The impact of maternal bariatric surgery on long-term health of offspring: a scoping review

ABSTRACT While pregnancy post-bariatric surgery has become increasingly common, little is known about whether and how maternal bariatric surgery affects the next generation. This scoping

review aimed to collate available evidence about the long-term health of offspring following maternal bariatric surgery. A literature search was conducted using three databases (PubMed,

PsycINFO, EMBASE) to obtain relevant human and animal studies. A total of 26 studies were included: 17 were ancillary reports from five “primary” studies (three human, two animal studies)

and the remaining nine were “independent” studies (eight human, one animal studies). The human studies adopted sibling-comparison, case-control, and single-group descriptive designs. Despite

limited data and inconsistent results across studies, findings suggested that maternal bariatric surgery appeared to (1) modify epigenetics (especially genes involved in immune, glucose,

and obesity regulation); (2) alter weight status (unclear direction of alteration); (3) impair cardiometabolic, immune, inflammatory, and appetite regulation markers (primarily based on

animal studies); and (4) not affect the neurodevelopment in offspring. In conclusion, this review supports that maternal bariatric surgery has an effect on the health of offspring. However,

the scarcity of studies and heterogenous findings highlight that more research is required to determine the scope and degree of such effects. IMPACT * There is evidence that bariatric

surgery modifies epigenetics in offspring, especially genes involved in immune, glucose, and obesity regulation. * Bariatric surgery appears to alter weight status in offspring, although the

direction of alteration is unclear. * There is preliminary evidence that bariatric surgery impairs offspring’s cardiometabolic, immune, inflammatory, and appetite regulation markers.

Therefore, extra care may be needed to ensure optimal growth in children born to mothers with previous bariatric surgery. You have full access to this article via your institution. Download

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PRECONCEPTION AND ANTENATAL LIFESTYLE INTERVENTIONS: A SYSTEMATIC REVIEW Article Open access 19 June 2024 INTRODUCTION Nearly 9% of US women enter pregnancy with severe obesity (body mass

index [BMI] ≥40 kg/m2).1 Maternal obesity is a well-established early life exposure that increases the risk for obstetrical complications during pregnancy, worsens birth outcomes, and

predisposes offspring to lifelong cardiometabolic, mental, and neurodevelopmental disorders.2 More concerningly, the degree of obesity progressively raises those risks in a dose-dependent

manner.3,4,5 To prevent or mitigate the deleterious consequences of severe obesity, women of reproductive age increasingly seek bariatric surgery—the most effective treatment for severe

obesity that results in significant and durable weight loss and comorbidity remission.6 Since 2015, more than 1.3 million bariatric operations have been performed in the US, and 40–50% were

in women of reproductive age.7,8 The weight loss, improved metabolic homeostasis, and restored hormonal balance resultant from bariatric surgery boost women’s reproductive efficiency, making

pregnancy post-surgery increasingly common. According to the most recent epidemiological data, the number of pregnancies after bariatric surgery in the US trended upward in recent years,

accounting for 0.3% of all pregnancies in 2016 and 0.5% in 2019.9 The expanded population of women who conceive following bariatric surgery has ignited interest in understanding whether and

how the surgery affects a subsequent pregnancy. Evidence is clear that preconception bariatric surgery brings both benefits and risks to mothers and neonates during the perinatal period

(e.g., reduced incidence of obstetrical complications, increased risk of small-for-gestational-age infants). However, a major gap remains in the transgenerational implications of maternal

bariatric surgery on the health of offspring in the long-term. Bariatric surgery in women before pregnancy theoretically produces lasting impacts on offspring through multiple mediators,

including the intrauterine environment, methods of delivery, birth outcomes, breastfeeding behaviors, and food-related parenting practices, all of which play a critical role in child growth.

In terms of the intrauterine environment, on the one hand, bariatric surgery reverses obesity-induced disruptions in neuroendocrine, inflammatory, and microbiota homeostasis in

mothers,10,11 exerting a positive programming effect on the fetus. Yet, on the other hand, the surgery increases the risk of maternal malnutrition, alters specific hormone expression and

signaling, and impairs placental function,12 which may collectively compromise fetal growth. Regarding methods of delivery, despite mixed evidence, there have been reports that women with

bariatric surgery were more likely to have cesarean delivery compared to those without bariatric surgery.13,14 For birth outcomes, while it is known that maternal bariatric surgery reduces

the incidence of large-for-gestational-age infants, the risk rises parallelly for intrauterine growth restriction and small-for-gestational infants,15,16 which would presumably influence the

growth trajectory in offspring. Concerning breastfeeding behaviors, a few human studies have shown that women with a history of bariatric surgery were less likely to initiate breastfeeding

and had lower median breastfeeding time than non-surgical counterparts with overweight/obesity or normal weight.17,18 Finally, patients who have undergone bariatric surgery often experience

certain eating restrictions (e.g., food intolerances) and are required to make profound eating modifications (e.g., high demand for protein intake). Those changes can potentially render

ripple effects on the home food environment and parenting practices and, subsequently, shaping the lifestyles and health of children living in the same household. Despite the theoretical

links, whether and how the various beneficial and detrimental effects derived from maternal bariatric surgery extend to the next generation, especially beyond the perinatal period, remains

poorly understood. Accordingly, the aim of this scoping review was to identify and map available literature characterizing the long-term health profiles of offspring born to mothers with

preconception bariatric surgery. METHODS STUDY DESIGN This study is a scoping review that followed the framework established by Arksey and O’Malley.19 The rationale for choosing a scoping

review instead of a systematic review is that the research on “long-term health of offspring following maternal bariatric surgery” is only recently emerging. The limited number and

heterogeneous nature of literature make it infeasible to formulate and answer a focused research question. Rather, a scoping review allows the embracement of diverse study designs with more

expansive inclusion criteria, which is particularly suitable for examining the potential size and scope of available literature pertaining to an emerging topic.20 Since this is a review

paper, approval from an Institutional Review Board is not required. INCLUSION/EXCLUSION CRITERIA Both human and animal studies were included. Studies that (1) described the long-term health

of offspring born to mothers with a history of bariatric surgery; or (2) compared the long-term health of offspring born to mothers with and without a history of bariatric surgery were

eligible. “Long-term” refers to an extended period of time beyond infancy, defined as age >1 year in human studies and >postnatal day 14 (weaning) in studies using rat models.

Single-group descriptive studies, case-control studies, case reports/series, and intervention studies were considered without limitation on the date of publication. Studies published in

non-English languages, and editorials, abstracts, book chapters, dissertation work, protocol papers, qualitative studies, and review papers were excluded. SEARCH STRATEGY The literature

search was conducted in November 2022 with three databases (PubMed, PsycINFO, and EMBASE) to obtain relevant studies. The search included the combination of the following keywords:

“children”, “adolescents”, “offspring”, “bariatric surgery”, “weight loss surgery”, “metabolic surgery”, “sleeve gastrectomy”, “gastric bypass”, “gastric banding”, and “biliopancreatic

diversion”. As an example, the search strategy for PubMed was (((children[tiab]) OR (adolescen*[tiab])) OR (offspring[tiab])) AND ((((((((bariatric surgery[tiab]) OR (sleeve

gastrectomy[tiab])) OR (gastric bypass[tiab])) OR (weight loss surgery[tiab])) OR (metabolic surgery[tiab])) OR (gastric banding[tiab])) OR (Biliopancreatic diversion[tiab])) OR (gastric

band[tiab])). The database search was complemented by a hand search of the reference lists obtained from the identified articles. The study selection flow is presented in Fig. 1. RESULTS

STUDY DESCRIPTION A total of 26 studies were included in the review, with 17 being ancillary reports21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 from five “primary” studies and nine

“independent” or “unrelated” studies38,39,40,41,42,43,44,45,46 (Table 1). Among the five “primary” studies (described below), there were two human sibling studies (seven ancillary

reports,28,29,30,31,35,36,37) one human case-control study (three ancillary reports,32,33,34) and two animal studies (seven ancillary reports.21,22,23,24,25,26,27) Among the nine

“independent” studies, there were eight human studies that adopted sibling-comparison,39,40 case-control,43,44 and retrospective or cross-sectional single-group designs,38,41,42,45 as well

as one animal study using rat model.46 Regarding offspring’s age groups, two “primary” (six ancillary reports32,33,34,35,36,37) and six “independent” human studies38,39,41,42,44,45 only

focused on childhood (1–12 years), one “independent” animal study46 on adulthood, and the remaining (one human “primary” [four ancillary reports,28,29,30,31] two animal “primary” [seven

ancillary reports,21,22,23,24,25,26,27] and two “independent” human studies40,43) entailed at least two developmental stages of childhood, adolescence, or early adulthood. DESCRIPTION OF THE

FIVE “PRIMARY” STUDIES A sibling study conducted in Canada (hereby referred to as the Canadian Sibling study)28,29,30,31 performed two surveys to compare the health of offspring born before

and after maternal biliopancreatic diversion. The first survey recruited all women who had given birth to children before (_n_ = 45) or after surgery (_n_ = 172) in a university-based

practice, and children’s weight patterns and neurodevelopment were reported (age range: 2 years to adolescence).28,29 A second survey was administered in a refined sample of mothers who had

given birth both before and after surgery, as well as additional age-matched mothers with children born before or after maternal surgery. In this later survey, weight status and metabolic

data were obtained from children born to mothers before (_n_ = 54, 16.0 ± 0.6 years) and after surgery (_n_ = 57, 10.7 ± 0.5 years).28 From the second survey cohort, a subset of 20 unrelated

mothers, along with 50 siblings born before and after surgery, were further extracted for epigenetic analysis.30,31 Another sibling study conducted in Sweden (hereby referred to as the

Swedish Sibling study)35,36,37 investigated the effects of maternal bariatric surgery on the weight patterns and epigenetics of offspring. Through linking several national registries, 164

children born before and 176 after maternal bariatric surgery were identified (including 71 sibling pairs), and their weight status at ages four, six, and ten were reported.36 A follow-up

analysis re-examined the weight status37 and characterized the methylation levels of genes associated with type 2 diabetes and obesity among 31 sibling peers.35 A case-control study

conducted in Belgium (hereby referred to as the Belgian case-control study)32,33,34 compared adiposity,33 neurodevelopment,33 and eating behaviors34 among three groups of children: 36 born

after maternal bariatric surgery (6.5 ± 1.3 years), 71 born to mothers with overweight/obesity (10.8 ± 0.3 years), and 36 born to mothers with a healthy weight (10.6 ± 0.2 years).

Additionally, in a subset of children, outcomes on endothelial function and a series of metabolic biomarkers were reported32 (_n_ = 26, 53, and 32 in the surgical, overweight/obesity, and

healthy weight groups, respectively). An animal study conducted in the US (hereby referred to as the US animal study)21,22,23,24 used a rat model of sleeve gastrectomy (SG) to examine the

impact of maternal SG on the physiology of offspring during childhood and adulthood. Female rats were placed on 4-week high-fat diets to induce obesity and were then divided into two groups

to receive SG or sham surgery. After a 5-week weight stabilization period, post-surgery female rats were mated with conventionally fed males, and pup litters were collected to assess

adiposity,24 immune,21 inflammation,21 leptin,22 and ghrelin functioning.23 Another animal study conducted in Brazil (hereby referred to as the Brazilian animal study)25,26,27 also adopted

rat models to evaluate the association between maternal Roux-en-Y Gastric Bypass (RYGB) and offspring outcomes. Following a cafeteria diet, female rats were submitted to RYGB or sham

surgery. The mating process began at five weeks post-surgery, and male offspring’s weight patterns,25,26 insulin,26 hepatic lipid metabolism,27 and brown adipose tissue thermogenesis25 were

assessed. The following sections qualitatively summarize the main findings from the 26 included papers, organized by different health outcomes that were examined. IMMUNE SYSTEM AND

INFLAMMATION The US animal study21 was the only study to examine the effects of maternal bariatric surgery on the immune system in offspring. Findings showed that at postnatal day 21,

offspring of SG vs sham dams had early deficits in certain immune cell populations, exemplified in reduced circulating CD45RA + B lymphocytes and reduced mRNA transcription for CD45 (a

marker for all hematopoietic cells) and Cd68 (a macrophage marker) in the spleen. Conversely, the immune cells in the neural tissue appeared to be stimulated as there was greater expression

of microglia markers in the hypothalamus. At postnatal day 60, most of those differences disappeared (except total and cytotoxic T-cell mRNA transcripts in the spleen were elevated in SG

relative to sham offspring), implying immune rebounds.21 Two human studies assessing inflammatory markers in the offspring of mothers with and without bariatric surgery failed to detect

significant differences. More specifically, the Canadian sibling study30 reported comparable C-reactive protein (CRP) levels in siblings born before and after maternal biliopancreatic

diversion (after adjustment for puberty and BMI percentile). The Belgian case-control study32 found no differences in high-sensitivity CRP levels among children born to mothers after

bariatric surgery, mothers with overweight/obesity, and mothers with a normal weight.32 In contrast to the human studies, the US animal study observed elevated expression of IL-1β (a

proinflammatory cytokine) in the hypothalamus and elevated mRNA expression of IL-1β in the spleen in SG compared with sham offspring, suggesting hyperactive inflammation in the central and

peripheral systems.21 EPIGENETICS Two human studies performed epigenetic analyses in siblings born pre- and post-maternal bariatric surgery, and both reported epigenetic variation within the

sibling peers. In the Canadian sibling study, the investigators applied DNA methylation, gene expression, and function and pathway analyses to quantify the impact of maternal

biliopancreatic diversion on epigenetic profiles in the offspring.30,31 Compared to children born before surgery, 3% of CpG probes were differently methylated in post-surgery siblings,

corresponding to biological functions related to disorders of glucose metabolism, pancreas disorders, autoimmune disease, and cardiovascular diseases.31 Further, genes involved in the type 1

diabetes signaling pathway were picked to validate the clinical implication of the methylation modification. The strong correlations between gene methylation levels, gene expression, and

plasma markers of insulin resistance (children born after surgery had improved insulin sensitivity)31 indicated that maternal bariatric surgery possibly modifies offspring’s cardiometabolic

health through epigenetic modification. Analogous to the Canadian sibling study, the Swedish sibling study35 evaluated the DNA methylation levels and the potentially altered gene functions

and pathways within 31 sibling peers born before and after bariatric surgery (e.g., gastric banding, gastric bypass). Distinct DNA methylation profiles were found between siblings,

especially in genes involved in type 2 diabetes, inflammation, and melanocyte signaling.35 WEIGHT STATUS Offspring’s weight status was examined in 13 studies, and the results were highly

mixed. Five studies (3 sibling-comparison, 1 cross-sectional, and 1 animal study) supported a lower weight status in offspring exposed to maternal bariatric surgery. In detail, several

ancillary reports28,29,30 from the Canadian sibling study documented lower mean BMI z-scores (boys only), lower waist circumference, and lower prevalence of overweight, obesity, and severe

obesity in children born after than those born before surgery. Concordantly, another two sibling studies39,40 similarly found a significantly decreased rate of overweight and obesity in

siblings born after vs before maternal bariatric surgery. Besides, a cross-sectional study conducted in Sweden41 also noted significantly lower body weights in 18-month boys born after

maternal RYGB compared to the national reference values. Finally, the Brazilian animal study reported that the offspring of RYGB dams had lower body weight and body weight gain throughout

life (at birth, weaning, and postnatal day 120) than offspring of sham dams.25,26 Five studies (1 sibling-comparison, 2 case-control, 1 cross-sectional, and 1 animal study) pointed in the

opposite direction. The Swedish sibling study36 documented a higher mean BMI in 10-year-old children (with a higher prevalence of obesity in girls) born after maternal surgery than those of

the same age born before surgery, after adjusting for important confounders such as maternal age. Two case-control studies,33,43 including one that used population-based design,43

demonstrated that children of mothers with a history of bariatric surgery had significantly higher body weight, BMI, excess fat percentage, waist circumference, and rates of obesity compared

to controls born to mothers with overweight/obesity or normal weight. Using the national value as a reference, a retrospective study in Italy42 reported a higher prevalence of overweight

(30.8% vs 22.4%) and obesity (23.1% vs 17%) in children born after maternal bariatric surgery (age: 19.0 years), although the statistical significance of the difference was not presented.

Lastly, the US animal study found at postnatal day 60, despite similar body weight,21 offspring of SG rats had greater adiposity than those of sham rats.24 One case-control study44 reported

nonsignificant findings. Each birth to mothers who underwent RYGB (_n_ = 32) was matched to two control births without bariatric surgery in women with prepregnancy BMI < 35 kg/m2 (_n_ = 

32) and ≥35 kg/m2 (_n_ = 32). At seven years of age, no difference was observed in the prevalence of overweight or obesity among the three groups.44 OBESITY-ASSOCIATED METABOLIC DISEASES:

DIABETES/INSULIN SENSITIVITY, BLOOD PRESSURE, AND DYSLIPIDEMIA Five studies (1 sibling-comparison, 1 case-control, and 3 animal studies) characterized cardiometabolic profiles in offspring

following maternal bariatric surgery, and most found a certain degree of impairments. The only study that yielded favorable outcomes was the Canadian sibling study, which reported

improvements in all cardiometabolic indices in siblings born after than those born before maternal surgery, including improved insulin resistance,28,30,31 lower blood pressure30,31 and

triglycerides,28 and higher levels of high-density lipoprotein cholesterol.28 In contrast, the Belgian case-control study32 reported that compared to children of non-surgical mothers with

obesity or normal weight, those of mothers with prior bariatric surgery had higher diastolic blood pressure and worse endothelial function. There were however no differences in serum lipid

levels, and after adjusting for baseline differences, there was no difference in endothelial function. A population-based case-control study in Israel43 examined endocrine morbidity as a

whole (hypothyroidism, diabetes, hypoglycemia, obesity), and found that maternal bariatric surgery was an independent risk factor for developing pediatric endocrine morbidity in the

offspring, even after adjusting for important confounding variables such as maternal age, gestational week, and smoking.43 In line with findings from the Israel endocrine study, three animal

studies similarly found impaired metabolic profiles in offspring of bariatric surgery dams. Specifically, the US animal study found that SG dams’ pups had higher cholesterol levels at

weaning and greater glucose intolerance in adulthood compared to sham dams’ offspring.24 The Brazilian animal study noted that at postnatal day 120, the offspring of RYGB dams exhibited

insulin resistance in muscle and adipose tissue, and displayed lower β-cell responsiveness to glucose in pancreatic islets.26 Another animal study documented that at 120 days of age, the

livers of female offspring of RYGB dams displayed higher amounts of lipogenic genes and proteins than those of sham dams, indicating a deleterious modification in the hepatic morphology and

lipid metabolism.27 APPETITE-REGULATION HORMONES AND EATING BEHAVIORS Two studies (1 sibling-comparison, 1 animal study) assessed levels/functions of leptin and ghrelin—two of the most

important appetite-regulation hormones—in offspring following maternal bariatric surgery. The Canadian sibling study reported significantly lower levels of leptin (which inhibits hunger) and

higher levels of ghrelin (hunger hormone) in siblings born after maternal biliopancreatic diversion than those before surgery.28 The US animal study conducted a more sophisticated analysis

of the leptin and ghrelin system, including an examination of its circulating levels, sensitivity to exogenously administered leptin and ghrelin, and neural gene expression and activation.

Results suggested altered leptin and ghrelin signaling in offspring of SG dams, reflected in blunted responses to exogenously administered leptin22 and ghrelin (males only),23 elevated mRNA

expression of leptin receptor22 and ghrelin receptor23 in the hypothalamus, and elevated neural activation to leptin injection.22 Offspring’s eating behaviors were evaluated in two human

studies. Using the Food Frequency Questionnaire, the Belgian case-control study34 found similar meal patterns (frequency of consuming breakfast, lunch, and dinner) among children of mothers

who underwent bariatric surgery and children of mothers with overweight/obesity or normal weight. Nonetheless, few differences in food choices emerged. For example, children in the surgical

group reported consuming less poultry, fruit juices, and salty snacks, but more milk desserts than those in the overweight/obesity group.34 Based on three 24-hour dietary recalls with the

parents, a cross-sectional study in Brazil reported that among 13 children of women who underwent RYGB, 7.6% presented with carbohydrate intake and 30.7% with lipid intake lower than the

recommendation.45 NEURODEVELOPMENT Four human studies reported the neurodevelopmental outcomes in children born after maternal bariatric surgery: with one exception, all supported a normal

developmental trajectory. Specifically, the Canadian sibling study reported that among 123 school-age children whose mothers had previous biliopancreatic diversion, all performed normally in

terms of intellectual and social functioning.29 In a prospective case-control study conducted in Brazil44 no group differences were found in fluid intelligence among children of RYGB

mothers and children of non-surgical mothers with prepregnancy BMI < 35 kg/m2 or BMI ≥ 35 kg/m2. Finally, another study in Brazil40 assessed the neuropsychomotor development (indicated by

social and personal development, language, fine motor skills, and gross motor skills) in 23 children born after maternal bariatric surgery, and results showed that all components fell in

the normal range. The only study with negative findings was the Belgian case-control study,33 in which children’s neurodevelopmental data (indicated by internalizing problems, externalizing

problems, and prosocial behavior) were compared among three groups of children whose mothers had preconception bariatric surgery, had overweight/obesity without surgery, or had a healthy

weight without surgery. Results indicated that children in the surgical group had a significantly higher number of total difficulties and externalizing problems, meaning more aggressive and

rule-breaking behaviors in this cohort.33 A caveat to consider however is that the surgical group contained the lowest levels of maternal education and the children of post-bariatric mothers

were also significantly younger—these differences did not appear to be accounted for in the statistical analyses. OTHER HEALTH OUTCOMES MORPHOLOGY OF SKELETAL MUSCLE One animal study46

evaluated the effects of maternal RYGB on the morphology of skeletal muscle of the male offspring. Obese rats were submitted to either RYGB or sham surgery. Compared to offspring of sham

dams, those born to RYGB dams had altered homeostasis of the skeletal muscle, demonstrated in reductions in the muscle weight, area of muscle fibers, and the nucleus/fiber ratio.

Nonetheless, those reductions were accompanied by an increased number of fibers and capillary density, signifying an attempt to increase the oxygen supply to support metabolic activities.46

THERMOGENESIS IN BROWN ADIPOSE TISSUE The Brazilian animal study analyzed whether maternal RYGB promotes changes in the offspring’s brown adipose tissue, including the morphological profile

of lipids deposition and protein expressions involved in the thermogenic process. It was shown that offspring of RYGB vs sham dams exhibited reduced lipids deposition and adipocyte size, but

increased number of nuclei and Uncoupling Protein 1 expression in brown adipose tissue, suggesting restored thermogenesis from the impairment induced by maternal obesity.25 DISCUSSION To

our knowledge, this is the first study that reviewed and synthesized available evidence concerning the long-term effects of maternal bariatric surgery on the health of offspring. The

examined health outcomes spanned various domains, including immune and inflammation, epigenetics, weight status, cardiometabolic risk profiles, lifestyle behaviors, and neurodevelopment.

Although the number of studies devoted to each health domain is limited and results were not entirely consistent, maternal bariatric surgery appeared to have an effect on the offspring in

terms of (1) modified epigenetics; (2) altered weight status (albeit conflicting direction of the alteration); and (3) worsened cardiometabolic indices. Additionally, there was some evidence

derived from animal studies that the surgery produced anomalies in immune, inflammation, and appetite-regulation hormones in offspring. EPIGENETICS While only two human studies have

evaluated the epigenetic programming effect of maternal bariatric surgery, both demonstrated significant alterations in DNA methylation, particularly in genes involved in glucose, immune,

and obesity regulation, in siblings born after vs before surgery.30,31,35 Importantly, the altered methylome of genes was accompanied by coherent changes in gene expression patterns,

strengthening the clinical relevance of the epigenetic modification. Those findings were supported by previous research that bariatric surgery modulated global47 and

gene-specific48,49,50,51,52 methylation levels in the surgery recipient. The findings also aligned with prior animal reports using rat and sheep models, which showed that prepregnancy weight

loss resulting from calorie restriction or exercise led to epigenetic modification of genes functionally associated with insulin and lipid metabolism.53,54,55 A methodological strength of

the two epigenetic studies is that they adopted sibling-comparison designs, which substantially reduced confounding due to genetic, social, and lifestyle factors, thus yielding higher

confidence that the observed epigenetic alterations reflect intrauterine programming caused by maternal bariatric surgery. Nonetheless, the interpretation of results is still challenged by

various limitations such as residual confounders, the use of whole blood for analysis, and the lack of longitudinal assessment. For instance, in the Swedish sibling study,35 women were

significantly older, had lower gestational age at delivery, and had lower smoking rates during post-surgery than before-surgery pregnancy. Those differences are likely to affect the

methylation profiles in the offspring. Additionally, DNA methylation patterns are known to be tissue- and cell-specific. Hence, it is unclear whether findings from the whole-blood analysis

can be extrapolated to other tissues. Also, as both studies included a single assessment, it is unknown whether the epigenetic alterations during childhood can persist into later life, and

how those alterations influence downstream cardiometabolic consequences. Collectively, current research supports an epigenetic mechanism through which maternal bariatric surgery exerts

transgenerational effects. Still, more studies are needed to ascertain the causal effect and clarify the reproducibility, durability, and long-term implication of the epigenetic alterations.

WEIGHT STATUS Most studies supported an altered weight status in offspring born to mothers with a history of bariatric surgery; yet, results were inconsistent regarding the direction of the

alteration. The discrepancies can be explained by the methodological differences across studies, such as surgery procedure performed (e.g., RYGB, SG, biliopancreatic diversion), study

design (sibling-comparison, case-control, cross-sectional), and weight measurements (objectively measured, parent-reported, medical record). In addition to different methodologies, as

children’s weight is strongly influenced by the weight of their mothers, the mixed findings may, in part, reflect the variations in the maternal BMI classification. In detail, the human

studies that supported reduced weight in offspring born to operated mothers predominantly utilized sibling designs. In these studies, the comparison group consisted of siblings of mothers

with severe obesity who had not undergone surgery, thus had not yet achieved substantial weight loss. In contrast, studies that supported higher child weight status post-bariatric surgery

mainly involved a comparison of mothers with normal weight or weight of national reference. Future studies that incorporate a comparison group matched on prepregnancy BMI would be helpful to

better understand whether and how maternal bariatric surgery modifies the weight pattern of offspring. The discrepancies can also be attributed to variations in child characteristics, such

as age groups and gender composition. Among the reviewed studies, some recruited children over a wide age range29,40 (e.g., 2 years to adolescence), while others focused on a narrower age

group.36,39 Since each age group corresponds to a distinct growth rate, it is possible that the weight trajectories in children of mothers with and without bariatric surgery diverge

differently depending on their developmental stage. Two studies in this review support this hypothesis: the Canadian sibling study reported a lower prevalence of overweight and obesity in

siblings born after maternal bariatric surgery in the 7-year age group (not 11–18 years);29 the Swedish sibling study noted a higher mean BMI in post-surgery children, but only in the

10-year age group (not 4 or 6 years).36 Also, several studies included in this review suggested that maternal bariatric surgery affected offspring weight status in a gender-specific manner,

with the differences manifested in boys only.28,29 This observation agrees with previous research, which proposed that male fetuses are more sensitive to intrauterine environments than

female fetuses.56,57,58 Another point worth discussion is whether children born to mothers with bariatric surgery experience catch-up growth. Studies in this review repeatedly noted lower

birth weight in neonates post-surgery.28,37,39 However, following the early period of growth inhibition, some children maintained the lower weight status into later life stages, but others

surpassed their peers due to accelerated growth. Studies outside the bariatric field have uncovered various sociodemographic, environmental, and behavioral factors that may influence the

likelihood of catch-up growth, such as gestational age, education, family income, and breastfeeding.59 All of these factors likely play a role in the weight status of offspring post-maternal

bariatric surgery. Further research with longitudinal designs to assess catch-up growth will contribute to a better understanding of weight trajectories in offspring following maternal

bariatric surgery. OBESITY-ASSOCIATED METABOLIC DISEASES: DIABETES/INSULIN SENSITIVITY, BLOOD PRESSURE, AND DYSLIPIDEMIA While expectations that weight loss in mothers would reverse the

obesity-induced negative effects in offspring, our review found that prepregnancy bariatric surgery may negatively impact children’s cardiometabolic profiles. To further clarify this, we

searched literature that evaluated the offspring’s metabolic outcomes following prepregnancy behavioral weight loss. The only identified study reported that a 6-month preconception lifestyle

intervention in women with obesity had no effect on children’s insulin sensitivity or blood pressure at age 6.5 years.60 Catch-up growth, an independent predictor of cardiovascular disease

and its risk factors in later life,61,62 may account for the less favorable metabolic outcomes observed in children exposed to maternal bariatric surgery. Another explanation could be the

complex physiological changes that occur after surgery, such as disrupted glucose kinetics,63,64,65 endothelial dysfunction,66 and impaired hepatic lipid metabolism.27,67 Taking glucose

kinetics as an example, studies that used continuous glucose monitoring have consistently shown that patients after bariatric surgery have an exaggerated glucose variability, characterized

by a wide range between glucose peak and nadir, more time exposed to glucose levels out of normal range during the day and overnight, and postprandial glucose abnormalities.63,64,65 This

dysglycemia in the post-bariatric maternal body may be contributing to the altered glucose metabolism of their offspring. It is important to note that although studies have raised concern

about the potential risks of maternal bariatric surgery on children’s metabolic profiles, data supporting these claims were largely derived from animal studies. Due to distinct gut anatomy

and physiology, surgical techniques in animals cannot fully mimic human operations. For example, current mouse gastric bypass models either maintain or exclude the entire stomach, whereas

clinical procedure preserves a small pouch. The metabolic implications of the deviated surgical techniques are not fully understood. Yet, there has been evidence showing varying weight loss

rates and differences in mechanisms that mediate the weight loss (e.g., bile acids profiles, energy expenditure),68 indicating the need for caution when applying findings from animal models

to humans. NEURODEVELOPMENT Results of this review generally indicated that maternal bariatric surgery was not associated with neurodevelopmental delay in the offspring. Although one study33

described more externalizing problems in children of mothers with vs without preconception bariatric surgery, it should be noted that education level—one of the most prominent confounders

that predict offspring cognitive development—was significantly lower in surgical mothers. Even with promising findings, considering the limited number of studies and the various limitations

in those studies (e.g., cross-sectional design, small and non-generalizable samples, and reliance on parent-reported data), it is too early to conclude that maternal bariatric surgery is

absent of adverse effects on offspring’s neurofunction. Concerns still exist due to surgery-induced maternal malnutrition (especially folate and vitamin B12 deficiency), substance use, and

mental health disorders, all of which are potential threats to fetal brain development. Future longitudinal studies with larger sample sizes, longer follow-up, and objective cognitive

assessments would be necessary to clarify the effect of maternal bariatric surgery on offspring’s neurodevelopment. IMMUNE, INFLAMMATION, AND APPETITE-REGULATION HORMONES A series of

ancillary reports from the US animal study uncovered multiple anomalies related to immune, inflammation, and leptin and ghrelin regulation in the pups of SG dams,21,22,23 and the authors

proposed that those anomalies might contribute to downstream physiological impairments. Markedly, previous works from the same research team found corresponding impairments in the maternal

body and placenta following SG, including disrupted immune milieu,69 increased proinflammatory marker expression,69 elevated stress responsibility,70 and reduced leptin levels,69 reinforcing

the potentially harmful effects of maternal bariatric surgery. While results from the animal study may not be readily translated to humans, current evidence at least indicates the

importance of additional research. This scoping review has several limitations. First, data obtained were limited to three databases, and a gray literature search was not conducted;

therefore, important information presented elsewhere or unpublished may have been missed. Second, a focus on the statistical significance rather than effect size precludes understanding the

strength of the relationships between maternal bariatric surgery and long-term health outcomes in offspring. Third, some limitations are inherent in the included studies, including small

sample sizes and a lack of longitudinal studies that cover different developmental stages. Furthermore, beyond those examined in the literature, maternal obesity is associated with a wider

range of health outcomes in offspring, such as depression and allergic diseases. Future studies could include those outcomes for a more comprehensive understanding of the transgenerational

implications of maternal bariatric surgery. CONCLUSION Findings from this scoping review support an effect of maternal bariatric surgery on offspring’s epigenetic profiles, weight status,

and metabolism. Not all effects are advantageous given evidence (though mostly from animal studies) on impaired cardiometabolic indices, altered immune cell populations and inflammation, and

appetite regulation in the surgery-exposed offspring. Many questions are waiting to be answered in future studies, such as the downstream changes associated with epigenetic modification,

the shape of weight trajectory in children born after maternal surgery, and the surgical influence in a broader spectrum of health outcomes (e.g., lifestyle behaviors, mental health) in

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a female rat model of vertical sleeve gastrectomy. _PLoS One_ 13, e0200026 (2018). Article  PubMed  PubMed Central  Google Scholar  Download references FUNDING Funding V.L. was supported by

the National Institute of Health, Building Interdisciplinary Research Careers in Women’s Health at UC Davis through Grant Number: 5K12HD051958. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

School of Nursing, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA Yang Yu & Susan W. Groth * Department of Surgery, University of California Davis, Sacramento,

CA, 95817, USA Victoria Lyo * Center for Alimentary and Metabolic Science, University of California Davis, Sacramento, CA, 95817, USA Victoria Lyo Authors * Yang Yu View author publications

You can also search for this author inPubMed Google Scholar * Victoria Lyo View author publications You can also search for this author inPubMed Google Scholar * Susan W. Groth View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Y.Y.: conception and design; literature search and review; interpretation of results; drafting the

article; final approval. V.L.: interpretation of results; revising the article; final approval. S.W.G.: interpretation of results; revising the article; final approval CORRESPONDING AUTHOR

Correspondence to Yang Yu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with

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surgery on long-term health of offspring: a scoping review. _Pediatr Res_ 94, 1619–1630 (2023). https://doi.org/10.1038/s41390-023-02698-9 Download citation * Received: 30 March 2023 *

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