macrosmia and DM

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MaternalFoetal Medicine

50 T O U C H B R I E F I N G S 2 0 0 9

Obesity, Diabetes and the Risk of Macrosomia

Nir Melamed 1 and Moshe Hod 2

1. Physician; 2. Professor and Director, Division of MaternalFoetal Medicine, Helen Schneider Hospital for Women, Rabin Medical Centre, Tel Aviv University

AbstractMaternal obesity, diabetes and pregnancy weight gain are independent risk factors for foetal overgrowth. Data regarding the relative

contribution of each of these factors are controversial. Nevertheless, owing to its increasing prevalence, maternal obesity probably exerts

a greater impact on the prevalence of macrosomia, especially when diabetes is well controlled. Reducing the rate of macrosomia may be

an ideal form of primary prevention of the development of obesity and diabetes later in adult life. Weight reduction prior to pregnancy and

strict glycaemic control may reduce the risk of macrosomia and interrupt this vicious cycle. Further studies are needed to determine the

optimal weight gain during pregnancy for obese women, as current recommendations may contribute not only to the development ofmacrosomia, but also to the global epidemic of obesity.

Keywords

Obesity, weight gain, diabetes, macrosomia, large for gestational age (LGA)

Disclosure: The authors have no conflicts of interest to declare.

Received: 15 December 2008 Accepted: 9 February 2009

Correspondence: Moshe Hod, Director, Division of MaternalFoetal Medicine, Helen Schneider Hospital for Women, Rabin Medical Center, Sackler Faculty of Medicine,

Tel Aviv University, Petah-Tiqva, 49100, Israel. E: [email protected]

Foetal macrosomia has long been associated with an increased risk ofCaesarean section, shoulder dystocia and birth trauma.1,2 More recently,

evidence has accumulated linking foetal macrosomia to an increased

risk of obesity and diabetes in early adult life. 39 This finding is similar to

the observations of Barker in growth-restricted foetuses,10 and thus

implies a U-shaped curve relationship between birthweight and the risk

of adult disease.6 Among the many factors that have been associated

with exaggerated foetal growth,1113 maternal obesity, excessive maternal

weight gain during pregnancy and diabetes have been shown to play

important roles.1416 However, the effect of each of these factors, as well

as their relative contribution to the risk of foetal overgrowth and

macrosomia, remains controversial. The purpose of this article is to

review current information regarding the relative contribution of

maternal obesity and diabetes to the risk of foetal macrosomia.

Maternal ObesityEpidemiology

Obesity has become a worldwide epidemic.17 The World Health

Organizations (WHOs) latest reports indicate that in 2005 approximately

1.6 billion adults were overweight and at least 400 million adults were

obese. As the prevalence of obesity is increasing, so is the number of

women of reproductive age who are overweight and obese. In the US,

the incidence of obesity among pregnant women ranges from 18.5 to

38.3%, according to different reports.1822

DefinitionsThe WHO defines being underweight as having a body mass index (BMI)

18.5, being of a normal weight as having a BMI of 18.524.9, being

overweight as having a BMI of 2529.9 and being obese as having a BMI

of 30 or greater. Obesity is further classified by BMI into class I (3034.9),class II (3539.9) and class III (greater than 40). 17,23 Some studies use

other measures to define obesity, including pre-pregnancy weight,24

weight at delivery16,25,26 and waist-to-hip ratio (WHR).27

Obesity and the Risk of Macrosomia

Maternal obesity has been shown to be associated with an increased

risk of macrosomia and large-for-gestational-age (LGA) infants24,2835

independent of other factors that affect foetal growth, including pre-

gestational14,15,36 and gestational12,14,29,34,37 diabetes (PGDM and GDM,

respectively). The magnitude of effect of obesity on the risk of

macrosomia in normal (non-diabetic) pregnancies varies considerably

between different studies and has been reported to range from 1.4- to

18-fold.14,22,30,3841 Several studies have shown a continuous relationship

between maternal obesity and the risk of foetal macrosomia/LGA

infants, so the higher the BMI, the higher the risk.14,15,35,4244 In a large

multicentre study of more than 16,000 patients, class I and class II

obesity patients were at increased risk of foetal macrosomia (odds ratio

[OR] 1.7 and 1.9, respectively).35 In another population-based study, the

risk of delivering a macrosomic infant increased with each level of

increasing BMI, using BMI


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E U R O P E A N O B S T E T R I C S & G Y N A E C O L O G Y 51

LGA infants, although this may be attributed to the relatively small

sample size in this study.14 Several studies found that other measures of

obesity (rather than pre-pregnancy BMI) were associated with

exaggerated foetal growth. In a recent retrospective study of 233

women with gestational diabtes, maternal weight at delivery was the

only factor that was significantly associated with LGA infants.16 Similarly,

in a case-control study of women without diabetes, birthweight prior to

delivery was the strongest predictor of macrosomia.25 Pre-pregnancy

weight was also found to be correlated with neonatal weight.45

Foetal growth is also influenced by the location of body fat stores in

the mother.41 Brown et al. investigated the influence of regional

distribution of fat on newborn size. WHR ratio was found to be an

independent predictor of neonatal weight; each 0.1-unit increase in

pre-gravid WHR ratio predicted a 120g greater birthweight. 27 Thus, it

appears that being obese or overweight is an independent risk factor

for macrosomia, and the risk is proportional to the level of obesity. The

mechanism by which obesity affects neonatal birthweight is unclear.

Possible explanations include obesity-related insulin resistance46 and

genetic factors.41,47 The co-presence of undetected type 2 diabetes orGDM, both of which have been shown to be associated with

obesity,35,48,49 is another possible explanation.

Weight Gain During Pregnancyand BirthweightApart from pre-gravid maternal obesity, weight gain during pregnancy

has also been reported to be an independent risk factor for

macrosomia.14,29,47,50,51 In a recent prospective study of 631 pregnancies,

pregnancy weight gain was the most important correlate with

birthweight.52 In another study of women with varying levels of glucose

intolerance, pregnancy weight gain was found to be at least as

important as glycaemic control in affecting birthweight.

50

Furthermore,Ray et al. calculated that for each 5kg increase in weight during

pregnancy, the risk of a LGA infant increased by 30%.14

Hutcheon et al. retrospectively studied 90 women who had at least two

pregnancies complicated by GDM in order to assess the effect of obesity

and diabetes on foetal growth within the same subject. They found that

weight gain during pregnancy was the only factor that affected neonatal

birthweight within the same woman.47

The timing of weight gain during pregnancy is also of importance. In a

prospective study of 389 uncomplicated pregnancies, weight gain

during the first trimester was the best predictor of neonatal weight

(31g for each 1kg maternal weight gain), followed by weight during the

second trimester (26g per 1kg). Weight gain during the third trimester

was not associated with newborn weight. However, several studies

found weight gain to have little (OR 1.08)29,45 or no effect16,34,53 on the risk

of macrosomia. Thus, the effect of weight gain during pregnancy on

neonatal birthweight remains controversial, and its contribution to

foetal overgrowth is probably less important than that of maternal

pre-gravid obesity.

Diabetes and BirthweightThe association between diabetes, either PDGM or GDM, and foetal

macrosomia is well established,12,15,34,36,51,54,55 and even minor degrees of

glucose intolerance have been shown to be associated with increasedneonatal birthweight.50 Several studies reported that PGDM is

associated with a higher risk of macrosomia than GDM. 14,15 In

concordance with these studies, decreased maternal pre-gravid insulin

sensitivity was reported to be one of the strongest correlates with

foetal growth, in particular fat mass at birth.46,56 Moreover, it is well

established that foetal overgrowth is associated with glycaemic control

during the first trimester,57,5861 although some have found that it is

hyperglycaemia during the third trimester that increases the risk of

macrosomia.36,37,62,63 As yet, the mechanisms by which insulin resistance

affects foetal growth are not well defined, but may involve altered

placental function in addition to increased foeto-placental availability of

nutrients in late gestation.46

Apart from the risk of macrosomia, diabetes and insulin resistance may

also be manifested as an increase in fat mass, even when foetal weight

is in the normal range.64 Interestingly, Catalano et al. found that while

insulin sensitivity in late gestation correlated best with newborn weight

and fat-free mass, the best correlate with neonatal fat mass was insulin

sensitivity prior to conception.56

Obesity or Diabetes Which Is Worse?A number of studies have tried to determine which of these two factors,

obesity or diabetes, is more important in the pathogenesis of foetalovergrowth and macrosomia, but results are conflicting. Several studies

have suggested that obesity plays a more important role than impaired

glucose tolerance (IGT) or diabetes during pregnancy. In a study of 300

women who underwent a 75g oral glucose tolerance test (OGTT)

following an abnormal 50g glucose challenge test (GCT), the correlation

of pre-pregnancy weight and pregnancy weight gain with birthweight

percentile was higher than that of the fasting and two-hour OGTT

values.65 In a large prospective cohort study of women without diabetes

who were screened for GDM by GCT, Yogev et al. found on multivariate

analysis that maternal obesity, but not the GCT result, was a significant

predictor of macrosomia (OR 2.9). Similarly, in a case-control study of

macrosomic infants of non-diabetic mothers, birthweight prior todelivery was the strongest predictor of macrosomia, while abnormal

GCT result was the least significant factor.25,66

However, it could be argued that merely the presence of glucose

intolerance of any degree is not an appropriate measure for

evaluating the contribution of diabetes to foetal growth, since most of

these studies lacked information regarding glucose levels and degree

of glycaemic control.29 Nevertheless, other studies found maternal

obesity to be a more important predictor of neonatal birthweight,

even when considering plasma glucose levels. In a prospective,

population-based study of 2,272 women with GDM, maternal weight

at delivery was the only significant predictor of birthweight percentile,

whereas the predictive value of plasma glucose levels was poor. The

authors concluded that factors associated with maternal obesity in

well-controlled GDM may be more significant than glucose control in

the development of LGA infants.26 This was also found to apply to

women with PGDM. In a retrospective study of women with PGDM

and GDM, birthweight closely paralleled pre-pregnancy BMI rather

than glycaemic control.11

In contrast, others have found diabetes to be more important than

maternal obesity in the prediction of foetal macrosomia.15,34,36,37,67,68 In a

retrospective cohort study, maternal BMI and GDM were independent

risk factors for macrosomia, but GDM seemed to play a more

important role.34 In another study of 90 women with diabetes, theassociation between birthweight and third-trimester glucose levels

was higher than that with pre-pregnancy BMI. 36 Furthermore, others

have found that it is only the presence of glucose intolerance that


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MaternalFoetal Medicine

E U R O P E A N O B S T E T R I C S & G Y N A E C O L O G Y52

determines the risk of macrosomia, whereas maternal BMI is not an

independent risk factor.67,68

The issue of the relative contribution of obesity and diabetes to the

development of foetal macrosomia and the interaction between these

two factors may be even more complex. Schaefer-Graf et al. reported

that the relative contribution of obesity and glucose intolerancedepends on gestational week.They found that obesity is more important

during the first and second trimesters, while later in the third trimester

maternal glycaemia predominates.37 In addition, Ehrenberg et al.

reported that the effect of diabetes is dependent on BMI. They found

that the effect of PGDM on the risk of macrosomia was more

pronounced in women in the lower BMI groups (i.e. normal and

underweight women). This finding was attributed to the fact that obesity

alone is associated with some degree of insulin resistance, so the

additive effect of PGDM in obese women is less significant.15

Reasons for Conflicting Results

There are several possible reasons for the conflicting results describedabove. Perhaps the most important factor in the interpretation of the

results of these studies is the level of glycaemic control. In some of the

studies no information is provided regarding the degree of glycaemic

control.29 In other studies where plasma glucose levels were considered

in the analysis, glycaemic control was relatively tight,47 thus limiting the

possibility of detecting a GDM-related effect. Indeed, it has been argued

that treatment of mothers with GDM may be masking the true effect of

glucose intolerance, leading to underestimation of the contribution of

diabetes to the development of foetal macrosomia.25

Another important factor is the possibility of undetected PDGM or GDM

diabetes in obese women. Indeed, numerous studies have found

obesity to be an independent risk factor for GDM and type 2

diabetes.30,31,35,48,49,6972 The risk of GDM in obese women is increased by

1.420-fold, and even overweight women have a 1.86.5 times greater

risk of GDM.19,20,30,3842,7376

The composition of the study and control groups is also of major

importance. In some of the studies that analysed the effect of obesity,

the reference group was underweight rather than normal-weight

women, thus leading to an overestimation of the effect of obesity.14,42 In

other cases, there was no distinction between different types of

diabetes, and thus women with GDM and type 1 and 2 diabetes were

included in the study group.14 Since type 1 diabetes is more likely to be

associated with a vascular component that compromises foetal growthand masks the relative overgrowth associated with hyperglycemia, a

lack of distinction between different types of diabetes may significantly

affect the results.

Other factors that may be responsible for the conflicting results include

differences in study designs, different definitions and measures for

estimation of obesity and lack of adjustment for possible confounders

that are over-represented in diabetic women, such as age and parity.

In summary, while some studies reported that diabetes or IGT is the

principal factor that affects foetal growth and that the contribution of

obesity may be due to undetected overt or gestational diabetes, others

have suggested that obesity and the associated peri-conceptional

insulin resistance makes obesity a more important contributor. Despite

the equivocal results described above, considering the fact that the

prevalence of obesity is nearly 10 times that of diabetes (45 versus

4.5%), abnormal maternal body habitus probably has the strongest

influence on the prevalence of macrosomia.46

Can the Risk of Macrosomia Associated withObesity and Diabetes Be Reduced?The prevention of macrosomia can reduce the rate of Caesarean section

and the risks of shoulder dystocia and birth trauma. Even more

importantly, considering the increased risk of obesity and diabetes inadult life that has been associated with foetal macrosomia (as described

earlier), reducing the rate of macrosomia appears to be an appealing

form of in utero primary prevention of adult cardiovascular disease,

especially when the poor success rates associated with treatment of

obesity in adults are taken into account. This strategy may provide an

important contribution to the interruption of the vicious cycle of obesity,

diabetes and foetal macrosomia (see Figure 1).46 This can be achieved by

weight loss prior to pregnancy, limitation of weight gain during

pregnancy or improved glycaemic control in pregnancies complicated

by diabetes (see Figure 1).

Weight LossObese patients should be encouraged to undertake a weight-reduction

programme before attempting pregnancy.77 Several studies have found

that significant weight loss prior to pregnancy in obese women through

physical activity, diet and pharmacological or operative interventions

markedly reduces maternal complications during pregnancy, including

foetal macrosomia.41,78 In contrast, in the study of women with

consecutive pregnancies complicated by GDM described above,

Hutcheon et al.47 found that a lower pre-pregnancy BMI on subsequent

pregnancy within the same woman did not decrease the risk of

macrosomia. They suggested that it is possible that obesity and

macrosomia are only the manifestations of another factor, such as

impaired glucose tolerance or genetic/hereditary factors. Nevertheless,

it should be noted that the mean decrease in pre-pregnancy weight in

this study was 4kg, which was associated with a mean BMI decrease of

1.6kg/m2. It is possible that more significant weight reduction will be

effective in reducing the risk of macrosomia.47

Limiting Weight Gain During Pregnancy

in Obese Women

As described above, weight gain during pregnancy is associated with

foetal macrosomia. However, the optimal weight gain during pregnancy

remains controversial. The current (1990) Institute of Medicine (IOM)

recommendations for weight gain during pregnancy advocate a marked

increase over prior guidelines, as their objective is to reduce the risk of

foetal growth restriction (FGR) associated with inadequate nutrition.Thus, the weight-gain recommendation for obese women is a minimum

increase of 6.8kg during pregnancy, even for morbidly obese women.79

However, most studies failed to show an association between low

Limit weightgain during

pregnancy

Weight gainduring

pregnancy

IGT/GDM/type 2

diabetes

Obesity Type 1diabetes

Macrosomia

Weight lossprior to

pregnancy

Glycaemiccontrol

Figure 1: Cycle of Obesity, Diabetes andFoetal Macrosomia

GDM = gestational diabetes; IGT = impaired glucose tolerance.


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E U R O P E A N O B S T E T R I C S & G Y N A E C O L O G Y 53

pregnancy weight gain and foetal growth restriction in obese

women,18,22,48,80 while increased weight gain in overweight and

obese women increases the risk of macrosomia. Moreover, increased

weight gain during pregnancy is a strong predictor for sustained weight

retention, and thus contributes to the global epidemic of obesity.8183

Accordingly, several authors have argued against current IOM

recommendations for pregnancy weight gain in overweight and obese

women.41,84 The IOM is currently re-examining these recommendations,

and updated recommendations are due in 2009/2010.85,86

Glycaemic Control

Numerous studies have shown that strict glycaemic control throughout

pregnancy in women with diabetes reduces the risk of macrosomia,87

although it remains unclear whether this also applies to obese diabetic

women. Leikin and colleagues88 found that non-obese GDM women with

fasting hyperglycaemia treated with diet and insulin had a frequency of

macrosomia no different than that of non-diabetic women, while diet

and insulin did not prevent excess macrosomia in women who were

obese. However, no information regarding the degree of glycaemic

control in the obese group is provided, thus limiting the interpretation ofthe results of this study. Similarly, Schaefer-Graf et al.89 concluded that in

obese women, the high rate of foetal macrosomia does not appear be

normalised by therapy based on maternal euglycaemia. In contrast,

Langer et al.90 found that obese and overweight GDM patients achieving

established levels of glucose control with insulin therapy showed no

increased risk of macrosomia and LGA compared with normal-weight

GDM patients. In contrast, even when diet-treated obese patients

achieved good glycaemic control, there was no improvement in

pregnancy outcome compared with normal-weight patients. The

improved outcome in insulin-treated overweight and obese women may

be due to additional effects of insulin itself on other metabolic fuel

pathways. Nevertheless, it should be noted that adequate glycaemic

control in morbidly obese women may be more difficult to achieve.91

Conclusion

Overall, it appears that maternal obesity, diabetes and, to a lesser

degree, pregnancy weight gain are independent risk factors for foetal

overgrowth. Despite conflicting results, maternal obesity, probably

owing to its increasing prevalence, exerts a greater impact on the

prevalence of macrosomia, especially when diabetes is well controlled.

Weight reduction prior to pregnancy and strict glycaemic control may

reduce the risk of macrosomia and interrupt the vicious cycle described

above. Further studies are needed to determine the optimal weight gain

during pregnancy for obese women, as current recommendations may

contribute not only to the development of macrosomia, but also to the

global epidemic of obesity.

Nir Melamed is a Physician in the Department of

Obstetrics and Gynaecology at the Helen Schneider

Womens Hospital, Rabin Medical Centre, Sackler

Faculty of Medicine, Tel Aviv University.

Moshe Hod is Director of the MaternalFoetal Medicine

Division of the Helen Schneider Womens Hospital, Rabin

Medical Centre, Sackler Faculty of Medicine,Tel Aviv

University. He is a member of the Executive Board of the

European Association of Perinatal Medicine (EAPM) and

Chairman of the Working Group on Diabetes and

Pregnancy of the EAPM. Professor Hod is the author of

more than 200 scientific publications.

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macrosmia and DM