Maternal cardiometabolic markers are associated with fetal growth: a secondary exploratory analysis of the LIMIT randomised trial

Obesity represents a major global health challenge, with over 50% of women entering pregnancy in high-income countries with a body mass index (BMI) greater than 25 kg/m² [1, 2]. There are well-recognised associations between obesity in pregnancy and maternal, fetal and neonatal health outcomes [3]. In the long-term, there are clear associations between maternal obesity, fetal overgrowth, high infant birth weight, and subsequent childhood obesity [4].

In 1969, Pedersen postulated that maternal hyperglycaemia stimulates hyperinsulinemia in the fetus, which in turn directly stimulates fetal growth through insulin growth factors [5]. In the past 10 years, there has been increasing recognition of the ‘indirect’ pathway, involving leptin, adiponectin, triglycerides, cholesterol and inflammatory cytokines which is mediated via placental transfer [6]. Furthermore, maternal obesity during critical time points for fetal development has been linked to fetal programming via epigenetic modification [7].

During pregnancy, triglycerides and fatty acids are required for fetal development and growth [8]. Lipoprotein receptors, binding proteins and lipases hydrolyse triglycerides to free fatty acids for uptake by the syncytiotrophoblast, enabling transportation to the fetus along with storage and metabolism within the placenta [9, 10]. Enhanced placental lipid transport in obese women has been hypothesised [11] but has not been demonstrated [12, 13]. Higher concentrations of triglycerides and lipids have been found in women who are obese [12] and those women who have delivered a large for gestational age infant [9, 14]. Studies investigating newborn cord blood concentrations of lipoproteins [15] have shown an association with adipose tissue in the fetus and newborn, contributing to higher infant birth weight [9] and neonatal adiposity [16].

A key component of the fetal overgrowth pathway is adiponectin, the endocrine link between maternal adipose tissue and fetal growth [17]. Adiponectin is secreted by maternal adipocytes, acting directly on the placenta without crossing into the fetal circulation [17, 18]. While adiponectin is known to be insulin sensitising in the skeletal muscle and liver [19], it exerts the opposite effect in the placenta [20]. During pregnancy, adiponectin inhibits insulin mediated amino acid transport in trophoblast cells via the insulin receptor (IRS) and mTORC1 signalling [19, 20]. As gestation advances, adiponectin levels decline due to the physiological resistance to insulin in maintaining serum glucose [21]. In non-pregnant adults, adiponectin concentrations are lower in obesity [22], cardiovascular disease [18] and Type 2 Diabetes mellitus [23]. During pregnancy, lower concentration of adiponectin is associated with gestational diabetes [24]. Maternal and fetal adiponectin appear to have opposite effects in relation to fetal growth [17], with low maternal concentrations of adiponectin stimulating fetal overgrowth [22]. Conversely, cord blood and neonatal adiponectin concentrations have been reported to be up to 7 times higher than maternal concentrations, with positive correlations with infant birth weight [25] and anthropometric measures of neonatal adiposity [25, 26].

With the widespread availability and technological advances in fetal ultrasound, there is growing interest in the measurement and prediction of fetal overgrowth and adiposity [27]. However, the current literature is limited to relatively small sample sizes and mostly involving women entering pregnancy with a normal BMI [28‐31].

The aim of this secondary exploratory analysis was to determine if maternal cardiometabolic and inflammatory markers were associated with fetal growth and adiposity measured by ultrasound in women who are overweight or obese in pregnancy at 28 and 36 weeks gestation.

The research methodology [32] and clinical findings [33] of the LIMIT randomised controlled trial have been published previously. The conduct of the LIMIT randomised trial adhered to CONSORT methodology [34]. Women with a BMI ≥25 kg/m², singleton pregnancy, without a diagnosis of diabetes and between 10 + 0 and 20 + 0 weeks gestation were recruited between June 2008 and December 2011 from 3 public hospitals across metropolitan Adelaide. The women were randomised to either the ‘Lifestyle Advice Group’, receiving standard antenatal care and diet and lifestyle, or ‘Standard Care Group’ receiving standard antenatal care without additional diet and lifestyle advice. The intervention was delivered by a research dietician and trained research assistants. Further details regarding content of the intervention [33, 35] and the fetal growth study [36, 37] have been previously published. Women included in this analysis were those randomised to the Standard Care Group.

The main findings of this secondary exploratory analysis showed that increasing concentrations of adiponectin was associated with a reduction in abdominal circumference and estimated fetal weight, with this effect increasing over time. Furthermore, a higher triglyceride concentration was associated with an increase in abdominal circumference z score and estimated fetal weight at 36 weeks gestation. There were no apparent associations between inflammatory markers, fasting glucose, triglyceride and leptin concentrations with fetal ultrasound measurements.

To the best of our knowledge, this is the first study to describe the relationship between cardiometabolic biomarkers with fetal ultrasound measurements of biometry and adiposity. The current literature to date has reported on maternal or cord blood sampling and postnatal measurements of neonatal adiposity [41] or child growth trajectories [42]. There have been two large studies which have evaluated maternal cardiometabolic markers in the setting of a randomised control trials testing the effect of an antenatal dietary and lifestyle intervention [38, 43].

The main finding of our secondary analysis relating to adiponectin is consistent with the current literature. In women entering pregnancy with a normal body mass index, Lekva and associates found a reduction in adiponectin concentrations in the 3rd trimester, and this occurred independently of body mass index and maternal insulin resistance [22]. Low adiponectin concentration is associated with a higher prevalence of newborns classified as large for gestational age and increased birthweight [22]. Regarding interventions during pregnancy, the LIMIT trial showed that a dietary and lifestyle intervention did not change the concentrations of the cardiometabolic biomarkers in women who were overweight and obese [38]. The Fit for Delivery intervention in low risk women [44] showed a reduction in insulin and leptin concentrations, but this did not reduce the incidence of gestational diabetes, the primary outcome.

While adiponectin concentrations do not alter with dietary change, there is increasing interest in the supplementation of adiponectin has promising applications in the adult populations [18, 22, 24]. In vivo and in vitro studies [2] have shown that adiponectin supplementation in pregnancy may alter fetal growth through improving insulin sensitivity [45]. The proposed mechanism relates to the down regulation of key placental nutrient transporters within the syncytiotrophoblasts, including amino acid transporters such as System A [22, 45]. Adiponectin as a therapy may reduce cardiovascular risk in the non-pregnant overweight and obese mouse model [18]. Further studies with experimental animal models along with clinical applications are required.

Interestingly, leptin did not show any consistent effect on fetal growth or adiposity in our study. This was supported by a recent study by Castro who performed maternal serum leptin sampling after delivery (to reduce the effect of placental leptin production), and found no association with neonatal adiposity [46]. Josefson measured the concentrations at 36 weeks gestation and found an association with neonatal adiposity [47]. This highlights that each cardiometabolic marker has a different pattern during pregnancy and the timing of sampling may impact on the interpretation of results. Interestingly, fetal exposure to leptin along with high cord blood concentrations, have been positively associated with birthweight, neonatal adiposity, postnatal and childhood growth trajectories [42].

Maternal triglyceride concentration at 36 weeks was associated with an increase in z scores for abdominal circumference and estimated fetal weight. This is consistent with studies from women with gestational diabetes, where fetal growth and adiposity correlate with maternal triglyceride levels, independent of body mass index [9]. The exact role of maternal triglycerides [48], lipoprotein receptors, binding proteins and lipases and the placental flow of maternal fatty acids [9] in the setting of obesity remains unclear [48] and further studies are required.

The relationship between maternal inflammatory markers and fetal adiposity is also interesting. There is evidence to support that maternal obesity increases pro-inflammatory cytokines [49], which in turn has been shown to stimulate the inflammatory pathways within the placenta [50, 51]. The effect of the inflammatory milieu related to maternal obesity on the fetus [52], newborn [53] and child [54] remains unclear [55, 56] and requires further evaluation. A reason for the lack of effect seen in this study may relate immune modulation in pregnancy, which may dampen down the chronic, low grade inflammatory response related to obesity [57].

In this study, maternal concentration of glucose at 28 weeks was not associated with fetal body composition. While the findings of the HAPO study found that a modest increase in maternal glucose levels was associated with an increase in birth weight [58], the HAPO study included women with a normal BMI. The effect of obesity has a more significant, stronger and long term effect on the risk of large for gestational age infants [59] when compared to pregnancy mediated insulin resistance, present from 28 weeks onwards [58].

Understanding of the mechanisms and timing of critical fetal growth changes represents an evolving area of obesity related research. From a public health perspective, the only preventive strategy to reduce the intergenerational transmission of obesity [60] is to optimise maternal weight and reduce obesity related morbidity prior to pregnancy. Current studies are underway to assess dietary and lifestyle interventions to reduce maternal obesity prior to pregnancy or in early pregnancy [61]. Further research is required to assess the role of adiponectin and supplementation in the setting of obesity in pregnancy [17].

Our exploratory study has contributed to the further understanding of the fetal overgrowth pathway. High concentrations of adiponectin were found to be associated with a reduction in abdominal circumference and estimated fetal weight in women who are overweight or obese. Adiponectin is a promising biomarker that may have a role in the modulation of fetal growth in the future.