Objective
The purpose of this study was to assess whether maternal factors that are associated with fetal lean and fat mass differ between sexes.
Study Design
Secondary analysis of a prospective cohort that delivered by scheduled cesarean section from 2004-2013. Maternal blood was collected before surgery for metabolic parameters. Placental weight and neonatal anthropometrics were measured within 48 hours. Anthropometric differences between sexes were assessed with the Student t test. Multiple stepwise regression analysis assessed the relationship between independent maternal variables and neonatal lean body mass (LBM), fat mass (FM), or percentage of fat as dependent variables in male and female infants combined and separately.
Results
We analyzed 360 women with normal glucose tolerance and a wide range of pregravid body mass index (16-64 kg/m 2 ) and their offspring (male, 194; female, 166). Male infants had more FM (mean difference, 40 ± 18 g; P = .03) and LBM (mean difference, 158 ± 34 g; P < .0001) than female infants. Percentage of body fat and measured maternal variables did not differ between sexes. In both sexes, placental weight had the strongest correlation with both neonatal LBM and FM, which accounted for 20-39% of the variance. In male infants, maternal height, body mass index, and weight gain were significant predictors of both lean and fat mass. In female infants, plasma interleukin-6 and C-reactive protein, respectively, were associated independently with percentage of body fat and LBM.
Conclusion
Our findings suggest that the body composition and inflammatory environment of the mother modulate the metabolic fitness of neonates, as predicted by fat and lean mass, in a sex-specific manner.
It is well-established that infants who are born small- or large-for-gestational age are at a higher risk of the development of cardiovascular disease, obesity, and metabolic deficiencies in later life. Understanding factors that influence fetal growth in utero are of clinical interest in the determination of a child’s long-term health. Maternal nutrition (ie, diet and body composition) and placental transport capability are key influences on fetal growth and are associated strongly with birthweight. However, increasingly, it is understood that birthweight is not the only marker of perturbations in fetal growth. It was reported previously that offspring of obese mothers have increased fat mass (FM), but not lean mass, in addition to increased insulin resistance, which suggests that fetal adiposity is sensitive to maternal nutrition and potentially underlies long-term metabolic fitness.
There is mounting evidence that the fetus responds to the maternal environment in a sex-specific manner. Male infants are born heavier and longer to well-nourished mothers, which suggests that male growth may be more sensitive to nutrient supply during pregnancy. Indeed, when mothers are nourished poorly, male infants tend to be more affected than female infants, which shows greater degrees of growth restriction (or fat deposition) and increases in cardiovascular disease risk in later life ; this sensitivity may be due to a mismatch in the supply and demand of nutrients. These findings suggest that the growth of male fetuses is more sensitive to maternal nutrition throughout pregnancy and that female fetuses may be more able to adapt to minor nutritional differences.
Maternal prepregnancy and early pregnancy body composition (fat and fat-free mass or, clinically, body mass index [BMI]) indicate long-term maternal nutrition and are thought to be better predictors of fetal outcome than weight gain, a marker of nutrition during pregnancy. Lampl et al showed that birthweights of male offspring were correlated more highly with maternal weight and height than female offspring birthweights. Although Lampl et al used birthweight as the primary outcome, the sex-specific effects of maternal anthropometrics on the growth of fetal fat and lean mass are unknown. We hypothesize that maternal anthropometric variables are correlated with neonatal body composition in a sex-dependent manner. To test this hypothesis, we analyzed a cohort of >300 healthy women with normal glucose tolerance levels in pregnancy who underwent scheduled cesarean delivery. Neonatal body composition was calculated from skinfold measurements collected within 48 hours of birth.
Materials and Methods
Data collection
This was a secondary analysis of a prospective cohort that delivered by scheduled cesarean section from 2004-2013. The indications for the vast majority of these women were elective repeat cesarean deliveries or breech presentation. Our exclusion criteria included pregnancies that were complicated by gestational diabetes mellitus, preeclampsia, chronic hypertension and illegal drug use, multifetal gestations, and infants with anomalies. Information on maternal demographics (from maternal report), height, and weight (from clinical records) was obtained after written informed consent and approval by the institutional review board at MetroHealth Medical Center. Maternal blood (after overnight fast) was collected before surgery for metabolic parameters. After delivery, the placenta was weighed. Within 48 hours of birth, neonatal anthropometrics were measured and recorded by a trained research nurse. Birthweight was measured on a calibrated scale, and a measuring board was used for length measurements. The flank skinfold was assessed in the midaxillary line directly above the iliac crest. Neonatal body composition estimates were made with the following validated equation : FM = 0.39055 (birthweight, kilograms) + 0.0453 (flank skinfold, millimeters) – 0.03237 (length, centimeters) + 0.54657. Lean body mass (LBM) was calculated as birthweight minus FM. Percentage of body fat was calculated as FM/birthweight × 100.
Metabolic measurements
Maternal fasting glucose level was measured on the YSI Glucose Analyzer (YSI Life Sciences, Yellow Springs, OH). Plasma insulin (Millipore, Billerica, MA), C-reactive protein (Alpha Diagnostic, San Antonio, TX), and interleukin-6 (R&D Systems, Minneapolis, MN) levels were measured by immunoassay according to manufacturers’ directions.
Analysis
Total pregnancy weight gain was calculated by weight at first antenatal visit (if <12 weeks of gestation) and last recorded pregnancy weight (>35 weeks of gestation). Net maternal gestational weight gain was calculated as total pregnancy weight gain minus neonatal birthweight and placental weight. Statistical modeling was used to determine maternal anthropometrics and metabolic parameters that predict neonatal growth in male and female offspring. Spearman correlation analysis was used to assess the association between neonatal anthropometrics and maternal and placental variables in male and female offspring separately. Variables that were found to be correlated with neonatal anthropometrics were included in the stepwise regression model. Forward stepwise regression analysis assessed the relationship between independent maternal variables and neonatal LBM, FM, or percentage of fat as dependent variables in male and female offspring separately. Semipartial correlation coefficients were calculated for each dependent variable in the resulting models. All statistical analyses were conducted with STATA software (version 10.1; StataCorp LP, College Station, TX).
Results
We analyzed the data for 360 women with normal glucose tolerance levels (based on a 1-hour 50-g glucose challenge test result of <135 mg/dL; if the results were positive, a 100-g oral glucose challenge was administered, according to the methods of Carpenter and Coustan ) and wide range of pregravid BMI (16-64 kg/m 2 ) and their offspring (n = 194 male and 166 female offspring). As shown in Table 1 , weight, length, and placental weight were higher in male than female offspring at birth. Male infants also had more FM (mean difference, 40 ± 18 g; P = .03) and LBM (mean difference, 158 ± 34 g; P < .0001) than female infants as measured by skinfolds. Adiposity (percentage of body fat) was similar between the sexes. No differences in maternal characteristics were detectable between male and female infants.
| Characteristic | Male | Female | ||||
|---|---|---|---|---|---|---|
| n | Mean ± SD | Minimum–maximum | n | Mean ± SD | Minimum–maximum | |
| Maternal | ||||||
| Gestational age, wk | 191 | 38.8 ± 0.7 | 36.0–41.0 | 164 | 38.8 ± 0.6 | 36.0–40.0 |
| Parity, n | 194 | 1.7 ± 1.0 | 0.0–6.0 | 166 | 1.7 ± 1.1 | 0.0–6.0 |
| Age, y | 194 | 28.1 ± 5.6 | 18.0–46.0 | 166 | 27.3 ± 5.9 | 18.0–42.0 |
| Race (black/Hispanic/white), % | 193 | 38/12/49 | 164 | 37/10/53 | ||
| Prepregnancy weight, kg | 194 | 81.2 ± 23.3 | 42.3–156.8 | 165 | 82.6 ± 24.6 | 43.1–164.5 |
| Height, m | 194 | 1.6 ± 0.1 | 1.5–1.8 | 166 | 1.6 ± 0.1 | 1.4–1.9 |
| Prepregnancy body mass index, kg/m 2 | 194 | 30.8 ± 8.4 | 16.0–55.2 | 165 | 31.3 ± 8.9 | 16.9–64.3 |
| Late pregnancy body mass index, kg/m 2 | 194 | 36.8 ± 7.9 | 20.8–57.5 | 166 | 36.6 ± 8.4 | 21.2–69.2 |
| Net weight gain, kg | 188 | 11.7 ± 8.3 | –5.3–42.9 | 153 | 10.5 ± 8.5 | –14.9–37.1 |
| Insulin, μU/mL | 190 | 18.3 ± 8.9 | 4.1–63.3 | 157 | 17.7 ± 9.8 | 3.0–73.4 |
| Glucose, mg/dL | 189 | 77.9 ± 9.0 | 54.0–118.0 | 156 | 77.0 ± 9.5 | 54.0–107.0 |
| Homeostasis model assessment-estimated insulin resistance | 189 | 3.6 ± 2.1 | 0.7–16.0 | 156 | 3.5 ± 2.3 | 0.5–19.4 |
| C-reactive protein, ng/mL | 124 | 9345 ± 7221 | 435–28,482 | 86 | 9334 ± 6891 | 795–26,721 |
| Iinterleukin-6, pg/mL | 111 | 3.8 ± 3.0 | 0.7–18.8 | 92 | 3.3 ± 1.7 | 0.9–8.5 |
| Triglycerides, mg/dL | 85 | 184 ± 78 | 56–541 | 67 | 195 ± 75 | 72–425 |
| Neonatal | ||||||
| Birthweight, kg | 194 | 3.4 ± 0.5 | 1.9–5.0 | 165 | 3.2 ± 0.4 a | 2.1–4.8 |
| Length, cm | 192 | 49.3 ± 2.1 | 39.8–54.4 | 164 | 48.5 ± 2.0 a | 42.4–57.1 |
| Fat mass, kg | 184 | 0.44 ± 0.19 | 0.02–1.12 | 156 | 0.40 ± 0.15 a | 0.07–0.87 |
| Lean mass, kg | 184 | 2.9 ± 0.3 | 1.9–3.9 | 156 | 2.8 ± 0.3 a | 2.1–3.9 |
| Body fat, % | 184 | 12.5 ± 3.7 | 1.1–23.8 | 156 | 12.2 ± 3.3 | 2.9–21.0 |
| Placental weight, g | 188 | 685.8 ± 172.7 | 294.3–1316.5 | 155 | 648.5 ± 148.9 a | 298.0–1189.5 |
| Fetal:placental weight | 188 | 5.1 ± 0.9 | 2.9–8.9 | 154 | 5.1 ± 1.0 | 3.1–11.4 |
| Insulin, μU/mL | 183 | 7.5 ± 4.4 | 1.9–30.2 | 155 | 7.8 ± 4.5 | 0.8–26.3 |
| Glucose, mg/dL | 184 | 66.6 ± 12.6 | 27.0–122.0 | 157 | 66.5 ± 11.5 | 33.0–111.0 |
| Homeostasis model assessment–estimated insulin resistance | 182 | 1.2 ± 0.8 | 0.3–6.6 | 154 | 1.3 ± 0.8 | 0.1–5.3 |
Univariate analysis with the use of Spearman rank correlation assessed the associations between body composition (FM, LBM, adiposity) at birth and maternal and placental variables in all infants and in male and female infants separately ( Table 2 shows correlation coefficients). In both male and female infants, placental weight was associated significantly with FM, LBM, and percentage of body fat. Maternal height ( Figure 1 , A) and gestational age were associated with LBM in both male and female infants, but all other maternal variables displayed sex-specific associations with neonatal body composition.
| Maternal variables | Neonatal lean body mass | Neonatal fat mass | Neonatal percentage of body fat | ||||||
|---|---|---|---|---|---|---|---|---|---|
| All | Male | Female | All | Male | Female | All | Male | Female | |
| Parity | –0.0544 | –0.0827 | –0.0346 | –0.0008 | –0.0614 | 0.0577 | 0.0392 | –0.0366 | 0.0991 |
| Gestational age | 0.1964 a | 0.2122 a | 0.1965 a | 0.1501 a | 0.1636 a | 0.1338 | 0.1271 a | 0.1540 a | 0.0916 |
| Age | 0.1540 a | 0.1486 a | 0.1281 | 0.0903 | 0.11 | 0.0522 | 0.0556 | 0.0821 | 0.0211 |
| Prepregnancy weight | 0.1276 a | 0.2079 a | 0.0593 | 0.1522 a | 0.2457 a | 0.0358 | 0.1554 a | 0.2423 a | 0.0512 |
| Height | 0.1956 a | 0.2193 a | 0.1772 a | 0.0949 | 0.1529 a | 0.0282 | 0.0557 | 0.1124 | –0.0122 |
| Prepregnancy body mass index | 0.0673 | 0.1435 | –0.0073 | 0.1284 a | 0.2062 a | 0.022 | 0.1453 a | 0.2160 a | 0.0533 |
| Net weight gain | 0.1398 a | 0.2350 a | 0.0166 | 0.1574 a | 0.2480 a | 0.046 | 0.1437 a | 0.2336 a | 0.0403 |
| Placental weight | 0.6543 a | 0.6906 a | 0.5950 a | 0.6107 a | 0.6748 a | 0.5044 a | 0.5514 a | 0.6271 a | 0.4369 a |
| Free fatty acids | 0.1211 | 0.0745 | 0.2422 | 0.1341 | 0.1022 | 0.1969 | 0.1314 | 0.1196 | 0.1492 |
| Triglycerides | 0.119 | 0.1712 | 0.1012 | 0.1885 a | 0.2103 | 0.1795 | 0.1959 a | 0.2221 a | 0.1766 |
| Insulin | 0.044 | 0.047 | 0.0444 | 0.1357 a | 0.1265 | 0.1403 | 0.1562 a | 0.1446 | 0.1708 a |
| Glucose | 0.0848 | 0.0696 | 0.08 | 0.0513 | 0.0248 | 0.065 | 0.0319 | 0.0113 | 0.0515 |
| Homeostasis model assessment–estimated insulin resistance | 0.0546 | 0.0472 | 0.0603 | 0.1285 a | 0.1066 | 0.1482 | 0.1435 a | 0.1207 | 0.1721 a |
| Interleukin-6 | 0.0273 | –0.0195 | 0.1162 | 0.1457 a | 0.1119 | 0.1988 | 0.1873 a | 0.1642 | 0.2155 a |
| C-reactive protein | –0.0946 | 0.0307 | –0.2650 a | –0.0087 | 0.1106 | –0.2052 | 0.0297 | 0.136 | –0.1632 |
In male infants only, FM and adiposity were correlated with gestational age, prepregnancy weight, prepregnancy BMI ( Figure 2 , A), and net weight gain ( Figure 2 , B). FM in male infants was also correlated with maternal height; percentage of body fat was associated with maternal triglycerides. Lean mass in male infants was associated with maternal age, prepregnancy weight, and net weight gain ( Figure 1 , B). Adiposity (percentage of body fat) in female infants was correlated with maternal insulin level, Homeostasis model assessment–estimated insulin resistance and interleukin-6 levels ( Figure 2 , C). Female LBM was associated negatively with maternal C-reactive protein levels ( Figure 1 , C).
We did not find any significant correlations between paternal BMI and neonatal body composition in combined or separate analyses of male and female infants (data not shown). Furthermore, neonatal body composition did not differ by maternal race/ethnicity within or between sexes (data not shown).
Based on univariate analysis, variables that were found to be correlated significantly with neonatal anthropometrics in male and female infants combined or analyzed separately were included in forward stepwise regression analysis for LBM, FM, and percentage of body fat as dependent variables in their respective groups: male and female infants combined ( Table 3 ) and separately ( Table 4 ). In the combined analysis (male and female infants), placental weight was responsible for 30-37% of the variance in neonatal lean mass, FM, or percentage of body fat. Maternal prepregnancy BMI accounted for only 1% of variance in FM and percentage of body fat. Gestational age and maternal net weight gain were minor, but consistent, predictors for all body composition measures. Maternal height and age were also minor predictors of LBM variance when male and female infant data were combined. When male and female infants were modeled separately ( Table 4 ), placental weight had the strongest correlation with neonatal LBM, FM, and adiposity that accounted for 20-39% of the variance in both sexes. Maternal variables altogether accounted for <10% of the variance in neonatal body composition. Similar to the combined regression analysis ( Table 3 ), in male infants, maternal anthropometrics were significant predictors of both LBM and FM. Conversely, in female infants, only maternal indicators of systemic inflammation were predictive of LBM (C-reactive protein) or adiposity (interleukin-6). Gestational age was a minor (accounting for 2-4% of variance), but consistently significant, predictor of fat and lean mass in male infants more so than female infants.
| Variable | Factor | All without plasma metabolites | All with plasma metabolites | ||
|---|---|---|---|---|---|
| Sr 2 a | P value | Sr 2 a | P value | ||
| Lean body mass b | Placental weight | 0.37 | < .0001 | 0.37 | < .0001 |
| Gestational age | 0.04 | < .0001 | 0.04 | < .0001 | |
| Maternal height | 0.02 | .001 | 0.02 | .001 | |
| Net weight gain | 0.01 | .008 | 0.01 | .008 | |
| Age | 0.008 | .028 | 0.008 | .028 | |
| Fat mass c | Placental weight | 0.37 | < .0001 | 0.40 | < .0001 |
| Gestational age | 0.02 | .003 | 0.02 | .015 | |
| Net weight gain | 0.02 | .003 | |||
| Prepregnancy body mass index | 0.01 | .017 | |||
| Percentage of fat d | Placental weight | 0.30 | < .0001 | 0.32 | < .0001 |
| Gestational age | 0.02 | .003 | 0.02 | .002 | |
| Prepregnancy body mass index | 0.01 | .017 | 0.007 | .066 | |
| Net weight gain | 0.009 | 0.034 | |||
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