Gestational Weight Gain and Small for Gestational Age in Obese Women: A Systematic Review and Meta-Analysis

Objective This systematic review and meta-analysis evaluates the relationship between gestational weight gain and the risk of small for gestational age in obese pregnant women. Methods Studies were identified by searching the Web of Science, Embase, and PubMed databases up to June 30th, 2022. The meta-analysis was carried out to determine the risk of small for gestational age with gestational weight gain (GWG) below the 2009 Institute of Medicine (IOM) guidelines compared with within the guidelines in obese women. The Newcastle–Ottawa Scale was used to assess the methodological quality. The chi-squared test, Q test, and I2 test were used to evaluate statistical heterogeneity. Subgroup analyses were conducted, and publication bias was assessed by funnel plots and Egger's test. Sensitivity analyses were performed for three groups of obese people (I: BMI 30–34.9 kg/m2, II: BMI 35–39.9 kg/m2, and III: BMI ≥ 40 kg/m2) to examine the association of obesity and SGA. Results A total of 788 references were screened, and 29 studies (n = 1242420 obese women) were included in the systematic review. Obese women who gained weight below the IOM guideline had a higher risk of SGA than those who gained weight within the guideline (OR = 1.27, 95% CI = 1.16–1.38, Z = 5.36). Both weight loss (<0 kg) and inadequate weight (0–4.9 kg) during pregnancy in obese women are associated with an increased risk of SGA (OR = 1.50, 95% CI = 1.37–1.64, Z = 8.82) (OR = 1.18, 95% CI = 1.14–1.23, Z = 8.06). The same conclusions were also confirmed for the three obesity classes (I: OR = 1.38, 95% CI = 1.29–1.47; II: OR = 1.39, 95% CI = 1.30–1.49; and III: OR = 1.26, 95% CI = 1.16–1.37). Subgroup analysis by country showed that GWG below guidelines in obese women of the USA and Europe was associated with risk for SGA (USA (OR = 1.30, 95% CI = 1.15–1.46), Europe (OR = 1.24, 95% CI = 1.11–1.40)) and not in Asia (OR = 1.17, 95% CI = 0.91–1.50). Conclusion Our findings indicated that obese pregnant women who had weight loss or inadequate weight (0–4.9 kg) according to the IOM guideline had increased risks for SGA. Moreover, we also evaluated that gestational weight loss (<0 kg) in these pregnancies was associated with an increased risk for SGA compared with inadequate weight (0–4.9 kg) in these pregnancies. Therefore, the clinical focus should assist obese women to achieve GWG within the IOM guidelines to decrease the risk for SGA.


Introduction
Obesity has increased dramatically around the world in these past decades, and it is a public health problem. Obesity in pregnancy is often associated with adverse outcomes such as pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus (GDM), cesarean section, macrosomia, and neonatal asphyxia [1][2][3]. Te Institute of Medicine (IOM) guideline revised the gestational weight gain in 2009 [4] and recommended that obese women should gain between 5 and 9 kg to obtain the best maternal and perinatal outcomes. However, the revision of the 2009 guideline did not provide recommended GWG for diferent classes of obesity.
Given the known relationship between gestational weight gain (GWG) above recommended and adverse perinatal outcomes, along with the long-term maternal health efects of obesity, physicians and women alike are exploring the possible benefts of weight loss during pregnancy-about 8% of all pregnant women reported attempting to lose weight, with the highest prevalence (13%) reported in obese women [5]. Moreover, the prevalence of actual weight loss increases with increasing obesity class, reaching as high as 15% in obesity class III [6,7]. In this context, both prepregnancy BMI and GWG have been associated with maternal and fetal complications. However, there was no agreement on whether inadequate weight (0-4.9 kg) or weight loss (<0 kg) in obese women can contribute to improving neonatal outcomes or on the correct GWG to be reached to reduce these complications.
Some groups and meta-analyses suggested inadequate weight (0-4.9 kg) or weight loss (<0 kg) in obese women was associated with increase of SGA and low birth weight [8][9][10][11][12]. SGA and low birth weight not only increased the neonatal morbidity and mortality, but also some other chronic diseases such as type 2 diabetes, cardiovascular disease, and mental problems in adulthood [13][14][15]. However there is no agreement on inadequate weight (0-4.9 kg) or weight loss (<0 kg) in obese women. Some groups have suggested that appropriate management of inadequate weight (0-4.9 kg) or weight loss (<0 kg) can contribute to improving neonatal outcomes [6,16,17]. Terefore, the objective of this systematic review and meta-analysis was to assess the relationship between inadequate weight gain during pregnancy and the risk of SGA in obese women.

Data Source and Search Strategy.
Tis review was registered in PROSPERO with the number CRD42022345753. We comprehensively searched the Web of Science, PubMed, and Embase to identify related articles published before June 30th, 2022, using keywords and MeSH headings for Pregnant Women, Pregnancy, Obesity, Gestational Weight Gain, Weight Gain, Infant, and Small for Gestational Age (Table S1). No language restriction was imposed. Reference lists were also assessed to acquire additional relevant articles. All relevant terms, including free-text terms and MeSH terms, were used in the literature search. All reference lists of the relevant reviews were hand-searched for additional relevant trials.

Eligibility Criteria.
Studies were selected if they examined outcomes in women with BMI defned as obesity (BMI > 30 kg/m 2 , I: BMI 30-34.9 kg/m 2 , II: BMI 35-39.9 kg/ m 2 , and III: BMI ≥ 40 kg/m 2 ) assessed by self-reported or objective measurement before pregnancy, during pregnancy, or postpartum). Studies were included if the following criteria were met: (1) Population of singleton pregnancies.
Studies were excluded if they assessed a population that is not representative (diabetes women and women with second pregnancy), if the combined efects between obesity and weight gain in obese women were not examined, and if they were duplicate or secondary publications, opinion articles, reviews, guidelines, posters, conference papers, case reports, nonhuman studies, non-English articles, and without enough data.

Data Extraction and Quality
Assessment. Two investigators (LJ and LBY) independently searched, selected, and extracted publications from the literature. Inconsistent data were discussed by the two investigators to reach consensus or evaluated by a third senior investigator (GKX). To assess the methodological quality of included studies, we used a modifed version of the Newcastle-Ottawa Quality Scale. Two researchers (CW and LBY) independently evaluated the study quality and assigned the quality grades. Discrepancies were resolved by consensus of them and another researcher (GKX). Te Newcastle-Ottawa Scale is composed of three categories: "Selection," "Comparability," and "Outcome." Our modifed Newcastle-Ottawa Scale excluded one item ("demonstration that outcome of interest was not present at the start of study") of the "Selection" category since the lack of relevance for our meta-analysis. Te elimination of the item left a maximum of three points for the "Selection" category. As our outcomes required follow-up until the end of pregnancy, another item, namely, "was follow-up long enough for an outcome to occur" under the "Outcome" category was excluded. A maximum of two points were awarded for this column. Te two "most important confounding factors" of the "Comparability" criteria were selected on the basis of a prior knowledge of their association with GWG and each outcome. Tis modifed Newcastle-Ottawa scale [19] ultimately conferred up to six points. Due to the shortage of validation studies that provided a cutof score for rating low-quality studies, an arbitrary cutof of four or fewer was used to categorize a study as "low quality." For the outcome (SGA), the points for confounding were allocated as follows: one point was allocated for controlling for parity, and an additional point for age, smoking, or diabetes mellitus (DM). We designated the lowest score for the outcome (SGA) without controlling all the items. Te fnal comparability score was the minimum score that a study received for all the outcomes. "0" means no point awarded; "1" means one point awarded [9].
Two reviewers (CW and LBY) independently extracted the following data from full-text articles: name of the frst author, year of publication, country of study, time span of the study (years), study setting, study design, characteristics of participants (including the population, source, and categories of BMI), confounding factors, and adjusted OR (95% CI). Te results were verifed again by another independent reviewer (CW) ( Table 1). International Journal of Endocrinology 3  International Journal of Endocrinology 5  6 International Journal of Endocrinology International Journal of Endocrinology 7  International Journal of Endocrinology 9

Quality Score.
One study scored two points, three scored three points, six scored four points, twelve scored fve points, and the others scored six points. Te articles scoring below or equal to four points were regarded as "low quality" and would be subsequently involved in the sensitivity analysis ( Table 2).

Sensitivity Analyses and Publication Bias.
Sensitivity analysis was used to evaluate the stability of the results. Te sensitivity analysis indicated, compared with the original pooled OR, excluding the ten studies assessed as "low quality" also resulted in a similar (OR � 1.31; 95% CI � 1.25-1.38; Z � 10.37, P < 0.00001).
No more evidence of publication bias showed in the funnel plots for the overall obesity, weight loss, and inadequate weight group (Figure 10).

Discussion
Our meta-analysis demonstrates that obese women who gained weight below the guideline recommendations had more risks of SGA than those of gained weight within the guidelines. Tese data covered not only the population of overall obese women but all three classes of obesity of pregnant women. Tese results were similar to prior systematic reviews [9][10][11]46]. However, these studies did not account for the difering socioeconomic, lifestyle, and racial backgrounds of patients. Te repercussions of weight loss in obese gravida may varied based on race and socioeconomic classes, so studying these topics in diverse patient populations was important. Moreover, in our study, we also evaluated gestational weight loss in obese pregnant women was associated with an increases risk for SGA, compared with inadequate weight (0-4.9 kg). Of the 29 articles we selected, only fve provided detailed information on the number of pregnancies at risk of weight loss (<0 kg) and inadequate weight (0-4.9 kg) for SGA. Terefore, our study added a subgroup analysis of race and found that obese women who gain weight below the guideline in the United States and Europe were associated with a higher risk for SGA, but not in Asia because the USA and Europe had  the greatest prevalence of overweight and obesity [47,48]. Asia women were more likely to be underweight than those in the USA and Europe [32].
Obesity during pregnancy is associated with a myriad of adverse outcomes such as preeclampsia, labour induction, postpartum haemorrhage, cesarean delivery, and preterm birth [49,50]. Terefore, more obese women in the USA and Europe attempted to lose weight during pregnancy [51]. Our study also analyzed that not only weight loss (<0 kg) but also inadequate weight (0-4.9 kg)    in obese pregnant women were associated with an increased risk of SGA. Our fndings in these meta-analyses were also in line with the fndings of a previous metaanalysis [10,11]. Moreover, our results were identifed by Class I, Class II, and Class III of obese women. Te mechanism of weight gain within the guideline range during pregnancy contributes to SGA may be that the lack of maternal nutrition can lead to the placental vascular development change and barrier thickness increases, thus resulting in reduced glucose, amino acid, and lipid transport, as well as chronic hypoxia, which ultimately afected the fetus normal growth and development process.

Strength and Limitations.
Te strength of this systematic review included the comprehensiveness of the search strategies in three databases. We performed a careful quality assessment using a modifed Newcastle-Ottawa scale. Sensitivity analyses corroborated the robustness of our fndings and argued in favour of their validity. Importantly, we addressed the evidence for each obesity class. All included studies were adjusted for multiple important confounders, and all but ten studies were of high quality.
However, this meta-analysis has several limitations. First, it lacked studies from developing countries. Te studies that met our inclusion criteria originated predominantly from United States. Hence, more research is Heterogeneity: Tau 2 = 0.00; Chi 2 = 8.96, df = 7 (P = 0.26); I 2 = 22% Test for overall efect: Z = 5.91 (P < 0.00001)  needed from diverse populations to be able to generalize our fndings. Second, some variables may also have infuenced fndings, such as maternal ethnicity, behavioral factors (diet, physical activity, and smoking), socioeconomic status, and women with prenatal complications, although some studies did adjust for these variables or excluded women with Heterogeneity: Chi 2 = 2.38, df = 2 (P = 0.30); I 2 = 16% Test for overall efect: Z = 2.29 (P = 0.02)   International Journal of Endocrinology preexisting complications from their analysis. Tird, the limits are related to the precision of self-reported GWG, the no possibility to obtain data on the dietary advice and dietary compliance of the women and on the long-term outcomes of neonates.

Conclusions
Our fndings indicated that obese pregnant women who weight loss (<0 kg) and inadequate weight (0-4.9 kg) below the IOM guideline had increased risks for SGA. Terefore, the clinical focus should intensify eforts to assist obese women to achieve GWG within the IOM guidelines to decrease the risk for SGA. We also found that gestational weight loss in these pregnancies was associated with an increased risk for SGA compared with weight inadequate. Tese fndings underline the importance considering the IOM guidelines in terms of gestational weight gain taking into consideration the diferent classifcations of obese women.

Data Availability
Te data described in this article can be freely and openly accessed from the original published articles in the database.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Wen Chen, Beiyi Li, Kexin Gan, Jing Liu, Yajing Yang, and Xiuqin Lv contributed substantially to the concept and design of the study, performed data collection or analysis, and interpreted the data. Te authors revised important substantive content. Wen Chen, Jing Liu, and Huijuan Ma have read and approved the fnal version of the manuscript.