Maternal Obesity and Occurrence of Fetal Macrosomia: A Systematic Review and Meta-Analysis

Objective. To determine a precise estimate for the contribution of maternal obesity to macrosomia. Data Sources. The search strategy included database searches in 2011 of PubMed, Medline (In-Process & Other Non-Indexed Citations and Ovid Medline, 1950–2011), and EMBASE Classic + EMBASE. Appropriate search terms were used for each database. Reference lists of retrieved articles and review articles were cross-referenced. Methods of Study Selection. All studies that examined the relationship between maternal obesity (BMI ≥30 kg/m2) (pregravid or at 1st prenatal visit) and fetal macrosomia (birth weight ≥4000 g, ≥4500 g, or ≥90th percentile) were considered for inclusion. Tabulation, Integration, and Results. Data regarding the outcomes of interest and study quality were independently extracted by two reviewers. Results from the meta-analysis showed that maternal obesity is associated with fetal overgrowth, defined as birth weight ≥ 4000 g (OR 2.17, 95% CI 1.92, 2.45), birth weight ≥4500 g (OR 2.77,95% CI 2.22, 3.45), and birth weight ≥90% ile for gestational age (OR 2.42, 95% CI 2.16, 2.72). Conclusion. Maternal obesity appears to play a significant role in the development of fetal overgrowth. There is a critical need for effective personal and public health initiatives designed to decrease prepregnancy weight and optimize gestational weight gain.


Introduction
The term macrosomia describes a newborn with an excessively high birth weight indicative of fetal overgrowth. Most studies define macrosomia as a birth weight greater than or equal to 4000 g; however others use 4500 g as the cutpoint [1,2]. There has been further interest in the group of infants whose birth weight exceeds 5000 g [3]. Based on the variation in cut-points, we propose that macrosomia can be subdivided into Class I (birth weight 4000-4499 g), Class II (4500-4999 g), and Class III (≥5000 g). Alternatively, fetal overgrowth can be defined as a birth weight greater than the 90th percentile, corrected for gestational age [4].
Excessive growth in the fetus is a major contributor to adverse obstetrical outcomes. Khashu et al. examined the perinatal outcomes of 1842 macrosomic newborns in British Columbia, and Canada and identified significantly increased maternal risks of emergency Caesarean section, obstetrical trauma, postpartum hemorrhage, and maternal diabetes (all outcomes, < 0.001) [5]. Further, the infants were at higher risk of having birth trauma, of needing resuscitation, and of having an Apgar score less than seven at five minutes of life ( < 0.001) [5]. There is also evidence that macrosomia is associated with shoulder dystocia, brachial plexus injury, skeletal injuries, meconium aspiration, perinatal asphyxia, hypoglycemia, and fetal death [6]. Based on existing literature, there is little doubt that fetal macrosomia is associated with adverse pregnancy outcomes for both mother and infant. In addition, there is a recognized association between fetal macrosomia and long-term consequences for the newborn, including obesity, diabetes, and heart disease [7][8][9][10][11][12][13][14][15][16][17][18][19][20].

BioMed Research International
Although there is a plethora of information available in the literature regarding the contribution of maternal obesity, both preexisting and due to excessive gestational weight gain, to fetal macrosomia, the exact effect size of this relationship remains imprecise [4,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. At the time of our analysis, only one previous meta-analysis could be identified, in which the relationship between obesity and fetal overgrowth was examined as a secondary outcome [41]. Therefore, the objective of this project was to systematically review the literature regarding maternal obesity and fetal macrosomia and to complete a meta-analysis to provide the best possible estimate for the increase in macrosomia that can be attributed to maternal obesity.

Sources
The following databases were searched by a librarian experienced in systematic reviews: PubMed, Medline (In-Process & Other Non-Indexed Citations and Ovid Medline, 1950-2011), and EMBASE Classic + EMBASE. Databases were searched using a comprehensive and sensitive search strategy aimed at identifying as many studies as possible. The search strategy was formulated with the assistance of the librarians at the University of Ottawa. Results were filtered to include studies involving human subjects. The terms used in PubMed were as follows: ( 3 or 4, (7) 3 and 6.
The references for the resulting studies were then reviewed to identify any additional studies that were not identified in the preliminary search. The full texts of articles that were felt to be potentially relevant were obtained. Finally, review articles on obesity and maternal outcomes published between 2000 and 2011 were reviewed and their reference lists searched for additional potential studies. We did not attempt to locate unpublished studies. Electronic messages were sent to some authors to obtain clarification where necessary.

Study Selection
Observational studies, including prospective and retrospective cohort studies as well as case-control studies were sought for inclusion. To be eligible for inclusion, studies had to identify cases using the Institute of Medicine (IOM) definition of obesity (BMI ≥30.0 kg/m 2 ). Maternal obesity defined as prepregnancy, first trimester, or first antenatal visit BMI ≥30 kg/m 2 comprised the exposure variable. There had to be sufficient data present to allow for quantification of the number of obese patients included in the study. Studies also had to identify a control group of women with a BMI in the underweight range (BMI <18.5 kg/m 2 ), normal weight range (BMI 18.5-24.9 kg/m 2 ), or combined underweight + normal weight range (BMI <25.0 kg/m 2 ) that must have been obtained prepregnancy, in the first trimester, or at the first antenatal visit. Studies were included if maternal weight was obtained by self-report or direct measurement and infant birth weight was reported. For the outcome measures, studies had to include data that allowed for quantitative measurement of risk of overgrowth, defined as large for gestational age (≥90% ile) or fetal macrosomia (≥4000 g and/or ≥4500 g).
All studies with an English abstract were considered for inclusion. Studies that did not have full text in English were translated for review. All potential studies were assessed for eligibility by the first reviewer (LG) according to the prespecified criteria outlined in the previous sections. Studies and abstracts were screened and duplicates were removed. Data were extracted from each publication by the first reviewer. All identified studies were then reviewed by a second reviewer (ZF) and data extraction completed. Discrepancies regarding inclusion and extraction were then resolved by consensus.
The quality of included studies was assessed using criteria from the Newcastle-Ottawa Quality Assessment Scale [72]. The representativeness of the exposed and control groups, the means by which the exposure was ascertained, and followup rates were assessed. The overall quality of the included studies was then graded as low, moderate, or high according to prespecified criteria. All data were extracted independently by both reviewers and quality grades assigned; discrepancies were resolved by consensus.
A structured data form was developed prior to beginning data abstraction. Data from the different studies were then combined by meta-analysis. Frequencies were then used to generate unadjusted odds ratios and confidence intervals and Forest plots were generated. Meta-analysis was completed using the Comprehensive Meta-Analysis Version 2.0. A random effect model was used to estimate the overall effect Drawn from a different source than exposed cohort N/A Drawn from the same source as the exposed cohort Ascertainment of exposure (obesity) Self-report height and weight Self-report height or weight Measured height and weight  [73]. To assess statistical heterogeneity and its magnitude, we used Cochran's ( = 0.10) and the 2 statistic, respectively. A sensitivity analysis was then undertaken, including assessment of the effect of study quality.

Results
Thirty studies met the inclusion criteria ( Figure 1). The quality of studies was assessed for those included and excluded. Criteria for quality assessment were determined a priori (Table 1). Four studies were judged to be of high quality, fifteen were of moderate quality and eleven were of low quality. Quality assessment of the included studies [23, 24, 42-46, 48-59, 61-69, 71, 74] can be found in Table 2 and characteristics of excluded [4, 6, 21, 25, 27-29, 31, 34-39, 47, 60, 70, 75-307] studies can be found in Table 3. Of the included studies, nine were conducted in the United States, four in the United Kingdom, four in Denmark, two in Canada, two in Germany, and one in each of Hong Kong, Australia, Norway, Italy, India, France, Finland, Saudi Arabia, and the West Indies. Thus, the information in this review applies primarily to upper/middle income countries according to the World Bank classification [308]. The year of publication ranged from 1992 to 2010. Of included studies, eight had prospective cohort design, twenty-one had retrospective cohort design, and 1 was a retrospective case-control study. Eleven of the studies were conducted using population-based databases; these studies contributed 1,443,449 women to the meta-analysis.
When studies were reviewed, the outcome measures of interest were identified. Six studies reported on more than one outcome measure; information for all relevant outcome measures was abstracted. Thus, thirteen studies reported on LGA, sixteen reported on macrosomia ≥4000 g, and eight reported on macrosomia ≥4500 g. In the thirteen studies that examined the relationship between maternal obesity and infant birth weight ≥90% ile, there were a total of 162,183 obese parturients. The control group consisted of 285 (Table 3) 30 eligible studies included in the systematic review 4 non-English articles without   Figure 2). In the sixteen studies that examined the relationship between maternal obesity and macrosomia ≥4000 g,        there were a total of 20,693 obese parturients. The control group consisted of 110,696 underweight or normal weight women. A total of 13,612 infants had a birth weight ≥4000 g (10.4%). Of these, 3,275 were born to obese mothers; thus, 15.8% of obese mothers gave birth to a macrosomic baby weighing ≥4000 g. By comparison, 9.3% of underweight or normal weight mothers gave birth to a macrosomic baby weighing ≥4000 g ( = 10,337). Meta-analysis revealed an overall unadjusted odds ratio of 2.17 (1.92, 2.45) ( Table 3, Figure 3).
In the eight studies that examined the relationship between maternal obesity and macrosomia ≥4500 g, there were a total of 18,909 obese parturients. The control group consisted of 62,712 underweight or normal weight women. A total of 1,739 infants had a birth weight ≥4500 g (2.1%). Of these, 746 were born to obese mothers; thus, 3.9% of obese mothers gave birth to an LGA baby. By comparison, 1.6% of underweight or normal weight mothers gave birth to an LGA baby ( = 993). Meta-analysis revealed an overall unadjusted odds ratio of 2.77 (2.22, 3.45) (Table 3, Figure 4).
There was some important clinical heterogeneity between the included studies. For example, some studies included only normal weight patients in the control (17/30) while others included normal weight and underweight women (13/30). Also, most studies determined BMI using selfreported prepregnancy weight or did not provide information on how BMI was derived (20/30), while those studies that used measured weights had differing criteria for when that weight was measured (varied from <8 weeks to <16 weeks). Furthermore, some studies excluded women with hypertension or diabetes, while others included them.
There was also a marked amount of statistical heterogeneity, as assessed by the 2 statistic. For obese women, the 2 value for LGA was 97%, for macrosomia of ≥4000 g the 2 value was 69%, and for macrosomia of ≥4500 g the 2 value was 48%. These indicate diverse results and a large    amount of heterogeneity that cannot be explained by chance alone. Sensitivity analysis showed that including only high quality studies decreased heterogeneity for LGA; the 2 value improved to 0% from 97%. Including only high quality studies for LGA gives an odds ratio of 2.54 (95% CI 2.22, 2.92). As there was only one high quality study for macrosomia ≥4000 g, a similar analysis could not be undertaken.

Conclusion
This systematic review and meta-analysis confirms that maternal obesity is associated with fetal overgrowth. The odds of delivering an excessively large baby are increased: for large for gestational age infant (≥90th percentile) by 142%, for birth weight ≥4000 g by 117%, and for birth weight ≥4500 g by 277%. Determinants [302]. Fetal growth is a complex biologic process that is regulated by both maternal and fetal factors including genes and environment. Maternal obesity likely contributes to macrosomia via mechanisms including increased insulin resistance (even in women who do not have diabetes) resulting in higher fetal glucose and insulin levels [309]. Placental lipases metabolize triglycerides in maternal blood, allowing free fatty acids to be transferred in excess to the growing fetus [310].
The sensitivity analysis suggested the importance of conducting well-designed high-quality studies. Of particular importance is ensuring that maternal weight and height are directly measured as early in pregnancy as possible. Data from a recent prospective cohort study found that pregnant women of all body masses under-report their prepregnancy weight when first trimester weight is used as a proxy which further substantiates the need for objective measurements [311]. The limitations of using either selfreported prepregnancy weight or first trimester weight as a surrogate for prepregnancy weight must be considered. Few women, however, will enter a different class of body mass on the basis of this potential misclassification bias.
The generalizability of the results should be interpreted with caution. The majority of the studies included in this review (including several national population-based cohorts) were completed in North America and Western Europe. Few studies examined the role of maternal obesity on fetal overgrowth in women from Africa, Asia, or South America. As there are fundamental differences in nutrition, socioeconomic and educational status, and prenatal/intrapartum care in these regions, results may or may not be applicable.
The results from this meta-analysis provide convincing evidence of the positive relationship between maternal obesity and fetal overgrowth. Clearly, optimization of weight prior to pregnancy is ideal; individual and public health measures should be in place to encourage women to have a normal body weight prior to pregnancy. Maternity and newborn care providers should be aware of the increased risk among obese women, encourage lifestyle modifications that decrease gestational weight gain, and manage abnormal glucose metabolism to optimize fetal growth. This is important to decrease both intrapartum complications and neonatal sequelae (such as birth trauma and hypoglycemia). Furthermore, optimal fetal growth contributes to in utero epigenetic programming that favours a healthy long-term weight trajectory and metabolic profile. The association between maternal obesity and fetal overgrowth may well represent the first opportunity through which obese mothers can modify the intergenerational obesity cycle and result in healthier, happier families.