Pregnancy after Bariatric Surgery: Balancing Risks and Benefits

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Pregnancy after Bariatric Surgery: Balancing Risks and Benefits Anne-Marie Carreau MD, MSc a,b, Mélanie Nadeau MSc b, Simon Marceau MD b,c, Picard Marceau MD, PhD b,c, S. John Weisnagel MD d,e,* a

Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Québec, Canada Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Québec, Canada c Department of Surgery, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada d Division of Endocrinology, Department of Medicine, Centre Hospitalier Universitaire de Quebec, Université Laval, Québec, Canada e Centre de Recherche du Centre Hospitalier Universitaire de Québec, Axe Endocrinologie/Néphrologie, Québec, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 24 March 2016 Received in revised form 16 August 2016 Accepted 5 September 2016

The majority of bariatric surgeries in Canada are performed in women of reproductive age. Clinicians encounter more and more often pregnancies that occur after bariatric surgeries. The appropriate management and education of women who want to conceive after bariatric surgery is still unclear due to the lack of consistent data about maternal and neonatal outcomes following bariatric surgery. Maternal obesity during pregnancy confers a higher risk for gestational diabetes, hypertensive disorders, congenital malformations, prematurity and perinatal mortality. Generally, pregnancies in severely obese women who have undergone bariatric surgery are safe, and the women are at significantly lower risk for gestational diabetes, hypertensive disorders and large-for-gestational-age neonates, but the surgery confers a higher risk for small-for-gestational-age infants and prematurity. This review aims to provide evidence from recent publications about the risks and benefits of bariatric surgeries in the context of future pregnancies. © 2016 Canadian Diabetes Association.

Keywords: bariatric surgery gestational diabetes maternal outcomes neonatal outcomes pregnancy

r é s u m é Mots clés : chirurgie bariatrique diabète gestationnel issues maternelles issues néonatales grossesse

La majorité des chirurgies bariatriques au Canada s’effectuent chez des femmes en âge de procréer et les cliniciens sont donc de plus en plus confrontés au suivi de grossesses chez des femmes ayant subi une chirurgie bariatrique. Cependant, la prise en charge et l’éducation appropriées des femmes qui veulent concevoir après la chirurgie bariatrique ne sont pas encore claires en raison du manque de données cohérentes sur les issues maternelles et néonatales à la suite de la chirurgie bariatrique. Il est bien connu que l’obésité maternelle durant la grossesse expose à un risque plus élevé de diabète gestationnel, de troubles hypertensifs, de malformations congénitales, de prématurité et de mortalité périnatale. Généralement, les grossesses chez les femmes ayant subi une chirurgie bariatrique par le passé sont sans danger et améliorent le risque de développer un diabète gestationnel, des troubles hypertensifs ou de donner naissance à un bébé gros pour l’âge gestationnel. Cependant, nous constatons qu’elles sont exposées à un risque plus élevé de donner naissance à un bébé petit pour l’âge gestationnel ou prématuré. La présente revue a pour but de fournir les données scientifiques de récentes publications sur les risques et les avantages des chirurgies bariatriques dans le cadre de grossesses futures. © 2016 Canadian Diabetes Association.

Introduction In 2013 and 2014, more than 6500 bariatric surgeries (BSurg) were performed in Canada, and 78% were performed in women; more than half were of reproductive age (1). The most recent clinical practice guidelines for the perioperative nutritional, metabolic and nonsurgical management of patients undergoing BSurg were

* Address for correspondence: S. John Weisnagel, MD, Centre de Recherche du CHU de Québec-Unité de recherche sur le diabète, Axe Néphrologie et Endocrinologie, 2705, boulevard Laurier local TR 27, Québec G1V 4G2, Canada. E-mail address: [email protected]

published in 2013, cosponsored by the American Association of Clinical Endocrinology (AACE), The Obesity Society (TOS) and the American Society for Metabolic and Bariatric Surgery (ASMB) (2). It was suggested that candidates for bariatric surgery should avoid pregnancy preoperatively and for 12 to 18 months postoperatively. These recommendations about pregnancy after bariatric surgery were grade D, reflecting the important lack of data about early and late effects of BSurg on maternal and fetal outcomes. These clinical guidelines also recommend that women who become pregnant after BSurg should be counselled and monitored for appropriate weight gain and nutrition supplementation and for fetal health (Grade C). Unfortunately, little is known about whether outcomes for fetal health are different depending on the timing between BSurg,

1499-2671 © 2016 Canadian Diabetes Association. The Canadian Diabetes Association is the registered owner of the name Diabetes Canada. http://dx.doi.org/10.1016/j.jcjd.2016.09.005

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conception and pregnancy, the periods of active weight loss or the stability of weight and optimal nutritional support needed. Recently, these considerations have been gaining more interest, and studies involving a growing number of patients and various outcomes are increasingly available to help clinicians manage this particular population adequately. This review focuses on recent available data concerning fetal and maternal safety of pregnancy after BSurg and on the risks and benefits of BSurg in maternal and neonatal outcomes.

Methods We reviewed recent literature using the following PubMed keywords: bariatric surgery, sleeve gastrectomy, biliopancreatic diversion, RYGB, Roux-in-Y Gastric Bypass, Gastric Bypass, gastric banding, LAGB, weight loss surgery and pregnancy, neonatal outcomes, maternal outcome, newborn, and specific keywords for each described outcome. Articles in French and English were evaluated and are included in the present review, depending on overall literature results.

Obesity and Pregnancy: What are the Risks? Multiple studies have assessed the risks of obesity in maternal and fetal health in comparison to the risks in normal-weight and lean women. These studies allowed quantification of the risks in pregnancy according to the large spectrum of increasing body weight, from overweight to severe obesity. Fertility is clearly affected by obesity, which is associated with menstrual irregularities and oligo-anovulation. Even obese women with regular menstrual cycles may have subfertility and increased time to conception (3,4). Beyond preconception, fertility issues associated with obesity, excess weight before pregnancy (body mass index [BMI] ≥25 kg/m2) is also associated with an increased risk for spontaneous miscarriage before 20 weeks of gestation (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.25 to 2.25) (5) and recurrent miscarriage (OR 3.51; 95% CI 1.03 to 12.01) in obese women (BMI ≥30 kg/m2) (6). Mechanisms explaining these poor reproductive outcomes are still unclear, but multiple factors may contribute, including increased adipokines and inflammatory cytokines secreted by adipose tissue; lipotoxicity, hypothalamo-pituitaryovarian axis and hormonal changes (3). Obesity is also associated with an increased risk for maternal and fetal complications. First of all, obesity is associated with a strongly increased risk for gestational hypertension and preeclampsia (OR 4.82; 95% CI, 4.04 to 5.7) (7). Prepregnancy overweight or obesity also substantially increases the risk for gestational diabetes mellitus (GDM). Meta-analyses of 70 studies in more than 670 000 women have confirmed that the risk for GDM increases with higher BMI in comparison to normal-weight women, with an OR of 1.97 in overweight, 3.01 in obese and 5.55 in severely obese women (8). Obesity or severe obesity is a more important risk factor for GDM than maternal age or ethnicity (9). Furthermore, it is well known that maternal hyperglycemia per se increases the risk for many maternal and fetal outcomes, including pre-eclampsia, assisted or caesarean delivery, large-for-gestational-age (LGA) newborn, shoulder dystocia or birth injury, premature delivery, neonatal intensive care, hyperbilirubinemia and neonatal hypoglycemia (10). Independent of the effect of GDM on fetal outcomes, obesity per se also increases the rate of congenital anomalies, including spina bifida (OR 2.24; 95% CI, 1.86 to 2.69); neural tube defects (OR 1.87, 95% CI, 1.62 to 2.15); hydrocephaly (OR 1.68; 95% CI, 1.19 to 2.36); anorectal atresia (OR 1.48; 95% CI, 1.12 to 1.97); limb reduction anomalies (OR 1.34; 95% CI, 1.03 to 1.73); cardiovascular anomalies (OR 1.30 95% CI,1.12 to 1.51); cleft palate (OR 1.23; 95% CI, 1.03 to 1.47); cleft

lip and palate (OR 1.20; 95% CI, 1.03 to 1.40); and septal anomalies (OR 1.200; 95% CI, 1.09 to 1.31) (11). The risk for prematurity, including giving birth to an extremely preterm infant (22 to 27 weeks) is approximately tripled in severely obese women (BMI >40 kg/m2) (12). In comparison to lean women (BMI <20 kg/m2), the risk for stillbirth (≥28 weeks of gestation) in obese women is doubled (OR 2.0; 95% CI, 1.2 to 3.3) in parous women and approximately quadrupled (OR 4.3; 95% CI, 2.0 to 9.3) in nulliparous women in a population-based cohort study from Sweden (13). The same group also reported an increased risk for infant mortality from 2.4 infant deaths per 1000 deliveries for normal-weight women (BMI 18.5 to 24.9 kg/m2) to a rate of 3.4 per 1000 for obesity grade 1 (BMI 30 to 35 kg/m2) and 5.8 per 1000 for obesity grade 3 (BMI ≥40 kg/m2) independently of GDM or hypertensive disorders (14). Excess risk for infant mortality in obese women was attributed to an increased risk for preterm deliveries (12), birth asphyxia, congenital anomalies, sudden infant death syndrome and other neonatal morbidities (14). The fraction of infant mortality that could be attributed to BMIs 25 kg/m2 or above was 11% within this cohort, and 45% of excess death occurred in preterm infants. A meta-analysis and systematic review of 38 studies that did not include this last study also concluded that obesity confers an increased risk for fetal mortality, stillbirth and neonatal mortality (15). Regarding birth weight, macrosomia and LGA, newborns are clearly more commonly at risk in cases of maternal obesity. This risk is at least doubled, and a meta-analysis showed that maternal obesity (BMI ≥30 kg/m2) increased the risk for macrosomia, which is defined as a birth weight ≥4000 g (OR 2.17, 95% CI 1.92, 2.45); birth weight ≥4500 g (OR 2.77, 95% CI 2.22, 3.45) and LGA, which is defined as a birth weight ≥90 percentile for gestational age (OR 2.42, 95% CI 2.16, 2.72) (16). The increased risk persists when prepregnancy BMI is considered independently of GDM (17,18). Furthermore, excessive gestational weight gain is also deleterious for the health of mother and child, including an increased risk for caesarean delivery, postpartum weight retention, LGA infants, increased fat mass in the newborn and childhood obesity (19). Lifestyle intervention during the antenatal period through diet or physical activity has been shown to decrease gestational weight gain but, unfortunately, was only associated with a significant decrease in the risk of hypertensive disorders and shoulder dystocia in the newborn (20).

Indications for Bariatric Surgery Severely obese women (BMI ≥40 kg/m2 or BMI ≥35 kg/m2 and comorbidities) who have tried to lose weight through lifestyle intervention but do not attain or sustain objectives are eligible for BSurg. An increasing number of these women are now seen in clinical practice because significant weight loss is rarely attained through lifestyle intervention (1,21).

Pregnancy after Bariatric Surgery: Published Evidence Literature concerning the effects of BSurg on pregnancy outcomes is very conflicting because most publications consist of smallcohort studies (generally no more than 150 subjects) that often include both restrictive and malabsorptive procedures. Furthermore, highly heterogeneous control groups have been studied, from women with comparable early pregnancy BMIs or pre-surgery BMIs to comparison of the same women before and after the surgery or to general population controls or obese populations. Even if some conclusions appear to be consistent, this has led to confusion about most pregnancy and neonatal outcomes. In the most recent literature, 2 systematic reviews and meta-analyses examined the effects

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of BSurg on several maternal and neonatal outcomes (22,23). Yi et al reported 11 studies that evaluated the effects of various bariatric surgeries (restrictive and malabsorptive), comparing outcomes in obese women with and without BSurg, excluding deliveries by the same individual before and after the surgery and without necessarily matching for BMI. The outcomes evaluated were GDM, hypertensive disorders, postpartum hemorrhage, caesarean delivery, preterm birth, macrosomia and small-for-gestational age (SGA) neonates. Galazis et al analyzed 17 observational studies in women after BSurg in comparison to obese women without Bsurg; presurgery or prepregnancy BMI-matched women without Bsurg; as well as in comparison to the same women before BSurg. They evaluated pre-eclampsia, GDM, maternal anemia, preterm birth, caesarean section, LGA and SGA neonates, neonatal intensive care unit admission and perinatal mortality in a total of 5631 women after BSurg and 166,134 pregnant women as controls (23). The study with the largest sample size of post-BSurg pregnancies published to date was included in these 2 meta-analyses and had a strong impact on the results obtained. This Danish cohort study included 2562 births compared to 12,379 controls matched for early pregnancy BMIs. Unfortunately, this study reported only the neonatal outcomes of preterm births and birth weights (24). These 2 meta-analyses were performed before the publication of a large and influential cohort study published in the New England Journal of Medicine; it consisted of a Swedish cohort of 670 births after BSurg (98% Roux-en-Y gastric bypass (RYGB) and up to 5 control births matched for the mothers’ presurgery BMIs, ages, parity, smoking histories, educational levels and delivery years. This study aimed to assess the risk for gestational diabetes, LGA and SGA infants, preterm birth, stillbirth, neonatal death and major congenital malformations in women after BSurg in comparison to severely obese women eligible for Bsurg (25). The present review summarizes the general conclusions concerning maternal and neonatal outcomes after BSurg as obtained mainly from these published studies.

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and metabolic profiles (28). In the most recent meta-analysis published, GDM was evaluated in 9 studies, including various types of BSurg. Altogether, women with past BSurg had significantly lower GDM rates than obese women without BSurg (OR 0.31, 95% CI 0.15 to 0.65) (22). GDM was also decreased after BSurg by about 50% as compared to obese women in studies included in a meta-analysis from Galazis et al (23), and the decrease was even more pronounced in comparison to women matched for presurgery BMIs, age, parity and other pregnancy risks in more recent studies (OR 0.25, 95% CI 0.13 to 0.47) and (OR 0.33, 95% CI 0.13 to 0.77) (25,29). After weight loss resulting from the surgery, the risk of GDM appears to return to levels comparable to those of women of the same BMI before pregnancy (23,30). These studies were not designed to determine how surgical weight loss protects pregnant women against GDM, but this observation may provide information about mechanisms underlying GDM “protection” after BSurg. Beginning a pregnancy with a lower BMI may be sufficient to counter the higher risk for GDM that occurs with severe obesity, without the effect of the BSurg per se. In these studies, the various types of BSurg were not compared. In observations of the resolution of type 2 diabetes mellitus after BSurg, a complex combination of metabolic effects of Bsurg, including caloric restriction, increased incretin effect, early improvement of hepatic insulin sensitivity and peripheral insulin sensitivity improvements following weight loss (31) may contribute to diabetes resolution and could be expected to contribute to changes in the pathophysiology of GDM as well. Gestational hypertension and pre-eclampsia In 9 studies evaluated by Yi el al, hypertensive disorders were less common in women who had undergone BSurg (OR 0.42, 95% CI 0.23 to 0.78; I2=83.3%; p<0.001) (22) than in obese controls, and pre-eclampsia was decreased by a similar amount in 17 studies evaluated by Galazis et al (OR 0.45, 95% CI 0.25 to 0.80) (23). There was also a trend toward a decrease in pre-eclampsia rates when comparing women with the same prepregnancy BMIs (OR 0.63, 95% CI 0.38 to 1.06; p=0.08).

Maternal outcomes Fertility outcomes Only a few retrospective studies with small sample sizes evaluated spontaneous pregnancies after BSurg and were analyzed in a recent systematic review with meta-analysis, combining a total of 589 infertile women who underwent various types of BSurg (intragastric balloon, sleeve gastrectomy, gastroplasty, RYGB and biliopancreatic diversion (BPD) (26). The incidence of spontaneous pregnancy was 58% after BSurg (340 successful pregnancies in 589 women) but ranged from 22% to 92%. These studies did not report on time to conception or duration of infertility in these women. The meta-regression analysis showed a negative association between BMI before BSurg and successful pregnancy rate after Bsurg; women with higher BMIs before surgery displayed lower rates of spontaneous pregnancies after surgery. There was no association with the amount of weight loss or BMI reduction, emphasizing the importance of optimal lifelong BMIs in fertility issues (26). There is also evidence that BSurg may impressively decrease the absolute incidence of menstrual irregularities by close to 50% (56.2% before vs. 7.1% after BSurg); of hirsutism by approximately 35% (67% before vs. 32% after); and of polycystic ovary syndrome by nearly 40% (45.6% before vs. 7.1% after) (27). Gestational diabetes mellitus GDM is an important comorbid condition in pregnancy that impacts fetal outcomes and lifelong metabolic risks in the child. It has been shown that biliopancreatic diversion with duodenal switch (BPD-DS), the most effective metabolic BSurg, reduced GDM, birthweight and childhood BMIs, along with improving offspring lipid

Caesarean delivery Conflicting results have been reported in past literature concerning caesarean delivery, concluding generally that caesarean delivery rates may increase after BSurg (32–37). This confusion may have resulted from differences in the control populations studied. In general, studies that concluded that there was an increased risk for caesarean delivery compared post-BSurg births to births from an unmatched general population or a normal-weight population (33–35). Overall, the latest literature suggests that caesarean delivery rates are not higher in women who have undergone BSurg than in obese women (OR 0.75, 95% CI 0.50 to 1.13 and OR 0.99, 95% CI 0.75 to 1.31; p=0.95) (22,23). This was also the case in subgroup analysis, when births by the same women were compared before and after the surgery (OR 1.26, 95% CI 0.87 to 1.83; p=0.22) and when only studies using high methodologic quality were included (OR 1.01, 95% CI 0.63 to 1.63) (23). According to the American Congress of Obstetricians and Gynecologists (ACOG), BSurg per se should not be an indication for caesarean delivery because there is no known physiologic reason to favour this approach (38). Neonatal outcomes Perinatal mortality and congenital malformations In a meta-analysis including 5 studies of 3800 births after BSurg, perinatal mortality was the same in the offspring of obese women with and without BSurg (OR 1.05, 95% CI 0.48 to 2.31; p=0.90) (23). These reassuring data concerning the safety of pregnancy after BSurg is contrasted by new data from a large study of women matched for presurgery BMIs and other major pregnancy risk factors, which

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shows a trend toward a higher combined risk for stillbirth or neonatal mortality in pregnancies following BSurg (1.7% vs. 0.7% OR 2.39; 95% CI, 0.98 to 5.85; p=0.06) (25). The low absolute number of cases of perinatal mortality did not lead us to conclude of an association with any particular risk factor (gestational weight gain, delay of surgery-to-conception, etc.), and nutritional status was not assessed in this study. For the moment, this possible increase in risk remains elusive. The risk for congenital malformation after BSurg showed conflicting results and depended on the control group. In the general population, congenital malformations increase with BMI (11,39). The risk for congenital malformation in births after Bsurg is not increased in comparison to women of the same BMI group (39), but it did not seem to decrease either when compared to women matched for presurgery BMIs (25). On the other hand, 1 study compared births after BSurg to births by obese women without BSurg and found that neonates born after BSurg had more congenital malformations (7.9% vs. 3.3%; p=0.006) (32). These pregnancies were not matched for other pregnancy risk factors, such as maternal age or parity, and BSurg was not an independent risk factor for congenital malformation in multivariate analysis. Preterm delivery was a significant independent risk factor (32), but the rates of prematurity were not a described outcome in either group. For the moment, there is no evidence that BSurg by itself could be a cause of congenital malformations, even if some nutritional deficiencies have been associated with congenital malformations. Prematurity Both meta-analyses showed a slight but significant increase in preterm births (OR 1.31, 95% CI 1.08 to 1.58 and OR 1.33, 95% CI 1.16 to 1.52%) in women who had undergone BSurg in comparison to obese women who had not (22,23). The study by Roos et al, including more than 2400 women after malabsorptive or restrictive surgeries, had a large effect in these results (24). This study compared women who had undergone BSurg with matched controls who had the same BMIs before their pregnancies (after BSurg) as the primary outcome and from matched controls eligible for BSurg (BMI ≥40 kg/m2). Preterm births were more common in BSurg pregnancies than in prepregnancy BMI-matched controls (9.7% vs. 6.1%; p<0.001) and in severely obese women eligible for surgery (9.4% vs. 7.5%; p=0.03). Markedly preterm births (<32 weeks) and spontaneous and medically indicated preterm births were all significantly higher in the BSurg group. Subgroup analysis did not show an effect of BSurg types of procedures or surgeryto-delivery intervals on prematurity risk, but women with prepregnancy BMIs below 30 had higher risk than their matched controls, and women with prepregnancy BMIs of 35 or above had risks for premature births similar to those of their matched controls (24). Conversely, 2 recent studies, not included in these meta-analyses, showed that women who had had BSurg, compared to severely obese women (matched for presurgery BMIs and other pregnancy risk factors), did not have higher risks for preterm labour (25,29). With the large sample size and a well-matched group controlling for confounding factors, Roos et al reported high-quality data that should alert practitioners to a possible increased risk for preterm birth in these women. Preterm and, particularly, very preterm births are associated with many complications and comorbidities. No studies have evaluated the effects of nutrition status (micro- and macronutrients), gestational weight gain or caloric intake on the risk for preterm birth, and this knowledge gap should be addressed in order to be able to prevent this risk adequately in the future. Birth weight Systematic reviews and large-cohort studies have concluded, overall, that there are lower risks for neonates born after a bariatric surgery to be LGA and/or to have macrosomia, with approximately half the risk (OR 0.40 to 0,46) in meta-analyses (22,23). This

decreased risk has been demonstrated in comparisons with women who had the same presurgery BMIs (25,29,30,40), the same prepregnancy BMIs (24,40,41) and in the same mother before and after Bsurg (29,42). However, purely restrictive procedures appear to have uncertain impacts on birth weight; results are conflicting in cohorts consisting exclusively of or in a majority of restrictive surgeries (30,32,36,42–46). Direct comparison between malabsorptive and restrictive surgeries also favour malabsorptive surgery for this outcome (30). Women have lower risks for GDM after BSurg, so it is difficult to distinguish the effects on lower birth weights of weight loss and decreased weight gain during pregnancy from the effects of decreased hyperglycemia. In 1 study, the amount of weight loss before pregnancy was associated with a decreased risk for LGA neonates but was not associated with the risk for GDM (25). On the other hand, it is also relatively clear that neonates born after BSurg have an increased risk for being SGA. This risk has been estimated to be approximately double (OR 1.93 to 2.16) from both meta-analyses (22,23). The most influential study, which had the largest sample size for this outcome (more than 2400 births) following malabsorptive and restrictive procedures, also showed consistency with these general conclusions—that there is a lower risk for LGA neonates (OR 0.6, 95 CI 0.4 to 0.7; p<0.001) and a higher risk for SGA neonates (OR 2.0, 95% CI 1.5 to 2.5; p<0.001) in pregnancies post-BSurg compared to those of women without BSurg but with the same prepregnancy BMIs. Subgroup analysis did not show statistically significant differences in SGA neonates when women were stratified according to their prepregnancy BMIs, but in women with prepregnancy BMIs 35 kg/m2 or above, pregnancies post Bsurg did not show increased risk for SGA compared to those of matched BMI controls without BSurg. In this study, the type of surgery and the surgery-time-to-conception interval did not impact the risk for SGA (24). However, malabsorptive procedures have been associated with important increased risks compared to restrictive surgery (30,47), and RYGB was an independent risk factor for SGA (OR 7.16, 95% CI 2.74 to 18.72), whereas restrictive procedures had no effect (OR 1.66, 95% CI 0.56 to 4.88) in 1 retrospective cohort study (30). These conflicting conclusions resulting from various cohort studies may reflect the differences in preconception care and pregnancy nutritional follow up and supplementation. Further studies will be necessary to elucidate whether SGA is associated with a particular type of procedure in order to help guide clinicians in the management of women who want to become pregnant after BSurg. Surprisingly, a longer time interval between surgery and delivery (≥1.8 years) was associated with an increased risk for SGA neonates in a population in whom 98% had undergone the RYGB procedure (25). This conclusion is contrary to the general hypothesis that active weight loss in the first 18 months after surgery may be deleterious to fetal growth, in addition to the nutritional deficiencies and adjustments in supplementation required acutely after malabsorptive surgery. Faintuch et al evaluated the impact on birth weight of nutritional intake and nutritional status during pregnancy in a cohort of women after RYGB. Linear regression analysis showed a positive correlation between birth weight and BMI in the second trimester (r=0.58; p=0.04); folic acid level (r=0.78; p=0.001); and high-density lipoprotein level (r=0.55; p=0.049). Conversely, plasma lipids (total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides) (r=−0.58 to −0.83; p≤0.043); plasma glucose (r=−0.60; p=0.03); uric acid (r=−0.81; p<0.001); vitamin B12 (r=−0.85; p<0.001) were negatively associated with birth weight (48). These latter relationships may also seem contrary to the logical positive association of these markers with BMI and, as a consequence, with birth weight, but the authors argued that these measurements (in the normal range) may reflect a general balanced nutritional status instead (48).

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However, the very small sample size (n=14) of this study forces us to be cautious with its results. It has also been demonstrated that maternal iron deficiency anemia in the first half of pregnancy is associated with low birth weight and SGA infants (49). Supplementation with multivitamins, including iron and folic acid introduced at the end of second trimester, is better than supplementation with iron alone so as to decrease risk for low birth weight in a general population of women, thus emphasizing the importance of other micronutrients in fetal weight gain during late pregnancy (50). However, this assumption may be different in women with poor nutritional status at the time of conception (50). Low gestational weight gain is associated with a 2- to 3-fold increased risk for SGA in the general population (19), but this correlation has not been confirmed in BSurg cohort studies until now. Unfortunately, optimal nutritional support and weight management in the BSurg population in order to reduce rates of SGA infants remain to be determined and probably should be individualized according to the type of procedure and the timing after BSurg.

Maternal Nutrition and Supplementation BSurg, particularly malabsorptive procedures that involve anatomic changes in the digestive tract, lead to a high risk for deficiencies in several micronutrients (mainly vitamin B12, vitamin D and other fat-soluble vitamins, folate, calcium, iron and other trace elements) and macronutrients (mainly proteins and fat) if supplementation is not adequate after the surgery (2,51). It is also well recognized that micro- and macronutrient deficiencies may be deleterious to the fetus and cause congenital malformations. Deficiency in folic acid may cause neural tube defects; deficiency in vitamin A may cause microcephaly, hypotonia, intrauterine growth restriction, optic nerve hypoplasia and many other malformations and may cause maternal immunosuppression; deficiency in vitamin K may cause intracranial hemorrhages and bleeding disorders; and deficiency in vitamin B12 may cause neurologic developmental delay and pancytopenia (52). Calcium and vitamin D deficiencies are common with malabsorption and may cause secondary hyperparathyroidism with mainly maternal bone loss and, in extreme conditions, reduced calcium concentration in breast milk and reduced fetal mineralization (2,53,54). A recent meta-analysis concluded that vitamin D supplementation during pregnancy decreased the risk for preterm birth and low birth weight in 3 trials involving 477 women (55). Zinc deficiency has been seen in a large proportion of patients after malabsorptive surgery (56,57). Zinc is associated with fetal growth, and poor maternal zinc status may be associated with growth restriction, congenital malformations and preterm deliveries (58). However, zinc supplementation before 27 weeks of gestation, mostly in women likely to have zinc deficiency, did not improve low birth weight/ SGA in randomized control trials (58). A few studies have evaluated the nutritional status of women during pregnancy after Bsurg, but they have used small sample sizes and have rarely compared them to a control population (23,35,48,59). Overall, the risk for anemia was higher in women after BSurg (OR 3.4, 95% CI 1.56 to 7.44) (23) and reached 15% after RYGB and 24% after BPD in a retrospective cohort of 115 subjects. However, no severe anemia requiring intravenous iron or transfusions were noted (35). Low levels of vitamin B12 were also seen in 11% to 15% of patients in the same cohort, but the levels were not compared to a control population. Other micronutrients were at sufficient levels, and folic acid increased during pregnancy. Of 83 subjects who had undergone BPD, 5 had hypoalbuminemia and 1 had severe hypoalbuminemia and required parenteral nutrition (this pregnancy began 10 months after surgery). In the group that had undergone

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RYGB and sleeve gastrectomy, no hypoalbuminemia was reported (35). According to AACE/TOS/ASBMS guidelines, patients who become pregnant following BSurg should have nutritional surveillance and laboratory screening for deficiencies every trimester, including tests for iron, folate and B12, calcium and fat-soluble vitamins (Grade D) (2). The ACOG position paper supported these recommendations and highlighted the importance of broad evaluation for micronutrients and supplementation at the beginning of pregnancy as well as close monitoring during pregnancy when proven deficits exist. However, limited evidence exists concerning optimal basal supplementation, and clinicians may use theoretical suggestions by experts to guide their practice, whereas practice guidelines do not suggest specific supplementation during pregnancy (2,38,48,52,60). The Canadian recommendations for dietary intake of macronutrients, vitamins and minerals during pregnancy are detailed elsewhere by Health Canada (61–63). The standard supplementations recommended for nonpregnant patients after BSurg (including malabsorptive and sleeve gastrectomy) in the more recent AACE/ TOS/ASBMS guidelines consists of a minimum of 2 multivitamin plus mineral tablets daily (containing iron, folic acid and thiamine), at least 1200 to 1500 mg of calcium (calcium citrate preferred), vitamin D 3000 IU daily titrated to optimal 25-hydroxyvitamin-D plasma level, vitamin B12 as needed for normal range and iron supplement for a total of 45 to 60 mg per day, including multivitamins (2). A minimal protein intake of 60 g per day and up to 1.5 g/kg ideal body weight per day should be adequate after Bsurg (2), but Health Canada recommends a minimal protein intake of 71 g per day or 1.1 g per kg during normal pregnancy (62) The supplementation after BPD may be different because fat-soluble vitamin and macronutrient deficiencies may be more severe. The case of supplementation of vitamin A is more complex because oversupplementation has been associated with teratogenic complications; a threshold of approximately 10 000 IU per day of supplementation is recommended (38,60). In Canada, for pregnancies without BSurg, the recommended minimum daily intake of vitamin A is 2500 IU (61). In women at high risk for vitamin A deficiency, such as in the setting of low-income countries, the World Health Organization recommends supplementation up to 10,000 IU per day for 12 weeks or longer to prevent infant night blindness (64). However, some experts have suggested limiting supplementation in pregnant women after BSurg to 5000 IU per day (38,60), but these recommendations are based on low-grade evidence. Additional studies will be required to evaluate the level of vitamin A deficiencies during pregnancy in this population and to suggest optimal supplementation. Gestational weight gain The recommended gestational weight gain (GWG) is the same in all women, regardless of BSurg, and is determined by pregestational BMI (4,38). Many women stay overweight or obese even after Bsurg, and the Institute of Medicine (IOM)’s guidelines suggest a total weight gain of 5 to 9 kg for obese women with prepregnancy BMIs ≥30 kg/m2 and of 7 to 11.5 kg for overweight women (BMIs 25 to 29.9 kg/m2) (19). Therefore, optimal daily caloric intake during pregnancy should target the recommended weight gain and be individualized (48). The effect of these recommendations on neonatal or maternal outcomes after BSurg have been evaluated in only 1 recent study after RYGB (65). In 43 women who became pregnant in the first 18 months after RYGB, half of the women had GWGs below IOM recommendations. On the other hand, in the 28 women who became pregnant more that 18 months after RYGB, half were over the recommendations for GWG. In this study, the newborn birth weight tended to decrease if GWG was insufficient in relation to IOM recommendations. However, these

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observations remain to be confirmed by other studies in this specific population. Surgery-to-conception interval It is during the first 12 months after bariatric surgery that patients are in the most active weight-loss phase, and it is recommended that pregnancy be postponed at least until after this period because of the theoretic risk of malnutrition and impaired fetal growth (2,66). To date, only 1 study has, to our knowledge, specifically assessed the surgery-time-to-conception interval and its impact on maternal and neonatal outcomes. This Danish register-based cohort study compared 158 women who conceived fewer than 12 months after BSurg to 128 women who conceived after the first year, and the study showed no differences between the 2 groups for neonatal birth weight, SGA or LGA infants, birth defects, preterm births (before 37 weeks), need for neonatal intensive care, risk for pre-eclampsia, GDM, labour induction, caesarean section or postpartum hemorrhage (>500 mL) (66). With these results, the authors questioned the recommendation to wait a minimum of 12 months before conception. We have to be cautious because these results were found in a small sample size without the statistical power to assess uncommon neonatal outcomes. Concerning nutritional status in relation to the timing of conception after surgery, the data in the literature are poor. One group evaluated correlations between surgery-time-to-conception and nutritional status, prospectively, in 14 women with mean time-toconception intervals of 24.2±21.6 months. They showed that folic acid measured during pregnancy increased with increasing timeto-conception intervals, but high-density lipoprotein and transferrin decreased significantly during pregnancy with increasing time after surgery (48). Other micronutrients, metabolic markers and components of complete blood count during pregnancy were not influenced by time-to-conception delay, which is relatively reassuring. Breastfeeding after bariatric surgery: is there a risk? There are no formal recommendations in the literature about breastfeeding after BSurg. To our knowledge, no studies have assessed the safety and benefits of breastfeeding after BSurg. In the ACOG recommendations, the only mention concerns the necessity of continuous postpartum surveillance of the nutritional status of women who breastfeed because of case reports of neonate B12 deficiency in this situation (38).

Conclusions In conclusion, data from the literature available to date show that bariatric surgery has an overall positive effect on maternal and neonatal outcomes by reducing significantly the risk for maternal GDM, hypertensive disorders, fetal macrosomia and LGA infants in mothers who have undergone the procedure. This could also lead to an improvement in the future metabolic health of these children. On the other hand, bariatric surgery increases the risk for having an SGA or preterm infant. Further studies will be required to identify factors that may affect these outcomes, such as type of surgery, surgery-time-to-conception delay and nutritional factors that could be corrected to prevent poor outcomes. With preconception counselling and close follow up and monitoring of nutritional status and weight gain, pregnancy after BSurg appears to be safe for the mother and fetus. Future obstetric and nutritional follow-up recommendations will have to be focused on fetal growth and maternal nutritional status; however, for the moment, very few studies exist to guide clinical practice. BSurg is the treatment of choice for severely obese women who do not achieve weight loss with lifestyle changes,

and it is often offered to women of reproductive age. With the increased prevalence of this condition, the need to resolve these important questions concerning medical management is becoming critical in order to improve outcomes in both obese women and their offspring.

Acknowledgments A-MC is supported by a Fond de Recherche Québec-Santé/ Ministère de la Santé et Services sociaux for Resident Physician Health Research Career Training Program. We thank Dr. André Tchernof, Jennifer Labrecque and Paule Marceau for their contributions and collaboration related to this manuscript.

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