Obesity in Pregnancy – Optimizing outcomes for mom and baby

Synopsis

Obesity is common in women of childbearing age and management of this population around the time of pregnancy involves specific challenges. Weight and medical comorbidities should be optimized both prior to and during pregnancy. During pregnancy, gestational weight gain should be limited, comorbidities should be appropriately screened for and managed, and fetal health should be monitored. Consideration should be given to the optimal timing of delivery, and to reducing surgical and anesthetic complications. In the postpartum period, breastfeeding and weight loss should be promoted. Maternal obesity is associated with adverse metabolic effects in offspring, promoting an intergenerational cycle of obesity.

INTRODUCTION

The high rates of obesity in women of child bearing age, has made obesity the most common medical problem in pregnancy. According to the 2013–2014 NHANES data, 37% of women between the ages of 20–39 have obesity and rates continue to rise.¹ The rates vary dramatically by ethnic group, from 10% of Asian women, 33% of non-Hispanic white women, 43% of Hispanic women and 57% of non-Hispanic black women.¹ Women with obesity are at a much higher rate of poor obstetrical outcomes across the continuum of reduced fertility, pregnancy complications and postpartum adverse events, of which some, but not all, are preventable through targeted medical care. The lack of good evidence for intervention, has resulted in differences across national clinical practice guidelines.²

In addition to being more at risk, women with obesity may suffer discrimination and humiliation at a time that should be joyful. In a study of obstetrics providers, 31% identified that they had made derogatory comments about obese women to colleagues and 66% felt more derogatory comments are made about women with obesity than those without obesity.³ Providers who care for women with obesity who of child bearing age need to identify strategies and tools that promote open, non-judgmental communication about the risks in pregnancy and provide safer care through adequate resources, specialized equipment and structured protocols.^4–7

GOALS AND STRATEGIES

Preconception

Improve Fertility

Obesity in females is associated with subfertility and with a longer time to achieve pregnancy.^8–10 Although partially explained by the higher prevalence of the polycystic ovarian syndrome (PCOS),¹¹ which is characterized by anovulation and hyperandrogenism,¹² the association between infertility and obesity exists even in women with ovulatory menstrual cycles.^8–10 In addition, women with obesity have higher miscarriage rates¹³ and those using assisted reproductive technologies (ART) such as in-vitro fertilization (IVF) seem to have decreased pregnancy and live birth rates compared to those with normal BMI.¹⁴ Thus, obesity is associated with numerous factors that decrease the likelihood of achieving and maintaining a pregnancy.

There is a paucity of rigorous studies evaluating interventions to improve fertility in women with obesity. Observational evidence suggests that lifestyle interventions may improve pregnancy and live birth rates prior to undergoing ART.¹⁵ One multicenter randomized controlled trial (RCT) evaluated the effect of a 6 month lifestyle intervention followed by 18 months of infertility treatment in infertile women with BMI >29, compared to a control group receiving 24 months of prompt infertility treatment.¹⁶ The control group had a higher frequency of the primary outcome, a vaginal term birth of a healthy singleton, than the intervention group (35.2% vs. 27.1%), although women in the intervention group were more likely to achieve conception without infertility treatments. In contrast, in women with obesity and PCOS, post hoc data aggregation from two separate RCTs suggests that lifestyle intervention for weight loss prior to ovulation induction with clomiphene citrate increases live birth rate compared to immediate ovulation induction.¹⁷ Observational studies suggest that bariatric surgery improves fertility in women with obesity,¹⁸ however infertility is not considered an indication for bariatric surgery.^19,20 Thus, infertility treatments are most effective at achieving live birth in women with obesity, however, in younger women in whom there is less urgency to conceive, weight loss via lifestyle interventions is a reasonable first step for infertility management, as it is likely associated with other benefits.

Preconception Weight Loss

Guidelines advise weight loss prior to conception for women with obesity.^21,22 The majority of evidence supporting this recommendation comes from studies of women who have undergone bariatric surgery. Pregnant women who have previously undergone bariatric surgery are less likely to develop gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), postpartum hemorrhage, and fetal macrosomia, compared to controls who have not undergone bariatric surgery.²³ However, the risks of preterm birth and having a small for gestational age (SGA) newborn are increased.^23–25 Given that interventions during pregnancy have been found to be relatively ineffective in preventing comordities such as GDM,²⁶ studies are currently underway to evaluate whether pre-pregnancy lifestyle interventions will be more effective in reducing adverse pregnancy outcomes in women with obesity.²⁷

Current guidelines recommend a waiting period of 12–24 months following bariatric surgery before conceiving.^19,22,28 Reduced absorption of oral hormonal contraception may occur following bariatric surgery,²⁰ and alternate forms of contraception should be prescribed.¹⁹ Women who have previously undergone bariatric surgery require careful monitoring during pregnancy, as there is a risk of nutrient deficiencies²¹and anatomic surgical complications in this population.²² The benefits of postponing pregnancy to undertake bariatric surgery must also be weighed against the risk of declining fertility as maternal age increases.²²

Congenital Anomaly Reduction

There is a “dose-dependent” increase in the rate of congenital anomalies among offspring of women with obesity. There are more neutral tube defects (OR 1.87; 95%CI 1.62–2.15), heart defects (OR 1.15; 1.07–1.23; including left and right ventricular outflow defects and hypoplastic left heart syndrome, but not conotruncal defects), cleft lip and/or palate (OR 1.20; 95% CI 1.09–1.31), anorectal atresia (OR 1.48; 95% CI 1.12–1.97), hydrocephaly (OR 1.68; 95% CI 1.19–2.36) and limb reduction anomalies (OR 1.34; 95% CI 1.03–1.73).^29–31 The exact cause for this increased risk remains debatable, but includes abnormal glucose metabolism and nutrient deficiencies.³²

Targeted management strategies are needed, but evidence for these remains elusive. Human organogenesis is largely complete by 9 weeks gestational age. While most women do access prenatal care in the first trimester, true prevention must begin pre-conceptually. Most importantly, abnormal glucose metabolism must be identified and glycemic control optimized prior to conception. Folic acid supplementation has been shown to reduce congenital anomalies. Women with obesity are less likely to take preconception supplementation which may be related to other health behaviours or unplanned pregnancies.³³ Also, BMI may affect the distribution of folate, with obese women having lower serum levels relative to RBC folate levels.³⁴ While further study into optimal nutritional supplementation is needed for women with obesity, current guidelines differ in recommendations with some suggesting 5 mg and others recommending 0.4 mg of folate.^2,35 Consideration should be given to recommending additional folic acid compared to normal weight for three months prenatally and until 12 weeks’ gestation and vitamin D (10µg daily during pregnancy).^35,36

Detect and Optimize comorbidities

Women with obesity are more likely to have other comorbidities including T2DM, hypertension, hyperlipidemia, sleep apnea and nonalcoholic steatohepatitis (NASH) which may or may not have been previously identified and treated. Each of these conditions can contribute to poor obstetrical outcomes and may worsen as part of the normal physiological changes in pregnancy. It is essential that the woman be screened for these prior to pregnancy allowing for investigations to be completed and treatment adjusted for upcoming planned pregnancy. Although a detailed discussion is out of scope for this article, key points for optimizing outcomes for each of these conditions are listed in Box 1.

Box 1. Key points for screening for and optimizing preexisting comorbidities.

1. Hyperglycemia

   • Screen: using HgA1c and/or fasting glucose prior to pregnancy.
   • Prior to pregnancy:

     • ◦
       target A1c of <7% to reduce congenital anomalies
     • ◦
       Discontinue medications without known safety profile including SGLT2 inhibitors, DPP4 inhibitors, GLP-1 analogues
     • ◦
       Consider discontinuing sulfonlyureas and metformin (unless metformin being used for ovulation induction)
     • ◦
       Optimize insulin and self management skills
     • ◦
       Assess for microvascular complications
2. Hypertension⁵⁸

   • Screen: if indicated, screen for secondary causes of hypertension
   • Prior to pregnancy:

     • Discontinue medications without known safety profile including ACE Inhibitors, Angiotensin receptor blockers, aldosterone antagonists
     • Consider using labetalol, methyldopa, nifidepine
3. Hyperlipidemia

   • Screen: reevaluate indication for treatment as safety during pregnancy not established
   • Prior to pregnancy:

     • Optimize nutritional management, especially for cases of severe hypertriglyceridemia
     • Consider discontinuing lipid lowering agents unless there is a clear indication
4. Sleep Apnea1^{46, 147, 148}

   • Screen: use validated screening tools and perform sleep studies as indicated
   • Prior to pregnancy

     • Optimize sleep treatments such as CPAP and mandibular repositioning devices
5. Non-alcoholic steatorrheic hepatitis^{149, 150}

   • Screen: for other causes of liver dysfunction, consider ultrasound/fibroscan

6. Optimize: lifestyle modifications, if treated medically with pioglitazone or other agents consider discontinuation if there is no safety data in pregnancy

Pregnancy

Limit Gestational Weight Gain

Excess GWG is associated with adverse outcomes including increased risk of developing GDM, T2DM and HDP,³⁷ elevated infant birth weight and adiposity, and increased risk of metabolic syndrome and childhood obesity in offspring.³⁸ Women with pre-pregnancy overweight and obesity are more likely to gain excess weight during pregnancy.^39,40 One Canadian study found that 47% of normal weight women compared to 78% of overweight and 72% of women with obesity exceeded recommended GWG.⁴⁰

The Institute of Medicine (IOM) recommends gestational weight gain ranges based on maternal pre-pregnancy BMI (see Table 1), with less weight gain recommended for higher BMI categories.⁴¹ A systematic review found that in women with obesity, less GWG than that recommended by the IOM is associated with increased risk of preterm birth and having a small for gestational age infant, but also with reduced risk of macrosmoia, HDP, and cesarean delivery.⁴² Some studies have even suggested that weight loss in women with obesity during pregnancy may be associated with some reduced adverse outcomes.^43,44 Professional guidelines state that while recommendations must be individualized, women with obesity who are gaining less weight than recommended by the IOM need not increase their weight gain if fetal growth is adequate.⁴⁵

Table 1.

Recommended Gestational Weight Gain by Pre-pregnancy BMI

Prepregnancy BMI	BMI (kg/m2)	Total Weight Gain Range (lbs)	Rates of Weight Gain 2nd and 3rd Trimester (Mean Range in lbs/wk)
Underweight	<18.5	28–40	1 (1–1.3)
Normal Weight	18.5–24.9	25–35	1 (0.8–1)
Overweight	25.0–29.9	15–25	0.6 (0.5–0.7)
Obese (Includes all classes)	≥30.0	11–20	0.5 (0.4–0.6)

From Committee to Reexamine IOM Pregnancy Weight Guidelines. Institute of Medicine and National Research Council. Rasmussen KM, Yaktine AL, eds. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: The National Academies Press; 2009; with permission.

GWG targets should be calculated and discussed with women early in pregnancy.^21,46 A recent systematic review and meta-analysis evaluated RCTs of antenatal interventions for preventing excess GWG and found that diet, exercise or diet plus exercise interventions reduced the risk of excess GWG by an average of 20% (RR 0.80, 95% CI 0.73–0.87).⁴⁷ The results also suggested a lower risk of cesarean section, maternal hypertension, macrosomia, and newborn respiratory distress syndrome in mothers who received the interventions. Pregnant women with obesity should receive diet and exercise counseling to assist with managing GWG.²¹ After the treating clinician has ruled out any contraindications to exercise,⁴⁸ an eventual goal of moderate-intensity exercises for 20–30 minutes/day on most days of the week can be advised.⁴⁸ An RCT evaluating the use of metformin vs. placebo starting at 12–18 weeks gestation in pregnant women with obesity but without diabetes resulted in reduced median GWG in the metformin group (4.6 kg vs. 6.3 kg) but no difference in the primary outcome of neonatal birth-weight z score. However, there was no significant difference in neonatal or obstetrical outcomes, and thus, the use of metformin to reduce GWG in women with obesity cannot be routinely recommended.

Screen early for hyperglycemia

Women with obesity who are not known to have T2DM should be screened at the first antenatal visit for hyperglycemia. There are two strategies for testing glucose levels in early pregnancy – using the non-pregnancy recommended screening tests (fasting plasma glucose (FPG) or A1C) or using the typical 24–28 week GDM screening criteria.⁴⁹ There has been no rigorous validation that criteria accepted for the diagnosis of GDM in the second or third trimester are appropriate for use in the first trimester. A fasting glucose >7.0 mmol/l or A1c >=6.5% should be diagnosed as likely overt diabetes and treatment implemented. However, both FPG and A1C decrease early in pregnancy and may lead to under-diagnosis of pre-existing diabetes. One study screened 16,122 women at a median of 47 days gestation, and found higher rates of major congenital anomalies (RR 2.67, 1.28–5.53), preeclampsia (RR 2.42, 1.28–5.53), shoulder dystocia (RR 2.47, 1.05–5.85) and perinatal death (RR 3.96,1.54–10.16) with an A1C of 5.9–6.4% in the first trimester.⁵⁰ Although consideration can be given to treatment of women with HbA1c 5.9–6.4% in the first trimester, whether intervention earlier in pregnancy makes a difference remains unknown. Unfortunately the lack of rigourous data has resulted in different professional groups and organizations having different criteria for diagnosis of early dysglycemia.^51,52 All women with overt diabetes diagnosed during pregnancy, should be retested postpartum as up to 41% will return to normal postpartum.⁵³

Reduce Hypertensive Disorders of Pregnancy

Maternal obesity is associated with increased risk of preeclampsia and gestational hypertension, and the risk increases as BMI increases.^9,54,55 Observational studies demonstrate an inverse association between maternal exercise and preeclampsia risk,^56,57 and the risk of maternal hypertension, but not preeclampsia specifically, was reduced in RCTs of diet and/or exercise interventions during pregnancy.⁴⁷ However, the role of exercise in pregnancy for preeclampsia prevention is felt to be unclear.^58,59 Strategies for prevention of preeclampsia should be considered, including recommending both ASA 81mg daily (taken orally at bedtime from the time pregnancy is diagnosed until 37 weeks’ gestation) and adequate calcium intake.^59,60

Improve Fetal Surveillance

Aneuploidy detection is now performed using either traditional first-trimester screening (IPS or its variations) or noninvasive prenatal testing (NIPT). Interestingly, the risk of Trisomy 21 is increased among women with obesity.⁶¹ A higher BMI does not affect the rate of positive first-trimester screening,⁶¹ making such testing appropriate. Fetal cell-free DNA levels are inversely proportional to gestational weight and mothers with obesity should be advised that there is a higher rate of insufficient DNA levels, necessitating a second blood draw for NIPT testing.⁶²

The ability of screening ultrasound to detect genetics syndromes, fetal anomalies and non-reassuring fetal wellbeing status is substantially reduced in this population. In the FaSTER trial, maternal obesity was associated with a 10% higher false-negative rate for the detection of two more soft markers of aneuploidy, a lower rate of detection of congenital anomalies in general (aOR 0.7, 95% CI 0.6–0.9) and a lower detection rate of congenital heart anomalies (8.3% versus 21.6%).⁶³ There is often an inability to both image completely and detect anomalies of cardiac and craniospinal structures in this population.^64,65 The limitations of prenatal ultrasound screening should be recognized and the women counseled accordingly.

Fetal surveillance is often indicated in later gestation to ensure fetal wellbeing. Common indications include concurrent diabetes and hypertension, but consideration may also be given to performing biophysical profile or nonstress tests on women with obesity in general, given their increased risk of fetal distress and stillbirth. Although it may be more difficult to physically perform such testing on women with obesity, they are not more likely to have nonreactive non-stress tests or to require additional time to a normal non-stress test.

Minimize Risk of Preterm Birth

The risks of both overall preterm birth and extremely preterm births are increased among women with obesity. These preterm deliveries are often iatrogenic and related to need for delivery due to medical comorbidities like hypertension and diabetes. In general, obesity is associated with prolonged pregnancy, but there appears to be an interesting increase in spontaneous extremely preterm labour (<28 weeks’ gestation) as shown in a population-based cohort study of women from Sweden (see table 2).⁶⁶ This rise was attributed to increased inflammatory markers and increased risk of intrauterine bacterial infection/chorioamnionitis.

Table 2.

Extremely Preterm Birth Among Women with Obesity in Sweden from 1992–2010

BMI (kg/m2)	Rate (%)	Odds Ratio (95% CI)
18.5–<25	0.17
25–<30	0.21	1.26 (1.15–1.37)
30–<35	0.27	1.58 (1.39–1.79)
35–<40	0.35	2.01 (1.66–2.45)
40+	0.52	2.99 (2.28–3.92)

Adapted from Cnattingius S, Villamor E, Johansson S, et al. Maternal obesity and risk of preterm delivery. JAMA 2013;309(22):2364; with permission.

Evidence for prevention of preterm birth among women with obesity is limited. Optimizing underlying medical conditions like diabetes and hypertension and incorporating strategies for prevention of preeclampsia should be considered. In women who are symptomatic or who have had a prior preterm birth, confirmed bacterial vaginosis should be treated with oral Metronidazole or Clindamycin for seven days.

Labour and Delivery

Reduce still birth risk through timing of delivery

Determining the optimal timing of delivery of women with obesity is complex. Multiple studies have now shown a consistent increase in the risk of stillbirth among women with obesity, at all gestational ages. Overall, a 10-unit increase in pre-pregnancy BMI appears to be associated with a 1.5- to2-fold increase in stillbirth risk.⁶⁷ Rates increase proportionately to BMI from an odds ratio of 1.37 (95% CI 1.02–1.85) for overweight women to an odds ratio of 5.04 (1.79–14.07) for women with a BMI higher than 50.⁶⁸ The lowest rates of neonatal death and cerebral palsy are associated with delivery at 39 weeks’ gestation.⁶⁹ The lowest rates of intrauterine demise and brachial plexus injury can be obtained by delivering earlier. A recent decision analysis suggested that the optimal gestational age of delivery may be 38 weeks – in the theoretical population of 100,000 singleton pregnancies in women with obesity, elective delivery at 38 weeks would prevent 203 intrauterine demises compared with expectant management until 41 weeks.⁶⁹

When the decision to proceed with delivery, whether for medical indications or to reduce the risk of stillbirth, has been made, the mode of delivery must be considered. Among women who have obesity, term elective induction of labour appears to actually decrease the risk of Cesarean delivery, particularly in multiparous women, without increasing the risk of adverse outcomes, including operative vaginal delivery, lacerations or neonatal respiratory distress syndrome (Lee II).⁷⁰ Thus, induction of labour at 38–39 weeks is currently preferred to elective Cesarean section for appropriate candidates.

Reduce Surgical Complications

Cesarean delivery is intuitively more difficult and risk-prone in women with obesity. Preparation is crucial – in addition to the usual requirements for Cesarean delivery, the availability of specialized equipment (eg. Retractors) is beneficial to both surgical team and patient. Surgeons should be familiar with and respect the weight capacity of wheelchairs, operating tables and other equipment, such as commodes. The presence of a large pannus can alter the anatomy of the abdominal wall considerably and strategies are needed to reduce risk (Table 3). As the umbilicus is usually more caudad than normal, the ideal position of the incision should be determined from more stable landmarks, including the symphysis pubis, the iliac wings and the fundus. The ideal choice of skin incision is still debated and should be individualized. A transverse skin incision can be made above or below the pannus and offers increased wound strength, reduced postoperative pain and improved respiratory status postpartum.^71,72 However, a transverse incision makes retraction and delivery of the fetus more difficult because of the pannus. The climate underneath the pannus also results in frequent wound infection. A vertical skin incision allows for better visualization of the surgical field and easier wound care postpartum, but causes more pain, resulting in decreased respiratory effort.⁷³ Vertical incisions do not necessarily decrease the risk of wound infection.⁷³

Table 3.

Useful Strategies for Cesarean Section of Women with Obesity

Strategy	Result
Pre-treatment of the skin under the pannus with antibacterial/antifungal dressings for 1–2 weeks	Improved skin health and decreased bacterial load
Skin cleansing with iodine or chlorhexidine	Decreased bacterial load
Antibiotics within 60 minutes of incision	Lower wound infection rates
Closure of the subcutaneous tissue with sutures when the fat thickness exceeds 2cm	Decreased wound disruption by 34%151
Retraction of the pannus cephalad	Improved ease of transverse skin incision
Suturing of the skin incision	Decreased wound infection and wound separation rates152

Improve safety of Anaesthesia

Anesthetic risks are increased in women with obesity, for both regional techniques (epidural and spinal) and general anesthesia. Consultation with anesthesia during the third trimester is often very helpful to allow for risk assessment, additional testing (such as EKG or sleep studies) and patient counselling and expectation setting.

Placement of regional techniques is often challenging because the usual landmarks may be difficult to find due to adiposity. These challenges may lead to multiple attempts at needle insertion and, ultimately, a higher failure rate. Ultrasound-guided neuraxial analgesia is sometimes helpful.

General anesthesia is avoided whenever possible, but is more common with increasing obesity. Intubation is made more difficult by increased breast mass, increased chest diameter and exaggerated airway edema. These features result in a diagnosis of difficult intubation in up to 33% of women with obesity.⁷⁴

Postpartum

Reduce Postpartum hemorrhage

The risk of postpartum hemorrhage is approximately doubled in women who are overweight or have obesity, an effect that is seen after both vaginal delivery (OR 2.11, 95% CI 1.54–2.89) and Cesarean section (OR 1.73, 95% CI 1.32–2.28).⁷⁵ When the effects of perineal laceration and retained placenta are controlled for, the elevated risk can be attributed to uterine atony. The risk of postpartum hemorrhage is increased with increased infant birthweight, antepartum hemorrhage and Asian ethnicity.

Before delivery, iron stores should be optimized by providing oral or parenteral iron as needed. In addition to the usual practices of active management of the third stage, increased vigilance and preparation for postpartum hemorrhage are advised and additional uterotonics should be available, including Carbetocin, ergotamine, misoprostol and hemabate. Internal uterine compression is a third line treatment option.

Prevent Venous Thromboembolism

Women with a prepregnancy BMI > 30 kg/m² who have undergone an emergency cesarean section are considered to be at high risk for postpartum venous thromboembolism (VTE).^76,77 Guidelines recommend that either prophylactic low-molecular-weight-heparin (LMWH) or mechanical prophylaxis, such as elastic stockings or intermittent pneumatic compression, be used in this population while in hospital following delivery.^76,77 In women with obesity who undergo a non-emergent cesarean section, VTE prophylaxis is recommended only in the presence of at least one additional risk factor for VTE, such as preeclampsia or fetal intrauterine growth restriction.^76,77 LMWH is considered to be safe in women who are breastfeeding.⁷⁶

Improve Breastfeeding rates

Guidelines recommend that babies be breastfed exclusively for the first 6 months of life, followed by ongoing breastfeeding up to at least 1–2 years of age.^78,79 Breastfeeding is particularly beneficial for mothers with obesity, as it is associated with improved future cardiovascular risk in mothers,⁸⁰ reduced risk of future T2DM,^81,82 and decreased visceral adiposity in later life.^83,84 Some,^83,85 but not all^86,87studies have reported less postpartum weight retention and future risk of obesity with breastfeeding.

Women with obesity are less likely than normal weight women to both initiate and maintain breastfeeding.^88,89 This has been attributed to delayed onset of milk production, higher prevalence of insufficient breast glandular tissue, and psychosocial factors such as reduced confidence to breastfeed.⁹⁰ There is some evidence that increased postpartum breastfeeding support can increase breastfeeding exclusivity and duration.⁹⁰ The potential for breastfeeding challenges should be discussed with women prior to delivery, and resources such as lactation consultant services made available to assist with breastfeeding difficulties.

Reduce Postpartum Weight Retention

Postpartum weight retention is of particular concern in women with obesity who are planning future pregnancies.²¹ In a Swedish population-based cohort study that evaluated BMI changes between first and second pregnancies, the risk of stillbirth in the second pregnancy was found to increase linearly with interpregnancy increase in BMI.⁹¹ Similarly, interpregnancy weight gain is associated with increased risk of gestational hypertension and preeclampsia.⁹² Weight gain between pregnancies is associated with an increased risk of GDM in a subsequent pregnancy, while a weight loss of just 10 pounds is associated with reduced GDM risk.⁹³ Weight loss between pregnancies in women with obesity decreases the risk of having a large-for-gestational age offspring in next pregnancy,⁹⁴ and improves chances of a vaginal delivery after a previous cesarean section.⁹⁵

A recent systematic review found that dietary interventions and diet with exercise interventions improved postpartum weight loss, as opposed to exercise only interventions.⁹⁶ There was no evidence that these interventions had any adverse effect on maternal breastfeeding success. It is recommended that postpartum contraception and planning for future pregnancies be encouraged in women with obesity so that weight can be optimized between pregnancies.²¹

NEW EVIDENCE LINKING MATERNAL OBESITY AND LONG-TERM IMPLICATIONS TO OFFSPRING

The number of infants and young children with overweight or obesity has tripled between 1990 to 2012⁹⁷ and is rising in parallel with rates of maternal obesity. Given that half of childhood obesity occurs by age 5, early life events may be contributing to pediatric obesity development.⁹⁸ Many studies have reported strong associations between intrauterine exposure to maternal obesity and excess GWG with adiposity at birth^99,100 and offspring development of obesity in childhood^101,102 and adulthood¹⁰³ (Figure 1). For example, increased adiposity at birth (but not birth weight) was correlated to adiposity at 6–11 years of age by DXA in offspring from a cohort of 89 mothers with either normal glucose tolerance or GDM.¹⁰² Childhood adiposity did not correlate with maternal GDM exposure but instead was strongly related to maternal obesity with an OR ~5.5.

Figure 1.

Maternal obesity is associated with adverse metabolic effects in offspring, promoting an intergenerational cycle of obesity.

In utero exposure to maternal obesity also increases obesity co-morbidities in offspring such as insulin resistance and changes in mitochondrial function,^104–106 cardiovascular disease,^107,108 and nonalcoholic fatty liver disease (NAFLD).^109–111 NAFLD affects ~34% of children with obesity ages 3–18 and half have already progressed to the more severe NASH at time of diagnosis.^112,113 Newborns at ~2 weeks of age who were born to mothers with obesity and GDM mothers demonstrated 68% more intrahepatic fat compared to the newborns from normal weight mothers and was correlated with maternal BMI (r = 0.05, p = 0.02).¹¹⁰ Whether early deposition of lipid in the fetal liver could prime it to be more susceptible to the postnatal influences of an unhealthy lifestyle resulting in NAFLD is unknown. The powerful influence of an intrauterine environment characterized by nutrient excess and obesity is also underscored by the marked decrease in the risk of obesity in children born to women with obesity who underwent bariatric surgery before their pregnancy as compared to their siblings who were born prior to their mother receiving bariatric surgery.^114,115

An intrauterine environment characterized by nutrient excess or obesity imparts long-term programming of offspring obesity risk,¹¹⁶ especially in babies born large for gestational age (LGA). Umbilical cord derived mesenchymal stem cells from infants born to mothers with obesity demonstrated greater capacity to develop into adipocytes. These findings suggest that progenitor cells that differentiate into various tissue types such as adipose tissue, skeletal muscle, or chondrocytes may already be detrimentally programmed in utero.¹¹⁷

Epigenetics as a Mechanism and Indicator of Fetal Programming

Metabolic programming can occur via gene-environment interactions that may produce epigenetic events. These intrauterine exposures may silence or augment gene expression to impact fetal brain function and organ development which impart risk for developing chronic disease(s).^118–121 Maternal nutrition can alter DNA methylation in infant tissues such as buccal cells,¹²² umbilical cord blood,^123,124 and umbilical cord.¹²⁵ Preconception maternal diet and nutritional status may be key determinants of the fetal epigenome [30, 31].^126,127 Studies on mother-infant dyads in the Gambia found that seasonal variation (rainy versus dry) in maternal diet at the time of conception altered DNA methylation at metastable epialleles (MEs) in infants at 2–8 months of age.^126,127 These changes correlated with maternal plasma levels of key methyl-donor pathways (e.g. methionine, choline, folate, homocysteine, B vitamins). DNA methylation at MEs is stochastically established during very early embryogenesis and are particularly sensitive to early maternal exposures, like nutrition and obesity. This early establishment of methyl groups at specific MEs allows methylation to be stably maintained systemically across cell lineages during differentiation. However, it still remains unclear whether maternal obesity, GWG, and maternal nutrition can permanently modify methylation patterns resulting in lasting changes in gene expression.

Potential Role of the Gut Microbiome in Maternal and Infant Obesity

Recently the gut microbiome has garnered significant attention as another mode of transmitting obesity risk from mothers to offspring. A seminal study described the effect on a germ free mouse when a first trimester (insulin sensitive) versus third trimester (insulin resistant) human microbiome was transplanted into a germ free mouse.¹²⁸ The mouse receiving the 3^rd trimester microbiome became fatter and demonstrated insulin resistance and gut dysbiosis compared to the mouse who received the first trimester microbiome. The exposure of the fetal intestine to maternal microbes at childbirth and possibly through amniotic fluid is an important contributor to gut maturation and, by extension, to infant health. Animal and human data strongly suggest that the composition of the neonatal gut microbiota is dependent both on maternal obesity and maternal diet during pregnancy and lactation¹²⁹ as well as mode of delivery.¹³⁰

The microbiome plays a major role in nutrition, extraction of energy, metabolism, protection against pathogens, resistance to infections, and immune system development. Studies in non-human primates have shown distinct effects of maternal high fat diet on offspring microbiota, as well as a decrease in overall bacterial diversity when compared to primates fed a control diet.^129,131,132 While the exact implications of these changes in microbiota are not fully known, decreased bacterial diversity is associated with adiposity, insulin resistance, dyslipidemia, and low grade inflammation in humans.^133,134 Another provocative study in primates has shown that after weaning, dysbiosis is only partially corrected by a controlled low fat diet,^131,135 demonstrating the lasting effects of a high fat maternal diet on the microbiome of the offspring. Human studies showed that the microbiome from newborns at 2 weeks of age born to mothers with obesity exhibited less gammaproteobacteria, an early colonizing bacteria essential for the development of immune tolerance and a higher trend in bacilli class in the firmacutes phylum, a high consumer of choline, which may be highly relevant since low choline is associated with the development of NAFLD.¹³⁶ The breast milk of women with obesity contains higher levels of insulin and leptin which may be able to pass through more permeable intestinal gap junctions in the newborn, potentially affecting appetite regulation, microbiome development, immune tolerance, and infant body composition and growth.¹³⁶

Early microbes from infants born to women with obesity or GDM may contribute to long-term health risks by triggering pro-inflammatory remodeling of the innate and adaptive immune system as well as other organs and tissues in the neonate.¹³⁷ Dysbiosis of the gut microbiome has been correlated with NAFLD in children and adults. However, if and how the early life microbial composition influences hepatic fat accumulation and inflammation before the disease occurs is unclear. Attempts to alter the infant microbiome by modifying the maternal microbiome by diet changes or pre- or probiotics in pregnancy have shown mixed results in prevention of GDM and GWG.^138,139 A large Australian RCT enrolling more than 500 women (SPRING) was recently completed using the same probiotic and the results should be available soon.¹⁴⁰

It is clear the –omics such as epigenetics, microbiome, and transcriptomics can advance our understanding of how obesity risk is transmitted to offspring. Metabolomics is another rising –omics platform that can provide information on macro- and micro-nutrient fluxes through metabolic pathways that can be altered by maternal diet or obesity, which could affect the offspring.^141,142 There is also emerging evidence driven by animal studies for paternal obesity influencing offspring risk.^143,144 Clinical studies suggest that sperm are altered by obesity¹⁴⁵ such that fathers may no longer be out of the loop in being metabolically accountable to their offspring!

CONCLUSION

It is extremely important for clinicians to discuss pregnancy plans with women with obesity well in advance of conception in order to ensure that medical comorbidities and medications can be optimized before pregnancy. Weight management prior to pregnancy should be promoted with the aim of improving both maternal and fetal health. During pregnancy, careful screening for maternal and fetal complications should take place, with consideration given to preventative strategies where appropriate. Recognition of the increased risk of stillbirth in this population should lead to careful consideration of the risks and benefits of induction of labour around 38–39 weeks of gestation. In the postpartum period, promotion of breastfeeding and reducing postpartum weight retention should be recommended to women with obesity to improve future health and reduce adverse events in future pregnancies.

There is increasing recognition of the adverse metabolic effects on the offspring of women with obesity, which has large implications for future generations. Further research is needed to determine how best to attenuate these negative effects in order to halt and hopefully reverse the increasing prevalence of obesity and metabolic disease.

Key points.

• Weight and obesity-related comorbidities should be optimized in women with obesity prior to conception.

• Special considerations in pregnant women with obesity include optimization of gestational weight gain, prevention and management of gestational diabetes and hypertensive disorders of pregnancy, and being aware of risks to fetal health.

• Labour and delivery in women with obesity carries increased risk of surgical and anesthetic complications.

• Postpartum considerations in women with obesity include prevention of complications, reduction of postpartum weight retention, and breastfeeding promotion.

• There is emerging evidence of adverse metabolic effects on the offspring of women with obesity.