Articles

The association between pregnancy weight gain and birthweight: a within-family comparison
David S Ludwig, Janet Currie

Summary
Lancet 2010; 376: 98490 Published Online August 5, 2010 DOI:10.1016/S01406736(10)60751-9 See Comment page 937 Department of Medicine, Childrens Hospital, Boston, MA, USA (D S Ludwig MD); and Department of Economics, Columbia University, New York, NY, USA (Prof J Currie PhD) Correspondence to: Dr David Ludwig, Department of Medicine, Childrens Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA david.ludwig@childrens. harvard.edu

Background Excessive weight gain during pregnancy seems to increase birthweight and the osprings risk of obesity later in life. However, this association might be confounded by genetic and other shared eects. We aimed to examine the association between maternal weight gain and birthweight using state-based birth registry data that allowed us to compare several pregnancies in the same mother. Methods In this population-based cohort study, we used vital statistics natality records to examine all known births in Michigan and New Jersey, USA, between Jan 1, 1989, and Dec 31, 2003. From an initial sample of women with more than one singleton birth in the database, we made the following exclusions: gestation less than 37 weeks or 41 weeks or more; maternal diabetes; birthweight less than 500 g or more than 7000 g; and missing data for pregnancy weight gain. We examined how dierences in weight gain that occurred during two or more pregnancies for each woman predicted the birthweight of her ospring, using a within-subject design to reduce confounding to a minimum. Findings Our analysis included 513 501 women and their 1 164 750 ospring. We noted a consistent association between pregnancy weight gain and birthweight ( 735, 95% CI 710759, p<00001). Infants of women who gained more than 24 kg during pregnancy were 1489 g (14171560) heavier at birth than were infants of women who gained 810 kg. The odds ratio of giving birth to an infant weighing more than 4000 g was 226 (209244) for women who gained more than 24 kg during pregnancy compared with women who gained 810 kg. Interpretation Maternal weight gain during pregnancy increases birthweight independently of genetic factors. In view of the apparent association between birthweight and adult weight, obesity prevention eorts targeted at women during pregnancy might be benecial for ospring. Funding US National Institutes of Health.

Introduction
The fetal origin of adult disease, or prenatal programming, has been the subject of much study during the past two decades. Compelling evidence exists in support of the hypothesis, proposed by Barker and colleagues,1 that undernutrition during pregnancy and low birthweight increase risk of diabetes and cardiovascular disease in adulthood.2,3 Indeed, the adverse eect of perinatal undernutrition on long-term health might equal or exceed that of many conventional risk factors measured in adulthood. In view of the rising prevalence of obesity, a variant of the original Barker hypothesis has been formulated wherein overnutrition during pregnancy and high birthweight might cause obesity and related disorders in adulthood.49 According to this idea, excessive maternal bodyweight or weight gain during pregnancy perturbs the intrauterine environment during fetal development, producing permanent changes in the hypothalamus, pancreatic islet cells, adipose tissue, or other biological systems that regulate bodyweight. Research in animals has provided an experimental basis for this hypothesis.10,11 Levin and Govek10 studied dietsensitive female rats on standard or high-energy diets before and during gestation. Progeny of the mothers in the high-energy diet group gained more weight and had
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higher leptin concentrations than did progeny of mothers in the standard diet group, even though ospring from both groups were fed the same diet. In man, high birthweight predicts body-mass index (BMI) and adverse health outcomes later in life.1221 Results of observational studies have generally shown direct associations between maternal bodyweight or weight gain during pregnancy and birthweight or infant adiposity.2226 Moreover, maternal adiposity tends to be more strongly related to birthweight27,28 or childhood BMI29 than does paternal adiposity. However, these studies involving comparisons between individuals have fundamental limitations, most notably confounding due to genetic and environmental factors. For example, excessive maternal weight gain might be related to high birthweight simply because a mother and her infant share obesity-related genes. Therefore, we aimed to examine the association between maternal weight gain, as a measure of overnutrition during pregnancy, and birthweight using state-based birth registry data that allowed comparison of outcomes from several pregnancies in the same mother. This within-subject design serves to reduce or eliminate potential confounding by genetic, sociodemographic, and other individual characteristics.
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Methods
Study design and population
Data for this population-based cohort study were from individual vital statistics natality records covering all births in Michigan and New Jersey, USA, from Jan 1, 1989, to Dec 31, 2003. These records provide information about birth outcomes and maternal characteristics, including weight gain during pregnancy. A summary of the data les, including covariates, is available from the US National Center for Health Statistics. The state of Michigan provided a le that identied children born to the same mother. For New Jersey, we did this match in the states Department of Health oces on the basis of mothers name, race, birth date, and, in some cases, address. The le was then de-identied. From an initial sample of singleton births, we made the following exclusions: gestational age less than 37 weeks or 41 weeks or more (to focus on term pregnancies); maternal diabetes; birthweight less than 500 g or more than 7000 g (ie, extreme values that could result from data entry error); missing data for pregnancy weight gain; and births to mothers with only one child in the database, per study design. All reported pregnancies for the included mothers were retained in the sample. The study was undertaken with approval from the institutional review board at Columbia University, New York, USA.

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Data collection
All data used in this study were mandated by state law to be routinely obtained and recorded in birth records. The variables were: pregnancy weight gain, birthweight, an indicator for diabetes during pregnancy, week of gestation, maternal age, maternal education, maternal marital status, maternal race and ethnicity, maternal smoking, adequacy of prenatal care,30 method of delivery, sex of child, child parity, and year of birth. Physicians were responsible for completing or verifying birth records. Previous assessment suggests that data for birthweight obtained by this method are highly reliable.31 Physician report of pregnancy weight gain might have somewhat lower reliability. Particularly for women with delayed prenatal care, physicians are likely to establish pregnancy weight gain partly on the basis of mothers selfreport. Consistent with this possibility, the weight gain variable shows evidence of heaping in the raw data with rounding to 10-lb increments, accounting for the irregular weight gain frequency distribution in gure 1, especially around the 1820 kg (40 lb) category. However, one validation study that compared birth certicate data to medical records for a random sample of births in North Carolina reported an exact concordance for pregnancy weight gain in 828% of cases.32 Moreover, pregnancy weight gain obtained from birth records, similar to those used in our study, has been associated with many infant and maternal health outcomes,33 providing evidence of validity. Prepregnancy weight and height were not routinely recorded on birth certicates. Therefore, prepregnancy
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Figure 1: Distribution of (A) pregnancy weight gain and (B) birthweight

BMI could not be assessed in this study. Because the data les link births to the same mother, we could not establish whether siblings had the same father.

For National Center for Health Statistics data see http://www. cdc.gov/nchs/births.htm

Statistical analysis
Our primary hypothesis was that maternal weight gain during pregnancy is positively associated with birthweight, independent of confounding factors. The sample selection criteria serve to reduce or eliminate some sources of potential confounding (eg, maternal diabetes or prematurity), but others remain. Of the remaining potential confounders, some were measured by variables in our data (smoking), but others are not (genetic determinants of birthweight). Our strategy was to control for observable confounders through inclusion in the statistical models, and to control for unvarying unobservable confounders by comparing several pregnancies in the same mother. Using this approach, we kept the eect of interindividual dierences in genes and other potentially relevant factors to a minimum. Our models regressed a measure of birthweight (continuous or dichotomous) on indicators for the following categories of maternal weight gain: 02 kg,
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>24 kg, >46 kg, and so on, until >2224 kg, >24 kg. Hence, the eects of weight gain were not constrained to be linear. Unless otherwise noted, all of our specications allowed this exible relation between the measure of birthweight and the measure of maternal weight gain. The other covariates in all our models were: sex of child, maternal education (less than high school, high school, some college, college or more), maternal marital status, an indicator for maternal smoking during pregnancy, child parity (indicators for parity of 1, 2, 3, 4, 5 or more; NB, the rst birth recorded in the data was not necessarily the mothers rstborn child), indicators for each year of maternal age, and indicators for each year of birth. We included year of birth as a covariate to control for possible secular trends in birthweight unrelated to maternal weight gain during pregnancy. Where categorical data for controls were missing, we also included controls for missing variables. For models in which birthweight was a continuous variable, we did two analyses. First, we estimated models that included maternal xed eects using the XTREG command in STATA (release 11). Any maternal covariate that did not change with time was controlled by this procedure.34 Thus, the eect of the mothers weight before the rst observed pregnancy was controlled for, as was the eect of maternal height (even though neither were recorded in our data). Although xed-eects estimates might be less precise than are ordinary least-squares models, this issue is of little concern in a large sample size.35 We accounted for the presence of multiple values for each mother by using the CLUSTER command in STATA to correlate and adjust the errors. This procedure did not change our mean estimates or condence intervals, and therefore data are presented without clustering. As an alternative, conceptually simpler, analytical method to control for covariates that change between but not within individuals, we calculated dierences in weight gain and in birthweight between adjacent pregnancies for each mother. We then regressed changes in birthweight on categories of changes in maternal weight gain (<12 kg, 12 to 10 kg, and so on, until >10 to 12 kg, and >12 kg), including those of the other covariates described above which can vary between births for the same mother. The sample in these models was restricted to sibling pairs in whom the dierence in gestational age was less than 3 weeks. In these rst-dierence models, changes in the year of birth and in maternal age were the same. Also, most changes in parity were equal to one. Therefore, we included indicators for each year of maternal age at the time of the rst observed birth, and indicators for parity of the rst birth observed in the dataset. We also estimated models using a dichotomous high birthweight (>4000 g) measure as the dependent variable. The independent variables were categories of maternal weight gain (02 kg, >24 kg, >46 kg, and so on, until >24 kg). We estimated a xed-eect logit (or conditional logit) using the CLOGIT procedure in STATA.36 These
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Participants included in analysis sample* Maternal characteristics Maternal weight gain (kg) Maternal age (years) Mothers education (years) Number of ospring recorded in dataset Parity Infant characteristics Birthweight (g) Birthweight >4000 g Sex (male) Ethnic origin African American Hispanic White/other Maternal smoking Adequate prenatal care Gestation length (weeks) 221 263 (19%) 116 622 (10%) 826 865 (71%) 154 221 (13%) 649 940 (56%) 393 (11) 3453 (473) 138 303 (12%) 594 297 (51%) 137 (57) 277 (58) 132 (25) 241 (073) 217 (124)

Participants in analysis sample plus those missing data for weight gain

277 (58) 131 (25) 246 (079) 217 (125) 3446 (477) 159 288 (12%) 692 899 (51%) 273 563 (20%) 134 818 (10%) 949 179 (70%) 173 357 (13%) 751 452 (55%) 393 (11)

Data are mean (SD) or n (%). *513 501 mothers and 1 164 750 ospring. 590 626 mothers and 1 357 560 ospring, including siblings of ospring for whom information about pregnancy weight gain was missing.

Table: Descriptive characteristics of mothers and infants

models controlled for the same variables as did the xedeects models. Finally, we did subgroup analyses to examine for eect modication. On the basis of our primary results, we constrained the main eect of pregnancy weight gain to be linearie, the weight gain categories included in the previous models were excluded, and only a single continuous weight gain variable (and its interaction) was included. We chose 810 kg as the reference category for pregnancy weight gain because this category was within the 70115 kg range recommended for overweight women by the Institute of Medicine,37 and because the mean BMI in adult women in the USA was within the overweight range. All data are presented as means and SDs for maternal cohort characteristics or 95% CIs for outcome data.

Role of the funding sources

Funding sources had no role in study design; in the collection, analysis, and interpretation of data; in writing of the report; or in the decision to submit for publication. DSL had full access to all data analyses and JC had full access to all primary data in the study; both had nal responsibility to submit for publication.

Results
From an initial sample size of 2 359 843 singleton births, we made the following exclusions: gestational age less than 37 weeks or 41 weeks or more (358 833 births);
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maternal diabetes (75 665 births); extreme values for birthweight (2225 births); missing data for pregnancy weight gain (192 810 births); and births to mothers with only one child in the database (1 204 249 births). The nal study sample consisted of 1 164 750 singleton births to 513 501 mothers. The table shows descriptive characteristics of mothers and infants included in the analysis. These characteristics were similar to the 77 125 women and 192 810 ospring excluded from the study because of missing data for pregnancy weight gain. Figure 1A shows that many women exceeded recommended limits for weight gain during a singleton pregnancy, currently established as 11516 kg for those of normal weight before pregnancy, 7115 kg for those who were overweight, and 59 kg for those who were obese.37 Weight gain of more than 20 kg occurred in 139 040 (12%) pregnancies. As expected, pregnancy weight gain was positively associated with length of pregnancy (p<00001) and inversely associated with smoking (p<00001). Figure 1B shows that the birthweight distribution was roughly normal, with very few infants weighing more than 5000 g. Figure 2A, using a xed-eects model, shows a remarkably consistent association between maternal weight gain and birthweight ( 735, 95% CI 710759, p<00001). Relative to the reference category of 810 kg, infants of mothers who gained 2022 kg weighed 1038 g (9701106) more on average, whereas infants of mothers who gained greater than 24 kg weighed 1489 g (14171560) more. Figure 2B plots coecient estimates from the rst-dierence model. As expected, women who gained the same amount of weight in both pregnancies had infants of similar mean birthweight. Women who gained over 12 kg more in the second pregnancy had second infants who weighed 1076 g (9821170) more than rst infants, and those who gained over 12 kg less in the second pregnancy had second infants who weighed 858 g (935781) less. The distribution of changes in weight gain suggested that on average women gained slightly less weight for higher order pregnancies. The 10th, 50th, and 90th percentiles of the distribution of the dierence in pregnancy weight gain between an older sibling and the next youngest sibling were 624 kg, 045 kg, and 862 kgie, most women gained similar amounts of weight during subsequent pregnancies. Figure 3 shows the odds ratio for birthweight higher than 4000 g according to pregnancy weight gain from the conditional logit models. Relative to the reference category of 810 kg, the odds ratio of having a baby with a high birthweight was 172 (159186) for women who gained between 20 kg and 22 kg, and 226 (209244) for women who gained more than 24 kg. To test for residual confounding, we excluded women who had ever smoked, those who delivered by caesarean section, and those who had any pregnancy with gestational length less than 39 weeks or more than 40 weeks. The
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Figure 2: Associations between pregnancy weight gain and birthweight (A) Data from fully adjusted xed-eect model; dierences in birthweight are relative to the reference group (infants of mothers who gained 810 kg). (B) Data from rst dierence model; values of variables from the rst observed pregnancy were subtracted from those of the second observed pregnancy for each mother. Red bands show 95% CIs.

results of these analyses did not dier from those of our other models (data not shown). To examine the reliability of the independent variable, we did an analysis limited to the 208 067 women and their 469 472 infants for whom adequate prenatal care was shown on the birth certicate for all siblings. The results were very similar to those of the full group (data not shown). The women excluded from this analysis would have less data in the medical record on which an accurate assessment of pregnancy weight gain could be based, causing the physician to rely more on maternal self-report. We also looked for evidence of eect modication in subgroup analyses that included a main eect of weight gain () and an interaction describing the dierential weight gain between the main group and the subgroup (). On the basis of our primary results, we constrained the main eect of pregnancy weight gain to be linear. The slope for the association between pregnancy weight gain and birthweight was slightly smaller for African American
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Figure 3: Odds ratio for high birthweight (>4000 g) Red bands show 95% CIs.

participants ( 763, 734 to 791; 105, 160 to 050) and larger for male infants ( 701, 669733; 066, 026105) than for the main group. There was no eect of increased maternal age (age 28 years: 739, 723 to 771; 011, 054 to 034) or state (Michigan: 762, 723 to 800; 046, 095 to 004).

Discussion
Weight gain during pregnancy has been associated with high birthweight and measures of adiposity early in life. Our study, using a state-based registry with more than one million singleton births, provides evidence for a causal association that is independent of shared genes. We noted that every kg increase in pregnancy weight gain increases birthweight by about 735 g, and that variation in pregnancy weight gain through the recorded range can aect birthweight by about 200 g. Because high birthweight predicts BMI later in life,12,14,1719,21 these ndings suggest that excessive weight gain during pregnancy could raise the long-term risk of obesityrelated disease in ospring. High birthweight might also increase risk of other diseases later in life, including asthma, atopy, and cancer.13,15,16,20 With respect to potential mechanisms, the physiological pathways that might link fetal overnutrition to high birthweight have been described. During pregnancy, insulin resistance develops in the mother to shunt vital nutrients to the growing fetus.38 Excessive weight or weight gain during pregnancy exaggerates this normal process by further increasing insulin resistance and possibly also by aecting other maternal hormones that regulate placental nutrient transporters.39 The resulting high rate of nutrient transfer stimulates fetal insulin secretion, overgrowth, and increased adiposity. Indeed, maternal postprandial glycaemia in the third trimester, even within the normal range, is strongly associated with birthweight.40 The mechanisms whereby in-utero overnutrition and related physiological derangements aect bodyweight later in life remain speculative,9,11,39 though
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the crucial role of maternal hyperglycaemia has been further emphasised by recent research.41 The primary limitations of this study surround the possibility of measurement error and confounding. The pregnancy weight gain variable, more so than birthweight, is subject to recall and reporting bias that might vary by BMI, education, and level of prenatal care, among other factors. However, the within-subject design would tend to keep systematic bias arising from such factors to a minimum. Thus, some individuals might tend to underestimate and others to overestimate weight gain, although each would likely do so in a similar fashion across several pregnancies. Any random measurement error would tend to diminish apparent eect size,42 causing our estimates to be conservative. Additionally, results of a secondary analysis excluding individuals with inadequate prenatal carea group especially subject to error in the measurement of pregnancy weight gainwere very similar to those of the primary analysis. Other evidence of reliability derives from associations in the expected direction here (with length of pregnancy and smoking) and elsewhere (with pre-eclampsia, cephalopelvic disproportion, failed induction, and caesarean delivery)33 involving the pregnancy weight gain variable obtained from birth certicates. Furthermore, results of a validation study showed an exact concordance between pregnancy weight gain obtained from birth certicates and from medical records 828% of the time.32 Our within-subject design should eectively eliminate confounding by genetic and other unvarying factors. An important study limitation is the absence of information about maternal BMI before pregnancy. We address this limitation to some degree through the use of xed-eects models and adjustment for age and parity, controlling in part for BMI before the rst pregnancy and weight change between pregnancies. In any event, we contend that absence of prepregnancy BMI could not account for the primary ndings for a fundamental statistical reason. For a confounder to account for a positive association between an independent variable and a dependent variable, it must be associated with both in the same way, either positive or inverse. But prepregnancy BMI is inversely associated with pregnancy weight gain,4345 and positively associated with birthweight.2226 Additionally, we used a secondary analytical approach to examine for residual confounding, comparing dierences in subsequent pregnancies for each mother (gure 2B). We found that weight gain had a similar eect on birthweight irrespective of which pregnancy had greatest weight gain. This eect would not have occurred if prepregnancy BMI had diered between pregnancies in a systematic way that confounded the ndings. We recognise that pregnancy weight gain might aect birthweight dierently in women with high compared with low prepregnancy BMI (ie, eect modication). However, the similarity in ndings from analyses of subgroups expected to dier in prepregnancy
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BMI, such as older and younger women or black and white women, provides evidence against this possibility (and against confounding). Moreover, unrecognised eect modication by prepregnancy BMI, diet quality, level of physical activity, or other factors would not threaten the validity of our primary ndings. Several other methodological issues merit consideration. Concern about reverse causation can largely be dismissed, because increased fetal weight would make a small contribution (<10%) to the associated increase in maternal weight. Even so, we cannot rule out the possibility that hormonal or metabolic signals from the fetus might have an additional eect on maternal weight. Some women with unrecognised diabetes might have been present in our sample and have contributed to the observed eect size, especially if they developed the disease in some but not all of their pregnancies. Furthermore, diagnostic criteria and screening practices might have changed during the study. We aimed to minimise these eects by excluding individuals who reported diabetes during any pregnancy, a group that would be at highest risk during every pregnancy. Additionally, there was no signicant dierence in a subgroup analysis of older women, who are at substantially increased risk for this complication.46 Finally, we recognise the absence of information about paternity as a study limitation. However, the similar eect of maternal weight gain on birthweight in rst and second pregnancies, irrespective of which had greater weight gain, argues against any systematic bias. In conclusion, our ndings suggest that excessive maternal weight gain during pregnancy increases birthweight; in view of the apparent association between high birthweight and adult adiposity, pregnancy might be an advantageous time to initiate obesity prevention eorts.
Contributors DSL and JC both contributed to the design of the study and drafting of the report. DSL formulated the study hypotheses and JC supervised data collection and analysis. Conicts of interest We declare that we have no conicts of interest. Acknowledgments Data collection for this project was supported under US National Institutes of Health grant R21 HD055613-01. DSL was supported in part by a career grant from the National Institute of Diabetes and Digestive and Kidney Diseases (K24 DK082730) and a grant from the New Balance Foundation. Cecilia Machado provided assistance with research. We thank Cara Ebbeling, Matthew Gillman, Steven Gortmaker, Joseph Majzoub, and Eric Rimm for critical review of the report. References 1 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595601. 2 Barker DJP, Godfrey KM, Gluckman PD, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993; 341: 93841. 3 Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005; 353: 180209. 4 Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet 2002; 360: 47382. 5 Barker DJ. Obesity and early life. Obes Rev 2007; 8: 4549.

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