Recent years have witnessed a rise in maternal obesity, which is independently associated with an increased risk of stillbirth. The pathophysiology is unclear, but it is likely related to abnormal placental function, and inflammatory, metabolic and hormonal imbalances in the mother. Obesity is associated with conditions such as diabetes, which can also cause stillbirth. In order to reduce the risk of obesity-associated stillbirth, women of reproductive age should be actively encouraged to optimise their pre-pregnancy weight as the safety of weight loss interventions during pregnancy is unproven. Obese and extremely obese women should be treated as high-risk obstetric patients, with increased antenatal surveillance and specialist input. The postnatal period may be a useful time to provide weight management advice to women to prevent interpregnancy weight gain and reduce the risk of stillbirth in subsequent pregnancies.
Highlights
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The risk of stillbirth increases with body mass index (BMI), especially at or after term gestation.
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The mechanism of the association between stillbirth and obesity remains unclear.
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Obesity is associated with other risk factors for stillbirth such as diabetes.
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Weight reduction should be considered before and between pregnancies.
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The safety of weight loss interventions during pregnancy is unclear.
Introduction
Stillbirth or delivery of an infant after 22–24 weeks of gestation with no signs of life is unexpected and devastating. In 2009, 2.6 million stillbirths were reported worldwide . Even in high-income countries where pregnancy outcomes have improved substantially, stillbirth continues to be common with a rate of one per 200 births . Along with a number of other adverse foetal outcomes, in utero foetal death is more common in overweight (body mass index (BMI) >25 kg/m 2 ) and obese mothers (BMI > 30 kg/m 2 ) . Obesity continues to be a global health epidemic affecting nearly 300 million women worldwide . With >30% of women of reproductive age (aged 20–39 years) obese, and >55% overweight , this is a very real problem in contemporary obstetrics.
Epidemiology
Obesity in pregnancy is rising. Between 1990 and 2002/2004, obesity (BMI > 30 kg/m 2 ) in Scottish pregnant women doubled from 9.4% to 18.9% and women were 60% more likely to be overweight or obese at antenatal booking (adjusted odds ratio (aOR) 1.62 (95% confidence interval (CI) 1.04–2.53)) . Data from the United States show a similar trend with maternal weight at booking increasing by 20% between 1980 and 1999 . With increasing levels of maternal obesity, it is likely that adverse obstetric and perinatal outcomes associated with obesity will also escalate. A study published in 2014 suggests that 20% of stillbirths and, in particular, one in four term stillbirths are associated with maternal obesity .
Epidemiology
Obesity in pregnancy is rising. Between 1990 and 2002/2004, obesity (BMI > 30 kg/m 2 ) in Scottish pregnant women doubled from 9.4% to 18.9% and women were 60% more likely to be overweight or obese at antenatal booking (adjusted odds ratio (aOR) 1.62 (95% confidence interval (CI) 1.04–2.53)) . Data from the United States show a similar trend with maternal weight at booking increasing by 20% between 1980 and 1999 . With increasing levels of maternal obesity, it is likely that adverse obstetric and perinatal outcomes associated with obesity will also escalate. A study published in 2014 suggests that 20% of stillbirths and, in particular, one in four term stillbirths are associated with maternal obesity .
Obesity as an independent risk factor for stillbirth
Obesity is a significant yet modifiable risk factor for stillbirth. A systematic review of observational studies found that mothers who were overweight (aOR 1.2 (95% CI 1.09–1.38) for BMI 25–30 kg/m 2 ) or obese (aOR 1.6 (95% CI 1.35–1.95) for BMI > 30 kg/m 2 ) were at a greater risk of stillbirth than those with a normal BMI . A systematic review published in 2014 revealed that women with a BMI of 40 were at twice the risk of stillbirth compared to women with a BMI of 20 (relative risk of 2.19 (2.03–2.36)) . Large observational studies agree that overweight and obese mothers are 40% more at a risk of stillbirth . A study in Aberdeen found that stillbirth was more common in obese women , while a large cohort study in England reported foetal death to be two to three times more common in obese, but not overweight women . There is a considerable body of evidence from large observational studies reporting a positive association between obesity and stillbirth . It is unclear if the potential insult of obesity is greater at different reproductive time points.
Pre-pregnancy weight
Pre-pregnancy weight appears to affect the risk of stillbirth. A meta-analysis of nine observational studies revealed women who were overweight (OR 1.47 (95% CI 1.08–1.94)) or obese (OR 2.07 (95% CI 1.59–2.74)) before pregnancy were at a greater risk of stillbirth than normal-weight women . In a large Danish cohort study, Kristensen et al. found that women who were obese (BMI > 30) pre-pregnancy were at a significantly increased risk of stillbirth (stillborn at ≥28 weeks of gestation) compared to normal-weight women (aOR 3.1 (95% CI 1.6–5.9)). Another large cohort study found that the risk of stillbirth was significantly higher for women with a pre-pregnancy BMI ≥30 kg/m 2 (aOR 2.7 (95% CI 1.8–4.1)) . Nohr et al. found that obese (BMI ≥ 30 kg/m 2 ) women were at a greater risk of intrauterine foetal death from 14 to >40 weeks of gestation (adjusted hazard ratio (aHR) 1.7 (95% CI 1.1–2.1)) but most marked after 28 weeks. A Swedish observational study suggests that if women with a BMI >25 kg/m 2 optimised their BMI prior to pregnancy it would lead to a 13% reduction in stillbirths . Overall, being overweight or obese at the time of conception may increase the risk of stillbirth. However, as these women are likely to remain overweight during pregnancy, it is unclear whether being overweight at conception or whether continuing to be overweight during pregnancy or both are associated with stillbirth.
Weight gain during pregnancy
The American College of Obstetricians and Gynecologists recommendations indicate that weight gain in pregnancy should be approximately 1 lb. per gestational week for normal-weight women (total weight gain of 25–35 lb.), and approximately 0.5–0.6 lb. per week for overweight and obese women (total weight gain of 10–25 lb.) . There is no similar guidance in the UK . A Canadian study found that most women (52.3%) gained more than the recommended weight during pregnancy . However, they did not find an association between excessive gestational weight gain and stillbirth . A large Danish study revealed that obese women were at a greater risk of stillbirth, but the study found that weight gain (100 g per week) during pregnancy did not increase their risk any further (aOR 0.94 (95% CI 0.87–1.03)) . Similarly, Getahun et al. and Stephansson et al. did not find an association between gestational weight gain and stillbirth. Women with elevated BMI were found to gain less weight overall during pregnancy . Excessive weight gain during pregnancy may not be associated with stillbirth. Instead, it could be that pre-pregnancy weight at conception along with continuing obesity during pregnancy may increase the risk of stillbirth.
Interpregnancy weight gain
A weight gain of ≥3 kg/m 2 between pregnancies was found to significantly and independently increase the risk of stillbirth in a large Swedish cohort study of 151,025 women (OR 1.63 (95% CI 1.20–2.21)) . Further subgroup analysis showed that interpregnancy weight gain increased the risk of stillbirth for term but not preterm deliveries . This could be explained by the presence of other causative factors associated with preterm stillbirths. The effect of interpregnancy weight gain on the risk of stillbirth was not influenced by BMI in a first pregnancy . Overweight and obese women are more likely to gain excessive interpregnancy weight (≥3 BMI units) according to a retrospective cohort study, although they failed to find an association between interpregnancy weight gain and stillbirth, which could be due to small sample size . The interpregnancy interval may be an important opportunity to motivate women to reduce their weight and their future risk of stillbirth.
Super-obesity
Super-obesity, representing persons with BMI ≥50 kg/m 2 , is increasing in the pregnant population and is associated with adverse maternal and perinatal outcomes . Almost 1 per 1000 pregnant women in the UK are super-obese . A large cohort study revealed that the risk of stillbirth was significantly higher in women with BMI ≥50 and that the risk increased with gestational age . Women classified as super-obese had a 5.7 times greater risk of stillbirth at 39 weeks of gestation and 13.6 times higher risk than normal-weight pregnant women at 41 weeks . Overall, there does appear to be a dose-dependent relationship with increasing BMI directly escalating the risk of stillbirth. Prevention and engagement strategies should specifically target extremely obese women.
Causality
The evidence for the association between stillbirth and obesity appears to satisfy some of Hill’s criteria for causality . Although observational studies have known constraints – including missing data, inability to adjust for some confounders and changes in clinical practice when using historical data – large observational studies and high-quality cohort studies, as well as systematic reviews of observational studies, have demonstrated a consistent association between BMI and stillbirth . However, a minority of studies have failed to demonstrate such a link, although some of them may have been underpowered or have missing BMI data . The major limitation with observational studies is the risk of confounding, and it is possible that there may be unmeasured confounding factors that lead to the higher risk of stillbirth in these women such as genetic influences, specific dietary factors or foetal risk factors. Several studies have adjusted for relevant confounding factors such as diabetes, hypertension, ethnicity, maternal age, parity, smoking and socio-economic status, and continue to show an association between raised BMI and stillbirth suggesting that obesity is an independent risk factor for stillbirth. A dose-dependent relationship has been widely demonstrated with increasing BMI leading to an elevated risk of stillbirth . A systematic review and meta-analysis found that even small increments of 5 kg/m 2 increased the risk of stillbirth . Having a BMI of >40 kg/m 2 doubles the risk of stillbirth (aOR 2.08 (95% CI 1.58–2.73)) . Obesity was 37% higher in women with recurrent stillbirth in a cohort study conducted in the USA of 261,384 women . Given the risk of other adverse pregnancy and perinatal outcomes associated with obesity , it is entirely plausible that obesity causes the observed increased risk identified of stillbirth. However, the pathophysiology of a causal relationship is not yet clear.
Pathophysiology
Most stillbirths in overweight and obese women are classified as unexplained or secondary to utero-placental insufficiency . Several hypotheses exist for the observed association of stillbirth with maternal obesity, and it is likely to be multifactorial. While there is a paucity of robust evidence to explain the exact mechanism behind the association of stillbirth in overweight and obese women , the suggested pathophysiological mechanisms include:
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Placental dysfunction
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Placental inflammation
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Impaired glucose tolerance and insulin resistance
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Excessive hyperlipidaemia
Changes to placental structure, nutrient exchange and utero-placental blood flow may contribute to the detrimental effects of maternal obesity on the developing foetus, but evidence is limited . Frias et al. demonstrated evidence of placental dysfunction in primates fed a high-fat diet, whereby maternal obesity appeared to lead to pronounced utero-placental insufficiency and increased risk of stillbirth. Another animal study found that overfed adolescent sheep had reduced placental growth and lower-birthweight lambs compared to moderately fed counterparts . Pregnancy induces a pro-inflammatory, hyperlipidaemic state with substantial changes to a woman’s metabolism including glucose and insulin responses. This becomes exaggerated in overweight and obese women. Obese women appear to have abnormal vascular function and changes to inflammatory mediators, which contribute to placental inflammation . This hyper-inflammatory state may contribute to adverse foetal outcome . It is suggested that this inflammation could instigate insulin resistance and hyperinsulinaemia . Insulin resistance is higher in the obese pregnant population and it is likely that the resultant excessive circulating insulin could have foetal growth implications . Obese women tend to have higher circulating levels of leptin and insulin growth-factor-1, which may also lead to aberrant foetal growth . This abnormal or excessive growth could lead to stillbirth. Pregnancy leads to hyperlipidaemia, which is exaggerated in obese women . Hyperlipidaemia may contribute to adverse foetal outcomes by contributing to endothelial dysfunction, placental dysfunction and platelet aggregation , but evidence is sparse. Although there are hypotheses that placental dysfunction and inflammation as well as metabolic or hormonal derangement are to blame for the association between obesity and stillbirth, we still know very little about the exact causal pathway behind this association . There are other risk factors for stillbirth that are related to obesity and may provide further clues to the relationship between obesity and stillbirth.
Diabetes and hypertension
Chronic hypertension and diabetes are considered major risk factors for stillbirth with 8.0% and 3.9% attributable to each, respectively (when measured as population-attributable risk (PAR)) . Pre-eclampsia and gestational hypertension are widely accepted as risk factors for stillbirth and increase the risk of adverse outcomes such as foetal growth restriction and placental abruption. Obese pregnant women are susceptible to impaired endothelial function and elevated blood pressure . Diabetes and gestational hypertensive disorders including pre-eclampsia and chronic hypertension are all reportedly higher in the overweight and obese pregnant populations . The risk of developing gestational diabetes appears to increase with increasing BMI . The association of obesity with stillbirth may be secondary to the higher incidence of diabetic and hypertensive complications in these women. However, several studies have adjusted for diabetes and hypertension and reported that the risk of stillbirth remains . Nohr et al. excluded women with diabetes, pre-eclampsia and any hypertensive disorders and found that obese women were still three times more likely to suffer stillbirth (aOR 3.4 (95% CI 2.1–5.5)) compared to normal-weight women . Gestational diabetes did not appear to increase the risk of stillbirth in a systematic review of observational studies, although only two studies were assessed . The evidence suggests that diabetes and hypertensive disorders are associated with both obesity and stillbirth, but that obesity poses an independent risk factor for stillbirth. Overweight and obese women may have more than one risk factor for stillbirth.
Obstructive sleep disorders
Obese women are at a higher risk of sleep disorders, which can cause sleep apnoea and oxygen desaturation . Reduced oxygenation could theoretically lead to foetal deoxygenation and increase the risk of stillbirth. Assessment of sleep disorders needs to feature in the antenatal assessment of overweight and obese pregnant women to identify those at risk.
Maternal age
Advanced maternal age is associated with an increased risk of stillbirth as well as an association with raised BMI . Increasing maternal age was associated with obesity in an English pregnant population . Advancing maternal age and being overweight or obese appeared to increase the risk of stillbirth in a Swedish population, and risk was most significant at term . Given the growing trend for delaying childbearing, this is an important association that women need to be aware of when making reproductive choices. A cohort study of 529,445 births in the USA also identified obese adolescents (aged <18 years with BMI ≥30 kg/m 2 ) were at an increased risk of stillbirth compared to normal-weight women aged 18–35 years (relative risk (RR) 1.8 (95% CI 1.1–2.9)) . The risk was greater for obese adolescents at term . Strategies to reduce obesity should specifically target women at extremes of reproductive age.
Ethnicity
African American women appear more susceptible to stillbirth associated with obesity compared to Caucasian American women (adjusted HR 1.9 (95% CI 1.7–2.1)) . However, a study in 2007 found no statistically significant difference between antepartum and intrapartum stillbirth between obese Caucasian American and African American women (HR 1.2 (95% CI 0.9–1.7) and HR 1.4 (95% CI 1.4 (0.6–3.6), respectively) . Ethnicity may play a role in the association between obesity and stillbirth, but the evidence is limited.
Congenital abnormalities
A systematic review and meta-analysis of observational studies found that maternal obesity is associated with an increased risk of congenital anomalies . Overweight and obese mothers have an increased risk of neural tube defects (obese women, OR 1.87 (95% CI 1.62–2.15)) and cardiovascular defects (obese women, OR 1.30 (95% CI 1.12–1.51)) compared to normal-weight women . Diabetes is widely recognised as a risk factor for congenital anomalies. Obese women may have multiple risk factors for congenital anomalies and potentially stillbirth depending on the severity of anomalies. However, a study that excluded women with foetal anomalies and diabetes found that the risk of stillbirth remained in obese women, again suggesting that these risk factors are independent . Overweight and obese women should be advised to take a higher prenatal and antenatal folic acid dose and a raised level of suspicion is needed for obese women during foetal anomaly screening.
Gestational age
Morbidly obese women are twice as likely to suffer antepartum stillbirth (aOR 2.79 (95% CI 1.94–4.02)), and similarly for obese women (aOR 1.99 (95% CI 1.57–2.51) than normal-weight women . Most striking is the brisk rise in the risk of stillbirth for women with elevated BMI nearer term ( Fig. 1 ) . Overweight and obese women were more at a risk of stillbirth from 37 weeks of gestation compared to normal-weight women in a sample of over two million singleton pregnancies ( Fig. 1 ) . The risk of stillbirth was greatest at 40–42 weeks of gestation and a dose-dependent relationship is demonstrated (HR 8.91 (95% CI 4.08–19.47) for BMI ≥50, see Fig. 1 ) . The risk remains high from 30 weeks of gestation for women with BMI >25–49 kg/m 2 compared to normal-weight women . Similar findings were shown in a large Danish study whereby, particularly from 37 weeks onwards, obese women were at a significantly higher risk of stillbirth than their normal-weight counterparts (for gestation >40 weeks, adjusted HR 4.6 (95% CI 1.6–13.4)) . Evaluation of increased third-trimester surveillance and induction at term is needed for the obese pregnant population.
Notably, post-dates pregnancies, those which continue over 40 weeks, are at a greater risk of stillbirth and post-maturity is associated with maternal obesity and particularly morbid obesity (aOR 2.32 (95% CI 1.73–3.12)) . A randomised controlled trial could evaluate the option of induction of labour near or at term and for post-maturity in the obese maternal population; however, this may not be feasible ethically, nor will it be appropriate to assess a less common outcome such as stillbirth. A prospective cohort study could evaluate outcomes of obese women who are induced at term to determine the effect on adverse pregnancy outcomes such as stillbirth. The mechanism for the sharp increase in the risk of stillbirth associated with post-maturity in obese mothers is uncertain.
There is conflicting evidence surrounding the association of obesity with preterm delivery. Some suggest that overweight or obese women are at a greater risk of preterm delivery, whilst others refute an association . The potential causal pathway is not clear, although prematurity may be secondary to interventions for maternal conditions such as pre-eclampsia.
Abnormal foetal growth
Obese women are more likely to deliver macrosomic infants even without maternal diabetes. Super-obesity is associated with a 44% lower risk of delivering a small-for-gestational-age infant (aOR 0.55 (95% CI 0.40–0.76)) but a substantially greater risk of delivering a large-for-gestational-age infant (aOR 3.49 (95% CI 9.1–22.0)) . Increasing BMI has been found to exacerbate the risk of macrosomia in a dose-dependent manner . Large-for-gestational-age infants or macrosomic infants are at a greater risk of stillbirth . Some studies suggest that overweight or obese women are less likely to deliver small-for-gestational-age babies . Another suggests that growth restriction is associated with maternal obesity ; however, this difference was lost after adjusting for pre-eclampsia. Antenatal ultrasound surveillance should aim to target overweight and obese women to identify foetal growth abnormalities – either small or large for gestational age. However, given the potential of placental dysfunction as well as abnormal glucose metabolism in overweight and obese women, there is a very real risk that both growth restrictions due to placental dysfunction may coexist with macrosomia. This could result in a potentially ‘normal’-sized baby using standardised ultrasound growth charts, but one whose growth is actually restricted with superimposed macrosomia. There is evidence that placental dysfunction is implicated in many unexplained stillbirths without accompanying growth restriction , which may be due to this ‘masked’ growth restriction. Customised foetal growth charts may be needed to adequately assess overweight or obese women.
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