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Keywords:

  • neonatal bone mineral content;
  • maternal smoking;
  • maternal body composition;
  • maternal activity;
  • parental birthweight

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Evidence is accumulating that intrauterine growth and development may influence an individual's risk of osteoporosis in later adult life. To examine maternal and paternal influences on intrauterine skeletal growth, we used dual-energy X-ray absorptiometry to measure the neonatal bone mineral content (BMC) and bone mineral density (BMD) of 145 infants born at term. Independently of the infant's duration of gestation at birth, the birthweights of both parents and the height of the father were positively correlated with neonatal whole body BMC. Women who smoked during pregnancy had infants with a lower whole body BMC and BMD; overall, there was a 7.1-g (11%) average difference between whole body BMC of infants whose mothers did and did not smoke during pregnancy (p = 0.005). Women with thinner triceps skinfold thicknesses (reflecting lower fat stores) and those who reported a faster walking pace and more frequent vigorous activity in late pregnancy also tended to have infants with a lower BMC and BMD (p values for BMC; 0.02, 0.03, and 0.05, respectively). Maternal thinness and faster walking pace but not maternal smoking or parental birthweight also were associated with lower bone mineral apparent density (BMAD). The influences on skeletal growth and mineralization were independent of placental weight, a marker of the placental capacity to deliver nutrients to the fetus. These observations point to a combination of genetic and intrauterine environmental influences on prenatal skeletal development and suggest that environmental modulation, even at this early stage of life, may reduce the risk of osteoporosis in adulthood.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

RECENT STUDIES suggest that the risk of osteoporosis in later life may be determined in part by environmental influences during intrauterine or early postnatal life. Cohort studies from the United Kingdom, Sweden, and Australia have shown that weight in infancy is a determinant of the bone mass, measured by dual-energy X-ray absorptiometry (DXA), of the same individuals during later childhood and adult life.1-4) Although weight at 1 year of age has been linked most strongly with subsequent bone mass, two studies have shown that birthweight also predicts later bone mass.(4, 5) One explanation of these findings is that candidate endocrine systems, most notably the growth hormone/insulin-like growth factor-1 (IGF-1) axis, might be programmed by an adverse intrauterine environment and that alterations in these axes subsequently manifest as different rates of skeletal growth and loss.(6) Alternatively, they could reflect consequences of altered skeletal development in utero.

Current data on the determinants of intrauterine skeletal growth have been derived largely from studies using ultrasound to assess fetal bone length or from neonatal anthropometry. Recent studies suggest that DXA can provide accurate and relatively precise measurements of bone mineral in neonates.(7) We report a population-based study in which we characterized the lifestyle, body composition, and diet of a sample of women through their normal pregnancies and relate these measures to the bone mineral measurements of their new-born infants.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The pregnant women were drawn from a consecutive group of 604 white women aged 16 years or older with singleton pregnancies and known menstrual dates who attended the antenatal booking clinic at the Princess Anne Hospital, Southampton, UK before 17 weeks gestation.(8) The women were approached for a study of maternal nutrition and fetal growth. Forty-four declined to take part or could not be visited until after 20 weeks' gestation, 11 had ultrasound scan results suggesting that their menstrual dates were unlikely to be correct, and 7 had infants that either died in the perinatal period or had major congenital abnormalities, leaving 542 who took part. A total of 519 delivered at term (≥259 days [37 weeks] gestation); 86% of those were approached for the study.

The women were visited by a trained research nurse in early pregnancy (median gestation, 14.7 weeks) and interviewed again later in pregnancy (around 28 weeks). They were asked about their menstrual and obstetric history and smoking habits. The women and the babies' fathers were requested to ask their parents about their own birthweights; these were obtained for 92% of the women and 80% of the fathers. Body mass index (BMI; weight/height2) was derived by using the woman's first recorded weight in pregnancy and her height measured in the antenatal clinic. The fathers were asked their height at the home visit. Social class was allocated according to the current or last occupation of the baby's father.(9) The women's skinfold thicknesses were measured at the triceps, biceps, and subscapular and suprailiac sites using Harpenden calipers.(10) Measurements at the four sites were highly correlated and studies of interobserver repeatability showed lowest measurement error at the triceps site (95% confidence limits: difference between observers −3.2 to 3.4 mm and difference between subjects 8.5 to 37.6 mm); data analyses focused primarily on the triceps skinfold thickness but also used the sum of skinfolds.(10) In early and late pregnancy a validated food-frequency questionnaire was administered, which assessed the average frequency of consumption of 100 foods or food groups in the preceding 3 months.(11) The nutrient content of a standard portion of each food was multiplied by its reported frequency of use to calculate average daily nutrient intake. Recent observations on diet in pregnancy(12) also led us to derive the average number of portions of green vegetables eaten by the women per week. In early and late pregnancy the women were asked to categorize their current walking speed into one of five groups (very slow, stroll at an easy pace, normal speed, fairly brisk, or fast) and on average of how frequently they performed any activities vigorous enough to work up a sweat or get out of breath.

After delivery, the infant and trimmed placenta were weighed, and the infant's crown heel length and head, abdominal, and mid-upper arm circumferences were measured.(13) Tests of repeatability have shown that discrepancies in measurements between fieldworkers were small in comparison with the overall between subject SD.(13) Duration of gestation at birth was calculated from the date of the woman's last menstrual period taking into account the length of her menstrual cycle.

From within the total group of 519 women who delivered at term, 210 gave birth to healthy infants on days when the whole body DXA scanner (Hologic QDR 2000; Hologic Inc., Waltham, MA, USA) was available for the study and were invited to take part in this investigation of neonatal bone mass; 145 (69%) were recruited and neonatal bone mineral measurements were performed using the high-resolution infant software package provided by the manufacturer (version V5.64P; Hologic Inc.). The typical radiation exposure during a whole body scan was <3 μSv. Using an anthropometric spine phantom, CVs for bone mineral content (BMC) and bone mineral density (BMD) were <1%. Scans were performed after feeding with the swaddled, sleeping infant on a pediatric platform; a satisfactory environmental temperature was maintained with a heat lamp. If a movement artifact was observed, a single repeat of the scan was performed after the infant had been pacified. This enabled measurement of whole body BMC in all but 2 of the 145 infants; movement artifact during part of the scan precluded measurement of spine BMC in 3 different infants. Measurements of whole body and spine BMC (g), BMD (g/cm2), and bone mineral apparent density (BMAD(14); g/cm3) were made within the first 13 days after delivery at a median of 2 days postnatal age. Within this narrow range, there was no relation between the infant's postnatal age and the bone mineral measurements.

All women provided informed written consent and the Local Research Ethics Committee approved the study. Statistical analysis was by linear regression of continuous variables, tabulation of means, two-sample t-tests, and analysis of variance (ANOVA). The independent effects of variables significantly associated with BMC and BMD in univariate analyses were examined by multiple regression. Where necessary, variables were transformed to satisfy assumptions of normality by taking logarithms.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Table 1 shows the characteristics of the 145 women, fathers, and infants. Comparison of these 145 subjects with the other 374 in the full cohort from whom they were drawn showed no statistically significant differences in maternal smoking during pregnancy (26% vs. 23%; p = 0.49), maternal triceps skinfold thickness (17.5 mm vs. 18.5 mm; p = 0.46), infant birthweight (3410 g vs. 3463 g; p = 0.24), or any of the other characteristics studied.

Table Table 1.. Characteristics of the Women, Fathers, and Infants
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Table 1 also shows the neonatal bone mineral measurements for the 81 male and 64 female infants. The infants' size at birth and neonatal bone mineral measurements increased with increasing duration of gestation at birth; whole body BMC rose by 0.738 g/day, whole body BMD rose by 0.00087 g/cm2 per day, spine BMC rose by 0.028 g/day, and spine BMD rose by 0.0011 g/cm2 per day. Male infants tended to be born after slightly longer gestation (281.6 days) than female infants (278.7 days; p = 0.05) and had a greater birthweight, crown-heel length, and head circumference (p values adjusting for duration of gestation; 0.02, 0.0004, and 0.001, respectively). In spite of these differences in the size of male and female infants, after taking account of gestation, there were only small and nonsignificant gender differences in neonatal bone mineral measurements.

There were strong (p < 0.0001) positive associations between birthweight, placental weight and neonatal head circumference, crown-heel length, abdominal circumference and ponderal index, and whole body BMC and BMD. These associations were similar in male and female infants and were weakened only marginally by taking account of the duration of gestation at birth (Table 2). The strongest associations were with birthweight (r = 0.79), abdominal circumference (r = 0.70), and crown-heel length (r = 0.61). With the exception of neonatal ponderal index, the infant's anthropometric measurements also were strongly associated with spine BMC and BMD (Table 2).

Table Table 2.. Mean Neonatal BMC and BMD According to Anthropometric Measurements for 145 Infants Born at Term
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Neonatal BMC and BMD were not related to maternal age, parity, or social class (data not shown). Whole body BMC and BMD were not related to maternal smoking at the time of their last menstrual period (p = 0.28 and 0.60, respectively) but were lower in the infants of women who continued to smoke during pregnancy (Table 2); there was no apparent dose effect of a higher reported number of cigarettes smoked per day. After adjustment for gestation at birth, the whole body BMC of infants whose mothers smoked during pregnancy averaged 7.1 g (11%) lower than that of infants whose mothers did not smoke (p = 0.005); their birthweights also were lower (by 306 g; p = 0.001), but there was no significant association between maternal smoking and placental weight (p = 0.25). Calculated BMAD was similar in infants of women who did and did not smoke during pregnancy (p = 0.65). Spine BMC and BMD were not related to maternal smoking before or during pregnancy.

As expected, both maternal and paternal height were associated with the infant's crown heel length at birth (r = 0.24 and 0.16, respectively). Paternal height also was associated with neonatal whole body BMC and BMD (gestation adjusted r = 0.22 and 0.14, respectively), but maternal height was not related to whole body BMC or BMD (r = −0.01 and −0.08, respectively; Table 3). Women of higher birthweight had infants with a greater whole body BMC and BMD (gestation adjusted p = 0.001 and 0.02, respectively; Table 3). Associations between paternal birthweight and the infant's whole body BMC and BMD were even stronger than those for maternal birthweight (gestation adjusted p < 0.0001 and 0.0003, respectively; Table 3). The heights of both parents and the birthweight of the father also were positively associated with spine BMC and BMD (Table 3).

Table Table 3.. Mean Neonatal BMC and BMD According to Parental Height and Birthweight and Maternal Smoking, Body Composition, and Activity During Pregnancy
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Women with thinner triceps skinfold thicknesses in early pregnancy had infants with lower whole body BMC and BMD (gestation adjusted p = 0.02 and 0.007, respectively; Table 3). Similar associations were found for maternal triceps skinfold thickness in late pregnancy and for the sum of the four site skinfold thicknesses. Maternal BMI was associated more weakly with whole body BMC and BMD (adjusted p = 0.21 and 0.13, respectively). Although thinner triceps skinfold thickness in early pregnancy was associated with lower spine BMC and BMD, these associations were weakened by taking account of the infant's duration of gestation at birth (adjusted p = 0.17 and 0.11, respectively).

The women's reported daily intakes of energy, calcium, and green vegetables in early and late pregnancy are shown in Table 1. Associations between higher reported energy intakes in early pregnancy and lower whole body BMC (gestation adjusted p = 0.03) and BMD (p = 0.10) were weakened by taking account of maternal smoking and triceps skinfold thickness (adjusted p = 0.25 for BMC and 0.53 for BMD); energy intakes in late pregnancy were not related to BMC or BMD. Likewise, maternal intakes of protein, carbohydrate, fat, calcium, and green vegetables in early or late pregnancy explained no additional variance in whole body BMC or BMD. Although intakes of energy, protein, carbohydrate, and fat in early pregnancy were not related to the infant's spine bone mineral, both spine BMC and BMD fell with increasing early pregnancy intakes of green vegetables (BMC and BMD fell by 0.20 per portion per week [p = 0.03] and 0.011 g/cm2 per portion per week [p = 0.03], respectively, after adjusting for gestation). Taking into account maternal triceps skinfold thickness and other parental characteristics strengthened these associations (both BMC and BMD, p < 0.001) and revealed positive associations between early pregnancy calcium intake and spine BMC and BMD (Table 4). Maternal intakes in late pregnancy explained no additional variance in spine BMC or BMD.

Table Table 4.. Final Multiple Regression Models Showing the Regression Coefficients and p Values
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Table 3 shows that although fewer women reported walking at “normal,” “fairly brisk,” or “fast” speeds in late pregnancy, there was an increase between early and late pregnancy in the reported frequency of activities that resulted in them working up a sweat or getting out of breath, perhaps reflecting an accentuated maternal response to exercise in late pregnancy. Maternal walking pace in early pregnancy was not associated with the infant's whole body BMC or BMD, but those who reported a slower walking pace in late pregnancy had infants with a higher whole body BMC and BMD (adjusted p = 0.03 and 0.008, respectively). In contrast, a slower walking pace in early pregnancy was associated with lower spine BMC and BMD (p = 0.008 and 0.03, respectively), but walking pace in late pregnancy was not related to spine BMC or BMD (p = 0.83 and 0.89, respectively). In a pattern similar to that for maternal walking pace, there were weak trends toward a lower frequency of vigorous activity in early pregnancy being associated with lower spine BMD (p = 0.11) and a lower frequency of vigorous activity in late pregnancy being associated with higher whole body BMC (p = 0.05) and BMD (p = 0.12).

Table 4 shows the results of multiple regression analyses, examining the independent effects of parental characteristics on neonatal bone mineral measurements, adjusting for the infant's sex and duration of gestation at birth. Maternal influences associated with lower whole body BMC and BMD were lower maternal birthweight, thinner triceps skinfold thickness, smoking, faster walking pace, and more frequent vigorous exercise in late pregnancy; lower paternal birthweight was associated with lower whole body BMC and BMD, and shorter paternal height was associated with lower BMC (Table 4). When placental weight was included in these models, it was a significant predictor of BMC and BMD (p < 0.001 and 0.001, respectively) but did not appreciably alter the coefficients for other variables. Including infant length in the BMC model weakened the effects of maternal smoking and paternal height (adjusted regression coefficients, −3.6 g [p = 0.08] and 11.6 g/m [p = 0.33], respectively) but had little effect on the associations with parental birthweight and maternal triceps skinfold thickness, walking pace, and activity; a similar pattern was found including infant length in the BMD model. Calculated whole body BMAD was lower in the offspring of women with a lower triceps skinfold thickness (p = 0.03) and a faster walking pace (p = 0.05) but not significantly related to the other parental characteristics. Substituting the infant's birthweight for BMD showed that lower birthweight was associated with maternal smoking, lower parental birthweight, and lower triceps skinfold thickness but not with maternal walking pace or activity (p = 0.92 and 0.95, respectively) in late pregnancy. Lower spine BMC and BMD were independently associated with shorter maternal height, thinner triceps skinfold thickness, lower paternal birthweight, slower walking speed, and greater green vegetable and lower calcium intakes in early pregnancy (Table 4). Spine BMAD was lower in the offspring of shorter women (p = 0.01), in those with a lower triceps skinfold thickness (p = 0.002), and in those with higher reported frequency of green vegetable consumption (p = 0.002) but was not significantly related to the other parental characteristics. Including maternal energy intake in the analyses explained no additional variance in whole body or spine bone mineral and all the associations with parental characteristics were similar in male and female infants.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

To identify the maternal and paternal determinants of neonatal skeletal mineralization, we prospectively studied a general population sample of term pregnancies. Our results confirm the strong, previously reported associations between birth size, duration of gestation at birth, and neonatal whole body BMC.(15) We found that the birthweights of both parents and the height of the father were positively correlated with neonatal whole body BMC. Women who smoked during pregnancy had infants with a lower whole body BMC; those with thinner triceps skinfold thicknesses (reflecting lower fat stores) and those who reported a faster walking pace and more frequent vigorous activity in late pregnancy also had infants with a lower BMC. Lower parental birthweight and maternal smoking, thinness, and faster walking pace also were associated with lower whole body BMD. These associations were independent of placental weight, a marker of the placental capacity to deliver nutrients.(16) The data suggest that parental birthweight and maternal cigarette smoking, body composition, and activity during pregnancy independently influence skeletal growth and mineralization in utero.

We, and others, have previously shown that weight at birth and, more strongly, weight at 1 year predict bone mass in later life.1-4) These relationships are independent of known genetic(17) and adult environmental(18) determinants of bone mass. Postnatal feeding patterns have been linked with infant weight and bone mass in childhood,(19, 20) but longer term follow-up studies have found no associations between infant feeding or other postnatal influences on growth such as infectious illnesses, and bone mass in later childhood or adult life.(2, 21) Mathematical analysis of growth after birth suggests that the transition between fetal and childhood phases of growth occurs at around age 1 year and has shown that infant growth rates are influenced strongly by the trajectory of intrauterine growth.(22, 23) These observations suggest that influences that determine the fetal phase of growth may have long-term implications for the risk of osteoporosis.

A woman's own birthweight is an established determinant of her offspring's birthweight and the trajectory of intrauterine growth, and our observation that maternal birthweight is related to neonatal BMC could be explained by this size concordance. Animal crossbreeding experiments and human ovum donation studies suggest that this association is more dependent on the intrauterine environment than on a shared genotype between mother and fetus.24-26) Consistent with our previous observation that paternal height and birthweight are associated with the infant's neonatal crown-heel length,(27) we found that these paternal influences were independent determinants of neonatal bone mass, indicating a genetic influence on fetal skeletal growth. Although nutritional effects on the fetal glucose-insulin-IGF-1 axis are thought to play a central role in mediating maternal effects on fetal growth,(28) constitutive expression of the paternally imprinted IGF-2 gene is important for fetal skeletal development28-30) and polymorphisms in genes regulating the level of expression of IGF-2 may mediate paternal effects on fetal growth.

Maternal smoking is known to result in reduced weight and crown-heel length at birth(31, 32) but is not associated with reduced neonatal fat mass,(31) suggesting a specific rather than a generalized growth impairment. To our knowledge, our data are the first to show an effect on reduced neonatal BMC. This remained highly significant after adjusting for placental weight but was weakened after taking into account neonatal length by including it as a covariate in the regression analyses or derivation of BMAD. This suggests that maternal smoking primarily influences skeletal growth, acting through mechanisms that are independent of placental size. The most widely cited potential mechanisms for the detrimental effects of maternal smoking are impaired placental function,(33) reduced uteroplacental blood flow,(34) and effects on fetal oxygen carrying capacity.(35) Another possible mechanism is a toxic effect of the heavy metal cadmium on fetal skeletal growth. Cadmium is present in high concentrations as a contaminant in tobacco smoke and has specific effects on osteoblast function(36) and on trophoblast calcium transport(37) that could have major implications for fetal bone development.

A further environmental determinant of intrauterine skeletal development identified in our study was the mother's body composition, reflected in her triceps skinfold thickness. Women with thinner skinfolds had infants with lower BMC and BMD. This may reflect a general effect of maternal thinness on fetal nutrient availability and growth.(12) Independently of maternal body composition, women who reported a slower normal walking pace and less frequent vigorous activity in late pregnancy had infants with greater whole body BMC and BMD. The effect of maternal activity on fetal skeletal development requires further exploration. An effect of maternal inactivity in late pregnancy on fetal bone accretion could result from inactivity accentuating maternal bone resorption during late pregnancy38-40) and a consequent increase in fetal calcium and/or phosphate availability.

Short maternal stature, slower reported walking speed, lower calcium intake, and higher green vegetable intake in early pregnancy were associated with lower neonatal spine BMC and BMD but not related to whole body BMC or BMD. These observations require confirmation. We cannot explain why maternal height was associated with spine BMC and neonatal crown-heel length(27) but not with whole body BMC or why maternal walking speed and diet in early pregnancy were associated with spine BMC. The observations might reflect a timing phenomenon: development of the spine and axial skeleton is most rapid during the “embryonic phase” of prenatal growth in the first trimester, whereas development of the appendicular skeleton is most rapid during the “placental phase” in the second trimester.(23) During the first trimester, there is increased calcium incorporation into the maternal skeleton(38) and placental nutrient transfer is not fully established; in this setting fetal calcium availability could perhaps be compromised by dietary influences(41) on maternal calcium absorption.

The mechanisms underlying a long-term effect of the intrauterine environment are not known but include fetal “programming” of endocrine systems that influence skeletal metabolism and persisting effects of altered skeletal growth and development in utero.(42) Detailed physiological studies in adults reveal strong associations between their weights at birth and in infancy and two pituitary-dependent endocrine systems that influence skeletal metabolism: the growth hormone/IGF-1 axis(7, 43) and the hypothalamic-pituitary-adrenal axis.(44, 45) Although it is not known whether variations in skeletal growth and development in utero may have persisting effects, an analogy with rickets suggests that it might. Support for long-term effects of the intrauterine environment comes from studies of children whose mothers smoked during pregnancy; maternal smoking results in low birthweight infants and recent data have shown that smoking during pregnancy is associated with a persistent deficit in the offspring's bone mass to age 8 years, even after adjustment for childhood height and weight.(19)

There are several weaknesses in our study. Although population-based and focusing on healthy infants delivered at term, we measured 145 neonates drawn from 519 term deliveries in women taking part in a study of maternal nutrition. However, there were no significant differences in maternal or neonatal characteristics between our sample and the group as a whole. Using the infant software developed by Hologic, Inc., DXA is now an established technique for measuring bone mass.(7) Although formal reproducibility data specific to infants have yet to be published, the whole body and spine BMC values we obtained were very similar to previously reported ranges in neonates.(15, 46, 47) In infants, variations in positioning may lead to error in estimating bone area, making BMD data less robust. Although this would tend to obscure associations, we found strong relations between maternal risk factors such as smoking and neonatal whole body BMD. We assessed the mothers' dietary intakes using a food-frequency questionnaire and asked the women and fathers to ascertain their own birthweights by contacting their parents. Although food-frequency questionnaires can be subject to bias,(48) validation of our questionnaire against food diaries indicated that it can be used to rank the nutrient intakes of individuals (e.g., unadjusted Spearman rank correlation coefficient for calcium intake = 0.41).(11) In keeping with other studies of recalled parental data,(49) validation of recalled maternal birthweights against a sample of those recorded at the time showed a high level of agreement.(50) Finally, there is considerable colinearity between birth size and neonatal bone mass, and it is difficult to delineate clearly specific influences on skeletal growth from general ones on body size. Future investigations incorporating detailed assessments of body composition and biochemical markers of bone turnover in cord blood will help to address this issue.

In summary, we have examined the determinants of neonatal bone mass in a population-based cohort of healthy term deliveries. Low parental birthweight, maternal cigarette smoking during pregnancy, thin maternal skinfold thicknesses, and higher levels of maternal activity in late pregnancy were independently associated with low neonatal bone mass. Because the fetal and early postnatal skeletal growth trajectory is known to be a determinant of bone mass in late adulthood and the future risk of hip fracture, further information is urgently required to better characterize the optimal intrauterine environment for later skeletal health. Meanwhile, measures to reduce cigarette smoking in pregnancy will enhance the skeletal development of the offspring in utero.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

We thank the mothers who gave us their time; the antenatal clinic, labor, and postnatal ward staff for their assistance; E.J. Thomas and P. Gillibrand for allowing us to include their patients; and S. Grant for performing ultrasound scans. Fieldwork was carried out by J. Hammond, V. Davill, L. Greenaway, and C. Sloan. This work was supported by a grant from the National Osteoporosis Society and subjects were drawn from a cohort study funded by WellBeing and the Medical Research Council.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
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