Gestational diabetes and fetal macrosomia: a dissenting opinion

Macrosomia, gestational diabetes mellitus and obesity

Fetal macrosomia, usually defined as birth weight >4000 g regardless of gestational age, is associated with an increased rate of birth anomalies, and consequently higher perinatal morbidity and mortality. The threshold for birth weight of >4000 g corresponds to a value above the 90th percentile at term. The management of pregnancies with a suspected macrosomic fetus is often challenging [1].

Maternal obesity before pregnancy is widely recognized as a significant risk factor for the development of macrosomic infants, and is a major contributor to several adverse pregnancy outcomes, including GDM and hypertensive disorders [2], 3]. Obesity increases the likelihood of developing GDM, which, in combination with the complex interaction of insulin resistance and other metabolic factors, significantly impairs fetal growth and often leads to macrosomia [2], 3]. Furthermore, maternal obesity increases the risk of complications in labor and delivery, cesarean section, and postpartum disorders and complications such as infection and delayed recovery. In addition, infants born to obese mothers are at increased risk of long-term health problems, including obesity and metabolic syndrome later in life [4], [5], [6].

The analysis by Sweeting et al. [7] clearly shows that as maternal BMI increases, particularly in overweight and obese women, there is a corresponding increase in the risk of conditions such as GDM, hypertensive disorders and cesarean delivery. Crucially, the risk of fetal macrosomia is more closely associated with maternal obesity than with GDM alone, emphasizing the importance of effective maternal weight management before and during pregnancy to mitigate these risks [8]. Key factors such as elevated glucose and triglyceride levels, which are common in obese women and those with GDM, further increase the risk of macrosomia [7]. The biological link between hyperglycemia in GDM and macrosomia is based on the Pedersen hypothesis that maternal hyperglycemia leads to excessive fetal insulin production, which promotes abnormal fetal growth and increases the likelihood of cesarean delivery, birth injuries and neonatal hypoglycemia [7], 8]. Elevated triglycerides contribute to increased fat deposition in the fetus, which increases the risk of preeclampsia and other hypertensive disorders.

Sweeting et al. advocate for comprehensive preconception and prenatal care strategies that focus on risk factors to ensure better health outcomes for both mothers and their newborns [3], 4].

There is controversy about the extent to which each of these variables contributes to macrosomia. Schaefer-Graf et al. [9] found that maternal obesity appears to be a strong risk factor for macrosomia in GDM pregnancies. They also found that maternal euglycemia did not normalize the incidence of macrosomia.

In the meta-analysis conducted by Gaudet et al. [10], the authors found that maternal obesity (pregravid or at the first prenatal visit) was significantly associated with a fetal birth weight ≥4000 g. Another frequently cited risk factor is hyperglycemia during pregnancy. In fact, the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study showed a modest but significantly increased risk of birth weight >90th percentile with maternal hyperglycemia [8].

Several studies have highlighted the critical role of maternal obesity and gestational weight gain (GWG) in the risk of fetal macrosomia, which often outweighs the impact of GDM. Nakashine et al. [11] demonstrated that both GDM and elevated triglyceride levels modestly mediate the relationship between pre-pregnancy obesity and macrosomia, emphasizing the importance of managing these factors. Maternal obesity, rather than GDM, is the strongest predictor of macrosomia and adverse pregnancy outcomes, with studies [12], [13], [14], [15], [16], [17] consistently highlighting pre-pregnancy BMI and excessive gestational weight gain (EGWG) as important independent risk factors that often overshadow the impact of GDM. Zheng et al. [18] emphasized that management of GWG after a GDM diagnosis is crucial, as even moderate weight gain can increase the risk of LGA. Overall, these findings suggest that effective pre-pregnancy weight management and control of GWG may reduce the incidence of macrosomia more than focusing solely on the management of GDM.

Trojner et al. [19] showed that women with pre-gravid class III obesity (BMI>40 kg/m²) had significantly more GDM and macrosomic infants as compared with class I obesity (BMI 30.1–35 kg/m²), suggesting a quasi dose-response relationship between severity of obesity and the incidence of GDM and macrosomia. Our group also observed [20] that obesity (without diabetes) is more frequently associated with macrosomia than GDM with obesity (“diabesity”) or GDM in non-obese mothers.

Although these and other associations with macrosomia have been reported previously, the studies have often been confounded. Two important confounding factors are parity and GWG. In the common context, the incidence of GDM and obesity increases with parity, so the potential direct association between parity, per se, and macrosomia remains uncertain or not properly assessed. In addition, excessive weight gain during pregnancy has been associated with increased birth weight and fetal growth (LGA) [21], 22].

To our knowledge, these four variables, namely GDM, obesity, excessive weight gain, and parity, have not been compared before. The aim of our study was to examine the effect of the interaction between these variables on the incidence of fetal macrosomia by examining a large series of singleton pregnancies from a well-validated population database.

Study population

We used data from the Slovenian National Perinatal Information System (PIS RS), in which registers all deliveries from 22 weeks gestation or birth weight over 500 g. Registration is mandatory by law and more than 140 variables are entered into the computerized database immediately after birth. Our study population included live singleton births at ≥38 weeks in the period 2016 to 2023. In Slovenia, guidelines based on the recommendations of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) were introduced and adopted in 2011.

As the analysis was based on individual deliveries, women who gave birth more than once during the study period were included multiple times, with each delivery counted separately.

The dependent variable of our study was birth weight >4000 g. The following dichotomous independent variables were analyzed: overweight and obesity or normal weight before pregnancy, being primiparous or multiparous, gaining weight according to the Institute of Medicine weight gain recommendations in pregnancy [23], and being without GDM, with GDM0 (GDM under control by nonpharmacologic treatment), or GDM1 (GDM requiring insulin treatment) (see below). We excluded patients with chronic arterial hypertension, smoking, and pre-gestational diabetes mellitus.

Clinical definitions and practices in Slovenia

Overweight and obesity were defined according to the pregravid BMI ≥25 kg/m² (defined as the individual’s body mass divided by the square of body height, kg/m², [24]). The PIS RS method of registering maternal pre-pregnancy weight is particularly accurate and presumably without recall error, as pre-pregnancy weight was measured and recorded at the first visit to the doctor at the beginning of pregnancy.

GDM has been defined according to the national guidelines for screening and diagnosing GDM. We follow a two-step screening approach. The first step is at the first visit to the doctor at the beginning of pregnancy, where the fasting serum glucose is measured. The limit value is 5.1 mmol/L. If blood sugar is below this, we perform 75 g oral glucose tolerance test (OGTT) between the 24th and 28th week of pregnancy according to the consensus of the International Association of Diabetes and Pregnancy Study Groups in 2010 [25]. GDM1 was defined as GDM requiring insulin treatment, while GDM0 was defined as when dietary changes and a healthy lifestyle were adequate to control glucose levels. GDM per se was not an indication for induction of labor or elective cesarean section before 40 weeks’ gestation.

As standard of care [26], women with GDM were referred to a multidisciplinary team of obstetrician, endocrinologist, and nutritionist to receive diabetic education, nutritional counseling, and encouragement to adopt a healthy lifestyle. The goal was to maintain fasting blood glucose below 5.3 mmol/L, achieved with both diet and lifestyle changes or together with insulin treatment. Glycemic control was assessed by traditional four times daily capillary blood sampling using calibrated glucose meters. The results were checked at regular intervals. Weight gain was defined by the difference between maternal weight at birth and pre-pregnancy weight. Mothers were considered to have a normal GWG or to be over-gainers, according to the Institute of Medicine standards endorsed by the American College of Obstetricians and Gynecologists (ACOG) [24].

In Slovenia, pregnant women with GDM have additional ultrasound examinations to assess the growth and well-being of the fetus. If accelerated fetal growth or an increased amount of amniotic fluid (polyhydramnios) is detected, the patient is referred to a secondary or tertiary level. Patients with other diagnoses that could complicate pregnancy or birth are also referred to the tertiary level [27].

Statistical analysis

IBM SPSS ^® Statistics software was used for statistical analysis of the data. Chi-square tests were used to compare categorical variables and to calculate odds ratio (OR) and the 95% confidence interval (CI). A logistic regression analysis was also performed to explain the relationship between one dependent binary variable (birth weight >4000 g) and several nominal and ordinal variables. The level of significance used in the statistical analysis of the data was set at p < 0.05.

This retrospective study of anonymous entries was exempt of approval by the Ethics committee. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Principal findings

Our data suggest that well-treated GDM, whether treated nonpharmacologically by diet and exercise (GDM0) or with insulin (GDM1), is not significantly associated with the development of macrosomia in our population. Instead, factors such as pre-pregnancy BMI, weight gain during pregnancy, and parity have a grater impact on this risk. This suggests that effective management of GDM may mitigate its influence on macrosomia, with the observed risk being primarily due to other maternal characteristics rather than GDM itself.

Overall, the graphs confirm our earlier statement that pre-pregnancy obesity and EGWG are of the main factors for macrosomia, especially in multiparous women. Effective weight management before and during pregnancy remains essential in reducing the risk of fetal overgrowth, as the consistent patterns in the different groups make clear.

Strengths and limitations

One of the biggest strengths of this study is the large sample size. The study utilizes a large dataset comprising nearly 200,000 singleton births, which strengthens the statistical power and generalizability of the findings. Furthermore, a well-validated population database was used, which adds credibility to the findings since the PIS RS in Slovenia is a legally mandated registry that ensures comprehensive, complete and accurate data collection. Another strength is that the entire population of pregnant women in Slovenia is covered by centrally regulated clinical guidelines that ensure standardized diagnosis and treatment practises. This consistency in care improves the comparability of results and supports the generalisability of our findings. The statistical in-depth analysis of the independent and combined effects of key variables — GDM, obesity, parity, and GWG — on the incidence of fetal macrosomia is certainly one of the biggest strengths of the study. This comprehensive approach allows for a nuanced understanding of how these factors interact and influence outcomes, addressing gaps in previous research that often considered these variables in isolation.

The study not only identifies significant associations but also explores the potential clinical implications of these findings. For instance, the discussion on the role of appropriate GDM care in potentially mitigating the risk of macrosomia highlights the importance of tailored clinical interventions based on individual patient profiles. Additionally, by challenging the traditional understanding of the relationship between GDM and macrosomia and emphasizing the stronger impact of obesity and weight gain, this study adds valuable insights to the existing knowledge. The findings suggest that interventions targeting obesity and weight management might be more effective in reducing the incidence of macrosomia than focusing solely on GDM management.

The study’s findings are directly relevant to public health and clinical practice, particularly in the context of designing interventions to reduce the incidence of macrosomia. The emphasis on pre-pregnancy obesity and weight management during pregnancy offers actionable insights for healthcare providers.

The main limitation of our study is the lack of information about glycemic control. This seems to be of importance as Langer et al. [35] concluded that targeted levels of glycemic control enhanced outcome only in cases with GDMA2 in obese women. This preferential effect of insulin is not supported by our study because GDMA2 mothers had no advantage in overweight/obese women as well as in women with pregravid normal BMI.

While the study’s findings are robust and relevant within the Slovenian population, generalizing them to other populations should be done cautiously, considering the differences in healthcare practices, population demographics, and the prevalence of the key variables studied. We acknowledge that the incidence of maternal obesity in our population is apparently lower as compared to other countries. Devlieger et al. [36] ranked our population (roughly 9% obese women) among the European countries with the lowest incidence of obese mothers (range 7 to 25%). Our incidence of pregravid obesity is certainly much lower than that reported in the USA [23]. Despite these variations, the robust conclusions of our study appear applicable to every population that includes obese gravidas. Further research in diverse settings would be beneficial to confirm the broader applicability of our conclusions.

Finally, we used the 4000 g cutoff to define macrosomia. Regardless of its statistical merit, clinician might be more comfortable with conclusions related to 4500 g as a cutoff. Regrettably, despite the dataset of nearly 200000 patients, the small number of infants weighing over 4500 g at birth did not permit meaningful conclusions.