Obstetrics

High Gestational Weight Gain and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis
Sarah D. McDonald, MD, MSc,1,2,3,4 Zhen Han, MD, PhD,5 Sohail Mulla,6 Olha Lutsiv,6 Tiffany Lee,6 Joseph Beyene, PhD4; on behalf of the Knowledge Synthesis Group7
1 2 3 4 5 6 7

Division of Maternal-Fetal Medicine, McMaster University, Hamilton ON Department of Obstetrics and Gynecology, McMaster University, Hamilton ON Department of Radiology, McMaster University, Hamilton ON Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton ON Department of Obstetrics and Gynecology, First Affiliated Hospital of Xian Jiao Tong University, Shaanxi Province, Peoples Republic of China Faculty of Health Sciences, McMaster University, Hamilton ON See Appendix

Abstract
Objective: Many women have high gestational weight gain (GWG), but potential neonatal consequences are not yet well quantified. We sought to determine the relationship between high GWG and preterm birth (PTB) and low birth weight (LBW) in singleton births. Data Sources: We searched Medline and Embase and reference lists. Study Selection: Two assessors independently performed all steps. We selected studies assessing high total or weekly GWG on PTB (<37 weeks) and LBW (<2500 grams). Data extraction and synthesis: Thirty-eight studies, 24 cohort and 14 case-control, were included involving 2 124 907 women. Most contained unadjusted data. Women with high total GWG had a decreased risk overall of PTB <37 weeks (relative risk [RR] 0.75; 95% CI 0.60 to 0.96), PTB 32 to 36 weeks (RR 0.70; 95% CI 0.70 to 0.71), and <32 weeks (RR 0.87; 95% CI 0.85 to 0.90). High GWG was associated with lower risk of LBW (RR 0.64; 95% CI 0.53 to 0.78). Women with the highest GWG had lower risks of LBW (RR 0.55; 95% CI 0.32 to 0.94) than women with moderately high GWG (RR 0.73; 95% CI 0.60 to 0.89). Women with the highest weekly GWG had greater risks of PTB (RR 1.51; 95% CI 1.47 to 1.55) than women with moderately high weekly GWG (RR 1.09; 95% CI 1.05 to 1.13). Women with high weekly GWG were at increased risk of PTB 32 to 36 weeks (RR 1.14; 95% CI 1.10 to 1.17 and <32 weeks (RR 1.81; 95% CI 1.73 to 1.90).

Conclusion: Although women with high total GWG have lower unadjusted risks of PTB and LBW, high weekly GWG is associated with increased PTB, and more adjusted studies are needed, as are more studies in obese women. Potential benefits of high GWG for the infant must be balanced against maternal risks and other known infant risks such as high birth weight.

Rsum
Objectif: De nombreuses femmes connaissent un gain pondral gestationnel (GPG) lev; cependant, ses consquences nonatales potentielles nont pas encore t bien quantifies. Nous avons cherch dterminer la relation entre le GPG lev et laccouchement prterme (APT) et le faible poids de naissance (FPN) dans le cadre de grossesses monoftales. Sources de donnes: Nous men des recherches dans Medline, Embase et les listes de rfrences. Slection des tudes: Deux valuateurs ont effectu, de faon indpendante, toutes les tapes. Nous avons slectionn les tudes valuant leffet du GPG total ou hebdomadaire lev sur lAPT (< 37semaines) et le FPN (< 2500grammes). Extraction et synthse des donnes: Trente-huit tudes (24 tudes de cohorte et 14tudes cas-tmoins) ont t slectionnes; elles couvraient 2124907femmes. La plupart de ces tudes contenaient des donnes non corriges. Les femmes qui avaient connu un GPG total lev taient exposes un risque globalement moindre dAPT <37semaines (risque relatif [RR], 0,75; IC 95%, 0,60 - 0,96), dAPT entre 32 et 36semaines (RR, 0,70; IC 95%, 0,70 - 0,71), et dAPT < 32semaines (RR, 0,87; IC 95%, 0,85 - 0,90). Le GPG lev a t associ un risque moindre de FPN (RR, 0,64; IC 95%, 0,53 - 0,78). Les femmes ayant connu les GPG les plus levs taient exposes des risques moindres de FPN (RR, 0,55; IC 95%, 0,32 - 0,94), par comparaison avec les femmes qui avaient connu un GPG modrment lev (RR, 0,73; IC 95%, 0,60 - 0,89). Les femmes ayant connu les GPG hebdomadaires les plus levs

J Obstet Gynaecol Can 2011;33(12):12231233 Key Words: High gestational weight gain, preterm birth, low birth weight, systematic review, meta-analysis Competing Interests: None declared. Received on February 23, 2011 Accepted on May 9, 2011

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taient exposes des risques accrus dAPT (RR, 1,51; IC 95%, 1,47 - 1,55), par comparaison avec les femmes qui avaient connu un GPG hebdomadaire modrment lev (RR, 1,09; IC 95%, 1,05 - 1,13). Les femmes ayant connu un GPG hebdomadaire lev taient exposes des risques accrus dAPT entre 32 et 36semaines (RR, 1,14; IC 95%, 1,10 - 1,17) et < 32semaines (RR, 1,81; IC 95%, 1,73 - 1,90). Conclusion: Bien que les femmes qui connaissent un GPG total lev soient exposes des risques non corrigs moindres dAPT et de FPN, le GPG hebdomadaire lev est associ une hausse du risque dAPT; la tenue dtudes mieux corriges savre donc requise, tout comme celle dtudes portant sur les femmes obses. Les avantages potentiels du GPG lev pour lenfant doivent tre mis en balance avec les risques maternels et les autres risques infantiles connus (comme le poids de naissance lev).

versionaimed to decrease low birth weight, which is a more easily and hence more frequently measured outcome in epidemiologic studies and another key predictor of neonatal mortality.10 Although focused on addressing (low) birth weight issues, the IOM guidelines acknowledged the need for further study of the effect of GWG on PTB8 and attempted to balance infant risks with maternal risks of postpartum weight retention.5 Although increasing maternal weight gain is moderately correlated with birth weight (r=0.66),11 increasing risks of certain maternal complications of high GWG such as preeclampsia12 might modulate such relationships. Hence, accurate understanding of the associations between high GWG and PTB and LBW requires a systematic, comprehensive, and unbiased accumulation and summary of the available evidence, examining adjusted data wherever possible. We have focused on singleton pregnancies because both the recommendation for GWG and the risks of PTB and LBW are markedly higher in twin pregnancies.13 We therefore undertook a systematic review of the literature and meta-analyses to determine the magnitude and direction of the risks of high GWG on PTB and LBW compared with normal GWG in singleton pregnancies in developing and developed countries.
METHODS

INTRODUCTION

he overweight and obesity epidemic facing many nations, including Canada,1 is exacerbated in women by high amounts of weight gain during pregnancy. Excess gestational weight gain is associated with a two- to threefold increased risk of becoming overweight after delivery.2 Yet the proportion of women with high gestational weight gain is increasing.3 The recently issued National Institutes for Health and Clinical Excellence guideline4 does not advocate specific amounts of weight gain during pregnancy. In contrast, the recently updated American Institutes of Medicine guidelines,5 which have been adopted by other countries including Canada,6 recommend that women with higher pre-pregnancy BMI gain less weight during pregnancy. Despite these guidelines, many pregnant women exceed the recommended gestational weight gain. For example, one study found that almost one half of women with normal weight, 70% of overweight women, and 57% of obese women gained more than the recommended amount.7 The earlier 1990 IOM guidelines8 acknowledged a paucity of studies on preterm birth, the principal predictor of neonatal mortality,9 butlike the updated
ABBREVIATIONS
aOR ELBW GWG I
2

We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) consensus statement on the conduct of meta-analysis of observational studies.14 We searched Medline (1950 to January 2, 2009) and Embase (1980 to January 2, 2009) with the help of an experienced librarian using individual comprehensive search strategies for each database. This study was part of a constellation of systematic reviews with a standardized search strategy examining maternal anthropometry and PTB and LBW.15,16 Additional eligible studies were sought by reviewing the reference lists of identified articles. For the constellation of systematic reviews examining maternal anthropometry, we included casecontrol and cohort studies if one or more of the following maternal anthropometry variables was assessed as an exposure variable: BMI* (*=assessed before pregnancy, during pregnancy, or immediately postpartum), weight*, gestational weight gain, attained weight, or height*; and one or more of the following outcomes was assessed: PTB (<37 weeks, from 32 to 36 weeks, or <32 weeks), LBW (<2500 g), VLBW (<1500 g), or ELBW (<1000g). A priori we decided to group together all studies reporting on any variation of PTB <32 weeks rather than subdivide this group, as we assumed there would be few studies. For this particular systematic review of high GWG, we

adjusted odds ratio extremely low birth weight gestational weight gain I-squared American Institutes of Medicine intrauterine growth restriction low birth weight preterm birth relative risk very low birth weight weighted mean difference

IOM IUGR LBW PTB RR VLBW WMD

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High Gestational Weight Gain and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis

included studies with any definition of either high total gestational weight gain or high weekly gestational weight gain that included a reference group. We included studies that used self-reported weight gain as well as studies in which the participants had objective assessments or in which information was obtained from medical charts or databases. Although most of the studies used self-reported weight, which has been shown to be accurate during pregnancy,1719 less is known about the accuracy of selfreported weight gain during pregnancy; however, this has been shown to correlate well with measured weight.20 We excluded duplicate publications and studies published only as abstracts, studies involving fewer than 10 patients, and studies which examined outcomes in multiples unless stratification was performed for singleton versus twin outcomes. English language studies were included. Two assessors (two of Z.H., S.D.M., and S.M.) independently reviewed the titles and abstracts of all identified citations. The full-text article was retrieved if either reviewer considered the citation potentially relevant. Each full text article was independently evaluated by two reviewers (two of Z.H., S.D.M., and S.M.). Disagreements were settled by discussion and consensus, with the third reviewer available as an adjudicator. Using a piloted data collection form, two reviewers (two of Z.H., S.D.M., and S.M.) independently extracted the following data from full text articles: country of origin, years of study, study design, characteristics of participants, weight gain cut-offs, outcomes, and information on bias. We included information available from the publications. Inconsistencies were checked and resolved through the consensus process described above. Review Manager Software (version 5.0; the Cochrane Collaboration, Oxford, United Kingdom) was used for statistical analyses. Crude and separately adjusted dichotomous data from cohort studies were meta-analyzed using relative risks, while crude and separately matched dichotomous data from case-control studies were pooled using odds ratios. Where possible, we used the IOM guidelines for GWG according to maternal pre-pregnancy BMI to determine whether or not GWG was high. For studies that did not report maternal BMI, we used 25 to 35 lbs (11 to 16 kg), the amount recommended by the IOM for women of normal BMI, as the reference group; we then performed a secondary analysis with 15 to 25 lbs (7 to 11 kg) because many women are overweight or obese. Continuous data were analyzed with a mean difference. The studies in the meta-analyses were weighted using a calculation based on the inverse variance of the study. The random effects model was chosen because it accounts for both random variability and the variability in effects among the studies; we expected a degree of clinical and statistical heterogeneity among the studies, which were all

observational. Crude, matched, and adjusted data were initially each pooled separately, and data that were matched and/or adjusted were then pooled together. Where required and when the incidence of the outcome was rare, adjusted RRs were calculated from aORs21 to pool the data. Clinical heterogeneity was evaluated and reported in the table of included studies. We calculated the I2 value to measure heterogeneity. An I2 value represents the percentage of total variation across studies due to heterogeneity rather than chance.22 I2 values of 25%, 50%, and 75% have been considered to show low, moderate, and high heterogeneity.22 Subgroup analyses were planned a priori to examine the effects of (1) level of material well-being (developed vs. developing countries23); (2) study quality (see Quality Assessment section following, details of which have been previously published15,16); (3) youth (adolescence vs. adult); and (4) race. Two post hoc subgroup analyses were performed examining the effects of high GWG on LBW in term infants versus preterm infants, and high GWG according to maternal BMI category, where available. Two reviewers (two of Z.H., S.D.M., and S.M.) independently assessed study quality using a pre-defined evaluation of six types of bias: selection, exposure, outcome, confounding, analytic, and attrition. This bias assessment tool has been described in other reviews of determinants of PTB/LBW undertaken by our group.24 To address publication bias, we showed results both with and without imputation (the former using Duval and Tweedies trim-and-fill method25,26 for estimating and adjusting for the number and outcomes of missing studies in a meta-analysis to adjust for any observed publication bias). We decided a priori to perform the trim and fill analyses for outcomes with at least 10 studies because there were concerns about reliability for outcomes with fewer studies. The generic inverse variance method was used to calculate studyspecific weights. All analyses were performed using the R statistical and programming software, version 2.9.0. (R Foundation for Statistical Computing, Vienna, Austria)
RESULTS

A total of 6283 non-duplicate titles and abstracts were identified in our searches (Figure 1). Based on our screening process, 503 citations were selected to undergo full text article review and a further 52 articles were identified from reference lists, yielding a total of 555 full articles for review. The most common reasons for exclusion were study design and failure to report any outcomes of interest. Thirty-eight studies were included; of these, 24 were cohort studies2750 (of which 18 had pooled data) and 14 were casecontrol studies5164 (all of which had pooled
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Figure 1. Study process of systematic review and meta-analyses of preterm birth and low birth weight in women with high gestational weight gain compared with women with normal gestational weight gain

Citations from Medline and Embase searches n = 8768 Medline search n = 4522 and Embase search n = 4218 (searches were performed on July 18, 2008 n = 689 Medline and n = 361 Embase, and with expanded terms December 28, 2008 n = 3833 Medline and n = 3857 Embase and n = 28 from other sources such as abstracts booklets, expert resources) Removal of duplicate publications n = 2485 (n = 220 from first search July 18, 2008, n = 2265 from second search December 28, 2008) Initial screening of titles and abstracts to identify unique citations n = 6283 Citations excluded based on review of title or abstract n = 5780 Citations identified from reference lists n = 52 (n = 15 from first search July 2008, n = 37 from second search December 2008)

Potentially eligible studies retrieved with a low threshold for retrieval. Studies assessed for eligibility (studies independently reviewed in duplicate) n = 503

Studies excluded because they did not meet inclusion criteria n = 392

163 studies were included in the anthropometry search of which there were a total of 38 studies included in this systematic review of high GWG: 24 cohort studies (18 cohort studies with data which were pooled and 5 cohort studies with data which were not pooled), 14 case-control studies (14 casecontrol studies with data which were pooled and 0 casecontrol study with data which was not pooled) Duplicate data extraction

Duplicate data entry and analysis

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High Gestational Weight Gain and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis

Figure 2. Forest plot of the risk of preterm birth in women with high total gestational weight gain compared with women with normal gestational weight gain in cohort studies
High GWG Reference Events Total Weight Total Events 53 34 88 900 10 338 1 242 000 86.4% 6 132 3 122 2.9% 26 1028 10.7% 12 396 Risk ratio M-H, random, 95% CI 0.72 [0.710.73] 0.54 [0.142.12] 1.20 [0.612.35]
0.75 [0.600.96]

Study or Subgroup DHHS 198050 Jensen 200531 Varma 198441

Risk ratio M-H, random, 95% CI

Total (95% CI) 889 518 1 243 160 100.0% 103418 53357 Total events Heterogeneity: = 0.02; = 2.35, df = 2 (P = 0.31); I = 15% Test for overall effect: Z = 2.34 (P = 0.02)

0.1 0.2 0.5 1 2 5 10 Lower RR in high GWG High RR in higher GWG

Sizes of data markers indicate the weights of each study in the analysis. Random indicates that the random effects model was used for statistical pooling.

data), involving a total of 2 124 907 women (see online eTables 1A and 1B). The studies originated predominantly in developed countries, although developing countries were also represented (see online eTables 1A and 1B).
Preterm Birth and High Total GWG

The overall risk of PTB <37 weeks in women with singleton pregnancies who had high total GWG was decreased, RR 0.75; 95% CI 0.60 to 0.96 (3 studies, crude data, Figure 2). None of the included studies had adjusted or matched data for any PTB outcome. The decrease in PTB was not significant when moderately high total GWG (RR 0.94; 95% CI 0.39 to 2.26, 1 study) or very high total GWG (RR 1.65; 95% CI 0.69 to 3.93) was examined (see online eTable 2A). None of the studies specified whether the PTB was spontaneous or induced. High overall GWG was associated with decreases in PTB at 32 to 36 weeks (RR 0.70; 95% CI 0.70 to 0.71, 1 study) and <32 weeks (RR 0.87; 95% CI 0.85 to 0.90, 1 study). The two large cohort studies, not included in the above meta-analyses because the format of the data did not permit pooling, supported the findings in the pooled data: one showed a decreased risk of PTB <37 weeks in women with high GWG (41 lbs compared with <41lbs, aOR 0.54; 95% CI 0.52 to 0.57),37 and the second study36 showed an aOR of spontaneous PTB at <37 completed weeks of 0.1 (95% CI 0.03 to 0.6) in women with a BMI >26 and high GWG from 14 to 28 weeks gestation. However, underweight and normal weight women with high GWG were not protected from PTB (aOR 1.0; 95% CI 0.4 to 2.3 and 1.0; 95% CI 0.6 to 1.9).36 Two casecontrol studies examining spontaneous PTB <37 weeks also supported the pooled analyses, with a decrease in women with high total GWG (dichotomous variable, crude OR 0.11; 95% CI 0.05 to 0.2457 and matched OR 0.41; 95% CI 0.32 to 0.52).52 In casecontrol studies that examined total GWG as a continuous variable, women

with PTB had a GWG similar to women who delivered at term in the crude data (WMD 1.14 kg; 95% CI 4.14 to 1.86, 4 studies) but a lower GWG in the single matched study (WMD 3.40 kg; 95% CI 5.12 to 1.68) (see online eTable 2B). Women with spontaneous PTB had a GWG similar to women who delivered at term (WMD 2.07 kg; 95% CI 5.01 to 0.87, 2 studies with crude data, not adjusted or matched).
Low Birth Weight and High Total GWG

Women with a high total GWG had a decreased risk of delivering a singleton with LBW (RR 0.64; 95% CI 0.53 to 0.78, 11 studies, Figure 3) (see online eTable 2A). Women with very high GWG had lower risks of LBW (RR 0.55; 95% CI 0.32 to 0.94, 3 studies) than women with moderately high GWG (RR 0.73; 95% CI 0.60 to 0.89, 3 studies). The single study with matched data that examined high GWG overall did not show a decrease in LBW (RR 0.91; 95% CI 0.42 to 1.95).29 There were no studies examining very LBW (<1500g) or extremely LBW (<1000 g). Results from three cohort studies whose data could not be pooled supported the above meta-analyses, with a significant reduction in LBW in women with high GWG (>41 lbs compared with those who gained less; aOR 0.41; 95% CI 0.39 to 0.43).37 There was a lower risk of LBW in white women whose weight gain was within the upper half of the range recommended by the IOM than in those who gained within the lower half (aOR 0.4; 95% CI 0.2 to 0.9), but no reduction was seen in black women (aOR 1.2; 95% CI 0.4 to 3.3).39 Interestingly, the reduction in LBW was not significant in women who gained above the IOMs recommended range in comparison with women who gained within the lower half of the recommended range (in both white and black women, aOR 0.7; 95% CI 0.3 to 1.2 and 1.4; 95% CI 0.6 to 3.6, respectively).39 A large study found lower rates of LBW in non-Hispanic white women who gained weight within the upper half of
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Figure 3. Forest plot of the risk of low birth weight in women with high total gestational weight gain compared with women with normal gestational weight gain in cohort studies
High GWG Events Total 38 1030 3 80 223 15315 35 560 889 000 15 869 1491 95 586 13 796 15 1446 10 350 58 406 11 1429 Reference Events Total 80 1745 5 97 294 10649 62 100 1 242 000 27 547 9849 353 639 17 801 84 4159 39 1049 165 1028 29 1611 Risk ratio M-H, random, 95% CI 0.80 [0.551.17] 0.73 [0.182.95] 0.53 [0.440.63] 0.80 [0.790.81] 0.35 [0.190.65] 0.56 [0.530.59] 0.77 [0.381.57] 0.51 [0.300.89] 0.77 [0.391.52] 0.89 [0.681.17] 0.43 [0.210.85] Risk ratio M-H, random, 95% CI

Study or Subgroup Barros 199643 Bianco 199846 Cogswell 199542 DHHS 198050 Frederick 200840 Helms 200630 Johnson 199245 Niswander 196949 Tsukamoto 200733 Varma 198441 Zhou 199744

Weight 10.1% 1.7% 14.4% 16.2% 6.1% 16.1% 5.1% 7.2% 5.4% 12.3% 5.4%

Total (95% CI) 1 006 307 1 617 325 100.0% Total events 37 437 72 689 Heterogeneity: = 0.06; = 191.97, df = 10 (P < 0.00001); I = 95% Test for overall effect: Z = 4.50 (P < 0.00001)

0.64 [0.530.78] 0.2 0.5 1 2 5 Lower RR in higher GWG Higher RR in higher GWG

Size of data marker indicates the weight of each study in the analysis. Random indicates that the random effects model was used for statistical pooling.

the IOMs recommended range than in those who gained within the lower half (in women with low BMI <19.8, aOR 0.7; 95% CI 0.6 to 0.9, and in those with BMI 19.8 to 26.0, aOR 0.8; 95% CI 0.6 to 0.9), as well as in nonHispanic black overweight women (OR 0.3; 95% CI 0.2 to 0.8 and underweight Hispanic women (OR 0.4; 95% CI 0.2 to 0.8), but not in other groups of women. This study also examined LBW risks in women who gained either 1 to 9 lbs or >10 lbs above the IOMs recommended range, and found significant reductions or trends towards decreased risks in underweight, normal weight, and overweight women, but not typically in obese women.35 In casecontrol studies that examined total GWG as a continuous variable, women with LBW infants had significantly lower GWG (WMD 1.93 kg; 95% CI 3.34 to 0.51, 5 studies of crude data, no adjusted/matched data) (see online eTable 2B).
Outcomes With High Total GWG Using an Alternate Reference Group of 7 to 11 kg (15 to 25 lbs)

to 25 lbs or 25 to 35 lbs was used as the reference group (RR 0.72; 95% CI 0.71 to 0.72 and RR 0.70; 95% CI 0.70 to 0.71, respectively). The risk of PTB <32 weeks was decreased in women who had high total GWG (RR 0.36; 95% CI 0.35 to 0.37) using 15 to 25 lbs as the reference, compared with (RR 0.87; 95% CI 0.85 to 0.90) in the primary analysis using 25 to 35 lbs as the reference. The overall risk of LBW <2500 g was decreased in women who had high total GWG (RR 0.61; 95% CI 0.54 to 0.68), which is similar to the results calculated in the primary analysis with 25 to 35 lbs as the reference GWG (RR 0.64; 95% CI 0.53 to 0.78). The primary and secondary analyses also indicate that the overall risk of IUGR was reduced in women who had high total GWG (RR 0.87; 95% CI 0.60 to 1.25 and RR 0.80; 95% CI 0.49 to 1.32, respectively). The mean birth weight was slightly greater (146.0 g; 95% CI 49.7 g to 242.2 g) in women with high GWG when 15 to 25 lbs was used as the reference than when the reference was 25 to 35 lbs (73.0 g; 95% CI 66.2 g to 79.8 g). In the cohort studies, high GWG did not protect against the development of IUGR (RR 0.87; 95% CI 0.60 to 1.25, 4 studies, crude data) or in the single29 study of matched data (RR 0.77; 95% CI 0.39 to 1.50) although the mean birth weight was higher by 73.0 g; 95% CI 66.2 g to 79.8 g (1 study) in the high GWG group.47 No included studies reported on the mean duration of gestation (see online eTable 2A).
Preterm Birth and High Weekly GWG Other Outcomes and High Total GWG

A secondary analysis was conducted using a reference group of GWG of 7 to 11 kg (15 to 25 lbs) for studies that did not stratify by pre-pregnancy BMI (see online eTable 2C). Given the high prevalence of overweight pregnant women, this alternate reference group was selected because 7 to 11 kg (15 to 25 lbs) is the gestational weight gain recommended by the IOM for overweight women. The overall risk of PTB <37 weeks in women with high total GWG (using 15 to 25 lbs as the reference) was non-significantly decreased (RR 0.73; 95% CI 0.52 to 1.04), similar in magnitude to the primary analysis using 25 to 35 lbs as the reference (RR 0.75; 95% CI 0.60 to 0.96). The risk of PTB at 32 to 36 weeks in women who had high total GWG was similar whether 15
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Women with a high weekly GWG overall were not shown to be at increased risk of PTB in either the crude data (RR 1.11; 95% CI 0.88 to 1.41, 3 studies) or the adjusted data (RR 1.00; 95% CI 0.79 to 1.26, 1 study) (see online

High Gestational Weight Gain and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis

eTable 2D), although women with both moderately high and very high weekly GWG were at increased risk (RR 1.09; 95% CI 1.05 to 1.13, 1 study and RR 1.51; 95% CI 1.47 to 1.55, 1 study, respectively). The risk of spontaneous PTB was decreased in the studies with adjusted or matched data (RR 0.96; 95% CI 0.94 to 0.98, 2 studies), but not in those with crude data (RR 0.90; 95% CI 0.76 to 1.05, 2 studies). The risk of induced PTB was increased in the adjusted/matched studies (RR 1.07; 95% CI 1.06 to 1.08, 1 study), but not in the crude data (RR 1.00; 95% CI 0.96 to 1.06, 1 study). The risks of PTB 32 to 36 weeks and <32 weeks were increased in women with high GWG (RR 1.14; 95% CI 1.10 to 1.17, 1 study, and 1.81; 95% CI 1.73 to 1.90, 1 study). Women with very high weekly GWG were at higher risk of PTB 32 weeks than those with moderately high GWG (RR 2.35; 95% CI 2.24 to 2.47, 1 study, and RR 1.13; 95% CI 1.04 to 1.21, 1 study). No included studies examined high weekly GWG and LBW, VLBW, or ELBW or high weekly GWG and IUGR. A single cohort study, not included in the above metaanalyses because the format of the data did not permit pooling, did not find significant increases or decreases in PTB with high GWG in women with low pre-pregnancy BMI (aOR PTB 28 to 36 weeks 2.03; 95% CI 0.44 to 9.31 or in women with average BMI (aOR 0.73; 95% CI 0.26 to 2.08).38 There were no casecontrol studies on PTB or LBW according to weekly GWG.
Quality Assessment

5. Many of the studies did not calculate a sample size or power calculation or use matched analyses when indicated. 6. Attrition bias was rare, given that follow-up occurred within the admission to hospital for delivery.
Trim and fill analyses

In order to assess publication bias, we planned a priori to conduct trim and fill analyses for outcomes with at least 10 studies. The trim and fill analysis of LBW according to high GWG did not result in any new imputed studies (data not shown).
A priori defined subgroup analyses for PTB and high total GWG

Many of the categories had no or very few studies, which limited our ability to explore heterogeneity (see online eTable 4). There were no included studies in the pooled cohort data (1) from developing countries, (2) with low quality (i.e., with high bias; see Quality Assessment section), (3) that specified adults or adolescents, or (4) that specified the study population was white.
A priori defined subgroup analyses for LBW and high total GWG

There were no included studies in the pooled cohort data (1) in developing countries, (2) with low quality (high bias; see Quality Assessment section), or (3) that specified adults or adolescents (see online eTable 4). Compared with women with normal GWG, black women with high GWG had lower risk of LBW (RR 0.82; 95% 0.80 to 0.84, 2 studies, although white women with high GWG did not have a lower risk of LBW (RR 0.53; 95% 0.20 to 1.43, 2 studies).
Post hoc subgroup analyses for PTB and high total GWG

Quality assessment (see online eTables 3A and 3B) was based on the evaluation of six types of bias: 1. Selection bias was unlikely in most studies as the women with high and normal GWG were often drawn from the same populations. 2. Exposure bias was unlikely in most studies, given that the GWG was objectively measured. 3. There was little outcome bias, given that our outcomes had standard definitions and were objectively measured (for instance, LBW was always defined as birth weight <2500g). 4. Confounding was assessed based on the number of variables for which adjustment was made. Confounding variables that might explain part or all of the relationship between high GWG and PTB or LBW were incompletely addressed by the included studies in a variety of ways: (1) exclusion, (2) matching, (3) comparison of some variables and determining that they were not significantly different between the exposed and unexposed women, and (4) controlling for some variables that were significantly different between the two groups using multiple regression. Most studies assessed some confounding variables, but no single study addressed all of them.

Studies that used an exact cut-off for the reference group of GWG of 25 to 35 lbs (11 to 16 kg), reported an RR of PTB of 0.83; 95% CI 0.53 to 1.29 (2 studies) while the study that used a cut-off close to this range reported an RR of 0.54; 95% CI 0.14 to 2.12 (see online eTable 4).
Post hoc subgroup analyses for LBW and high total GWG

The risk of LBW in women with high total GWG was similar when the cut-off for the reference group of GWG was exactly 25 to 35 lbs (11 to 16 kg) (RR 0.64; 95% CI 0.49 to 0.83, 6 studies) and when it was close to, but not exactly, 25 to 35 lbs (RR 0.72; 95% CI 0.54 to 0.95, 4 studies) (see online eTable 4). High GWG overall was associated with decreased risks of LBW in normal weight women (RR 0.51; 95% CI 0.42 to 0.60, 3 studies) and overweight women (RR 0.58; 95% CI 0.42 to 0.80, 2 studies), but not in underweight women (RR 0.68; 95% CI 0.30 to 1.54,
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2 studies) or obese women (RR 0.90; 95% CI 0.59 to 1.37, 2 studies). The risk of LBW was decreased both in studies that specified term infants and in those that did not specify term or preterm (RR 0.65; 95% CI 0.44 to 0.95, 3 studies, and RR 0.64; 95% CI 0.53 to 0.78, 11 studies, respectively). Because of the low number of studies of weekly GWG for both PTB and LBW, we did not perform post hoc subgroup analyses.
DISCUSSION

analysis using a GWG of 7 to 11 kg (15 to 25 lbs, the amount recommended for overweight women) as the reference group. Although high total GWG appears to be associated with some immediate perinatal benefits in terms of decreased PTB and LBW, other perinatal outcomes outside the scope of this meta-analysis are adversely affected, such as (infant) macrosomia, birth trauma, or gestational diabetes mellitus.11 Moreover, concerns over long-term health risks associated with high GWG are mounting for both mothers and children. High GWG has been associated with postpartum weight retention and increasing BMI,65 and hence contributes to maternal obesity, which has been shown to be associated with increases in PTB, and after accounting for publication bias it was not found to be protective against LBW.15 Obesity carries risks for a large number of chronic diseases, including diabetes and cardiovascular disease.66 GWG above the IOM guidelines has been associated with a 48% increase in the risk of the child being overweight, even after adjustment for confounders (aOR 1.48; 95% CI 1.06 to 2.06).67 Interestingly, the association between high GWG and overweight in the offspring was strongest for women who were underweight before pregnancy (P <0.01).67 To our knowledge, this is the first complete systematic review of the effect of high GWG on PTB and LBW. A previous study by the World Health Organization, without the standard literature search that forms the basis of systematic reviews, meta-analyzed 13 data sets with weight gain information that were identified by investigators attending a 1990 conference.68 The study compared GWG below the 25th percentile with GWG above the 75th percentile, and found that low GWG by the seventh month was associated with an increased risk of LBW (OR 2.4; 95% CI 2.1 to 2.7) but not PTB (OR 0.9; 95% CI 0.8 to 1.0). Low GWG by the ninth month was associated with a similar increased risk of LBW (OR 2.5; 95% CI 2.2 to 2.9). A systematic review by Siega-Riz et al. did not examine PTB, and examined outcomes only in relation to the IOM guidelines, but found similar decreased risks of LBW with higher GWG in studies published from 1990 to 2007.69 A 2008 publication by the same group, with a literature review from the same time span, was published as a systematic review but did not include any meta-analyses.70 Strengths of this meta-analysis include the thoroughness with which both PTB and LBW were explored (including <37 weeks, 32 to 36 weeks, and <32 weeks, spontaneous labour, induced labour, LBW, VLBW, and ELBW), the graded relationship between increasing GWG and stronger associations with the perinatal outcomes we examined, and the detailed quality assessment of the original studies. There were often few or no studies within subgroups, limiting our ability to explore heterogeneity. We compared the results of crude and, where available, matched or adjusted data to

In this systematic review and meta-analysis, we determined that singletons born to women with high total GWG have a decreased risk of PTB at <37 weeks, 32 to 36 weeks, and <32 weeks (dominated by a few large studies37,50), although one study suggested a benefit mainly in obese women, with a decreased risk of PTB at <37 completed weeks.36 Women with high total GWG typically had a lower risk of LBW, although this may not be consistent across all BMI categories, particularly in obese women.35 These findings on PTB and LBW were generally consistent across study design in the minority of studies that adjusted for other factors. In contrast, women with high weekly GWG had a trend towards an increase in PTB <37 weeks and significantly increased risks of PTB at 32 to 36 and <32 weeks (dominated by a single study27). The seeming contradiction between the observation that high total GWG was associated with decreased risks but high weekly GWG was associated with increased risks of PTB points to the need for more study, although this effect may be due to the association of conditions such as preeclampsia, which is often accompanied by edema and significant short-term increases in weight. The IOMs 1990 guidelines8 recognized the dearth of information on PTB, the most significant problem in obstetrics and pediatrics,9 and called for more studies. However, few have been published in the intervening years. This dearth is disappointing, because the original goal of the guidelines was to decrease PTB and LBW. Where possible, we used the IOM guidelines for GWG according to maternal pre-pregnancy BMI in order to determine whether or not GWG was high. The IOM guidelines were used as a frame of reference because the National Institutes for Health and Clinical Excellence guideline4 does not make specific recommendations, and also because countries other than the United States have adopted them.6 For studies that did not report maternal BMI, we used a GWG of 11 to 16 kg (25 to 35 lbs) as the reference group because this is the amount recommended by the IOM for women with a normal BMI. We then did a second
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try to determine whether the perinatal outcomes we found were due to GWG or explained by confounding factors, although few studies provided adjusted data. Lastly, we tried to address publication bias in a thorough manner with trim and fill analyses. There are limitations to this systematic review, particularly potential confounders, factors besides high GWG (such as gestational diabetes) that might explain the relationship with PTB and LBW but were not explored in most or any of the original studies. The heterogeneity in the pooled studies examining LBW was high (I2 95%), suggesting caution is required in interpreting the results. Many studies examining the impact of gestational weight gain exclude preterm births,70,71 limiting our statistical power. The revised IOM guidelines for weight gain during pregnancy acknowledge that the literature on preterm birth is more ambiguous because of a less extensive body of epidemiologic evidence, a nonlinear relationship between gestational weight gain and preterm birth and uncertainty about biologic mechanisms.5 The updated guidelines acknowledged that among obese women, the measured effect of weight gain on birth weight is weak.5 The IOM recommendations have been variably viewed as too high,72 suitable,73 and too low.11,74 Further research (particularly adjusted data) is needed on the impact of GWG on PTB. In addition, studies of weekly GWG are required, because this provides a window of opportunity in which care providers can act, unlike total GWG, which can be evaluated only at the end of the pregnancy when outcomes have already occurred. In particular, GWG in obese women warrants more study. Research is needed into the optimal dietary content of protein, carbohydrate, and fat, and the effect of this content on perinatal outcomes. Research is also required into methods to increase accurate counselling on GWG by health care practitioners, as one study found that 27% of women did not receive any advice; of the remainder who received advice, 14% were advised to gain below recommendations and 22% above.75
CONCLUSION

is supported by a State Scholarship Fund by the China Scholarship Council. Dr McDonald is supported by a Canadian Institutes of Health Research New Investigator Award. Dr Beyene is supported by a Canadian Institutes of Health Research grant no. 84392. None of the funding agencies had any role in the analyses, the writing of the report, the interpretation of data, or the decision to submit the manuscript. We thank Ms Elizabeth Uleryk, Chief Librarian, Hospital for Sick Children, Toronto, for her assistance in developing the search strategy.
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Women with high total GWG have lower risks of PTB at <37 weeks, 32 to 36 weeks, and <32 weeks, and LBW. However, there was significant heterogeneity in the LBW analyses, few reports contained adjusted data, and high weekly GWG was generally associated with increased risks of PTB. Potential benefits of high GWG for the infant must be balanced against maternal risks and other known risks to the infant such as high birth weight.
ACKNOWLEDGEMENTS

This work was supported by a Canadian Institute of Health Research operating grant no. KRS 86242. Dr Han

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APPENDIX
Members of Knowledge Synthesis Group on Determinants of Preterm Birth/Low Birthweight
Prakesh Shah, Associate Professor, Department of Paediatrics, Mount Sinai Hospital and Department of Health Policy, Management and Evaluation, University of Toronto, Toronto ON Arne Ohlsson, Professor Emeritus, Department of Paediatrics, Mount Sinai Hospital and Departments of Paediatrics, Obstetrics and Gynaecology, and Health Policy, Management and Evaluation, University of Toronto ON Vibhuti Shah, Associate Professor, Department of Paediatrics, Mount Sinai Hospital and Department of Health Policy, Management and Evaluation, University of Toronto, Toronto ON Kellie E. Murphy, Associate Professor, Department of Obstetrics and Gynecology, Mount Sinai Hospital and University of Toronto, Toronto ON Sarah D. McDonald, Associate Professor, Division of Maternal-Fetal Medicine, Departments of Obstetrics & Gynecology, Clinical Epidemiology & Biostatistics, and Diagnostic Imaging, McMaster University, Hamilton ON Eileen Hutton, Associate Professor, Department of Obstetrics and Gynecology, McMaster University, Hamilton ON Christine Newburn-Cook, Associate Professor & Associate Dean Research, Faculty of Nursing, University of Alberta, Edmonton AB Corine Frick, Adjunct Professor, Faculty of Nursing, University of Calgary, Calgary AB Fran Scott, Associate Professor, Dalla Lana School of Public Health, University of Toronto and Toronto Public Health, Toronto ON Victoria Allen, Associate Professor, Department of Obstetrics and Gynaecology, Dalhousie University, Halifax NS Joseph Beyene, Associate Professor and John D. Cameron Endowed Chair in Genetic Epidemiology, McMaster University, Hamilton ON
Dr Christine Newburn-Cook died August 15, 2011.

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