994 and 1996. The original study design and population have been described previously.9 Approval from the human subjects review board was received at each institution. All women provided written informed consent. Briefly, women with singleton pregnancies at increased risk for preterm birth (history of one or more spontaneous preterm deliveries between 20 and 36 weeks of gestation, or second-trimester vaginal bleeding in the current pregnancy) were recruited. Women receiving or planning to use home uterine activity monitoring, prophylactic tocolytic therapy, or with a cervical cerclage in place were ineligible, as were those diagnosed with placenta previa or major fetal anomaly.
Screening for eligibility took place before 22 weeks of gestation as confirmed by ultrasonography. Enrolled subjects underwent twice daily home uterine activity monitoring from 22–34 weeks and were seen for study visits scheduled at 22–24 (visit 1), 25–26 (visit 2), 27–28 (visit 3), 29–30 (visit 4), 31–32 (visit 5) weeks, and 33 or more (visit 6) weeks. Women were instructed by trained research nurses to monitor for contractions using a uterine activity monitor for a period of 1 hour at least twice daily in sessions at least 2 hours apart. The first session was to be between 4 am and 3:59 pm, and the other was to be between 4 pm and 3:59 am. Monitoring was performed on 2 or more days per week from enrollment to 28 weeks and on 4 or more days per week after 28 weeks. Subjects were considered compliant if they held to the schedule of home monitoring and returned for visits 3 and 5. Cervicovaginal fluid swabs for fetal fibronectin testing were obtained at each study visit and quantitatively assayed according to previously published protocols.11 Transvaginal ultrasound cervical length measurements, obtained as previously described12 and digital examinations were performed at visits 1, 3, and 5.
For this analysis, data were analyzed from subjects grouped according to BMI at 22–24 weeks as “obese/overweight” (BMI more than 25 kg/m2) or “normal/underweight” (BMI 25 kg/m2 or less). For each specified period, the mean number of contractions per hour and maximal number of contractions per hour were calculated for each patient and compared between the two groups.
Statistical analysis was conducted using SAS 8.2 (SAS Institute Inc., Cary, NC). Continuous variables were compared using the Wilcoxon rank sum test. Categorical variables were analyzed using χ2, Fisher exact, or Mantel Haenszel χ2 trend13 test, where appropriate. Multivariable analysis included logistic regression to evaluate the independent association between maternal body habitus (as a discrete variable, obese/overweight compared with normal/underweight, and as a continuous variable, increasing BMI) and contraction frequency on spontaneous preterm delivery, both with and without adjustment for fetal fibronectin and cervical length measures. This modeling was restricted to three periods (22–24, 27–28, and 31–32 weeks) when both fetal fibronectin and cervical length were collected. A two-tailed nominal P<.05 was considered significant. No adjustments were made for multiple comparisons.
Two-hundred fifty-three compliant subjects with singleton pregnancies and BMI data available were included in this analysis (156 obese/overweight and 97 normal/underweight). Indications for inclusion were a history of one prior spontaneous preterm birth, (n=194, 76.7%), two or more prior preterm births (n=56, 22.1%), and second trimester vaginal bleeding (n=8, 3.2%). Five women had both vaginal bleeding and at least one prior preterm birth. At enrollment, baseline characteristics, including maternal race, parity, tobacco use, height, Bishops score, ultrasonographic cervical length, and fetal fibronectin level, were similar between groups (Table 1). When compared with normal/underweight women, obese/overweight women were older (27.3 years compared with 24.6 years, P<.01). The use of tocolytic drugs was evenly distributed between groups, with 24 (24.7%) subjects exposed in the low/normal weight group and 31 (19.9%) in the overweight/obese group (P=.36).
Spontaneous preterm birth before 35 weeks occurred in only 8.3% (n=13) of overweight and obese women, as opposed to 21.7% (n=21) of normal and underweight (P<.01). In this same cohort, indicated preterm birth rates were not different between groups (5 of 156 [3.2%] of the overweight/obese and 4 of 97 [4.1%] of the normal/underweight (P=.74)]. For each gestational age interval before 32 weeks, obese/overweight women had fewer mean contractions per hour (P<.01 for each; Table 2) and maximal contractions per hour (P<.01 for each; Table 2) than normal/underweight women. Table 3 describes the results for multivariable analysis, including various clinical characteristics. When mean contraction frequency and overweight/obese were simultaneously used to predict spontaneous preterm birth at less than 35 weeks, overweight/obese was always associated with decreased risk of early delivery (P<.02 for each period), but there was no association between contraction frequency and early delivery after adjusting for obese/overweight status (P>.05 in all cases). When BMI was analyzed as a continuous variable, a significant interaction between BMI and contraction frequency was found in relationship to spontaneous preterm birth at less than 35 weeks (P<.05). In the presence of increasing BMI, the relationship between contraction frequency and risk for spontaneous preterm birth strengthens. This interaction was significant at 22–24 weeks and 31–32 weeks, but not at 27–28 weeks.
Distinct multivariable analyses were performed that included cervical length and fetal fibronectin. These analyses revealed that fetal fibronectin was associated with an increased risk, and maternal obese/overweight status was associated with a decreased risk of spontaneous preterm birth before 35 weeks at 22–24 weeks (P=.02 for both), but not at 27–28 or 31–32 weeks. Increased mean and maximal contractions were associated with an increased risk at 27–28 weeks only (P=.01), whereas increased cervical length at all three periods was associated with a lower risk of spontaneous preterm birth (P<.01 for each). Findings were similar when BMI was analyzed as a continuous variable. However, the interactions between BMI and contraction frequency observed in the unadjusted model did not remain significant after adjustments for fetal fibronectin and cervical length.
We have found that obese and overweight women who are at risk for preterm birth have less frequent uterine contractions and lower maximal contraction frequency between 22 weeks and 34 weeks of gestation, as detected by external tocometry. Increasing BMI and decreasing contraction frequency remote from delivery were independently associated with a lower risk of spontaneous preterm birth, after controlling for other factors at some gestational ages, but not others. In this cohort at high risk for spontaneous preterm birth, we have confirmed prior data showing that heavier women are at a lower risk for spontaneous preterm birth before 35 weeks.7 After controlling for other factors, our analysis did not find significant relationships between contraction frequency and spontaneous preterm birth at 22–24 weeks or 31–32 weeks, but did at 27–28 weeks.
Published literature regarding a possible protective effect of obesity on preterm delivery risk is inconsistent in both study groups and outcome. Our work concurs with previous studies by Hendler et al7 and Smith et al14 showing a reduction in the rate of spontaneous preterm delivery among obese parturients. Hendler et al showed obese women to have significantly fewer preterm births less than 37 weeks (6.2% compared with 11.2%; P<.001) and less than 34 weeks (1.5% compared with 3.5%; P=.012). Smith et al showed that as BMI increased, the risk of indicated preterm birth increased whereas that of spontaneous preterm birth decreased (P<.001). Others have observed an increased risk of preterm birth among obese gravidas. In a large retrospective study evaluating the role of body habitus in prematurity among nulliparous women,15 obesity was associated with an increased risk of preterm birth less than 32 weeks when compared with lean control subjects (BMI less than 20 kg/m2) after adjustment for other factors (odds ratio 1.6; 95% confidence interval 1.1–1.3). Study of the same cohort by Cedergren found increased risk of preterm birth at less than 37 weeks and less than 32 weeks (5.4% compared with 4.5% and 0.8% compared with 0.6%, respectively). These studies did not distinguish clearly between indicated and spontaneous deliveries and were retrospective in nature. The differences in these studies may be due in part to differences in study populations, definitions of weight categories, and evaluated outcomes.
Potential explanations for our findings include an endocrine effect of increased adipose tissue on uterine contraction frequency or a technical measurement artifact related to difficulty in monitoring uterine contractions when the maternal abdomen is obese. The latter explanation is plausible, but if true would be expected to decrease in significance with gestational age, because the uterine fundus is more easily identified in women with normal or low BMI. Furthermore, after controlling for other confounding variables, the risk of spontaneous preterm birth was decreased in the obese and overweight group independent of uterine activity when screened at 22–24 weeks of gestation. As a consequence, when screening for risk of preterm delivery, overweight and obese women who demonstrate similar contraction frequency patterns to normal and underweight women may therefore be at particular risk to deliver before term.
The relationship between obesity and a reduced risk of spontaneous preterm birth is unexplained. Obesity is known to be a proinflammatory state in which the serum levels of inflammatory modulators associated with preterm birth, eg, TNF-α, IL-6, and IL-8, are elevated. On the other hand, obesity is associated with lower rates of cervical length less than 25 mm. Abnormal body habitus may affect timing of parturition through changes in cervical length.
Maternal obesity seems to be associated with less frequent spontaneous preterm birth through an unknown mechanism other than uterine quiescence. Although lack of cervical shortening may play a role, further study will be needed to describe the influence of body habitus on parturition and to perhaps take advantage of whatever process is at work in future efforts to prevent spontaneous preterm birth.
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