Yi Ying Ong, Yung Seng Lee and Navin Michael
Fetal undernutrition followed by abundant food after birth might be a recipe for disaster — it is linked to increased risk of obesity and cardiometabolic diseases later in life. The Dutch famine birth cohort study is a tragic “natural experiment” that exemplified this phenomenon. It observed that people born to mothers who experienced a transient period of severe famine during pregnancy, followed by a return to normal diet postnatally, had an increased risk of obesity and cardiometabolic diseases.
This mismatch between a poor fetal nutritional environment and a rich postnatal nutritional environment might cause fetal adaptive responses to become maladaptive, leading to greater cardiometabolic risk in adulthood. This is known as the developmental mismatch hypothesis.
However, is developmental mismatch still a pertinent health issue affecting cardiometabolic risk in contemporary well-nourished populations, who are not facing famine or drastic environmental stresses? In these populations, fetal undernutrition is more likely to result from uteroplacental insufficiency than maternal malnutrition.
To answer this question, we studied a mother–offspring cohort in Singapore, a developed urbanized city and one of the richest countries in the world by GDP per capita.
In the absence of any hard clinical end-points in childhood, we measured an extensive panel of cardiometabolic risk markers to capture early subclinical changes in the children’s cardiometabolic profile. These risk markers included body fat and abdominal fat sub-compartments, intramyocellular lipid and liver fat, insulin resistance, carotid intima-media thickness, pulse wave velocity and blood pressure trajectories.
We also aimed to overcome the problem of misclassifying children who are constitutionally small as having poor fetal growth. This is a common problem in earlier studies that used birthweight or birth size as a crude proxy for fetal nutritional environment. Instead, we used longitudinal ultrasound measures as an improved indicator to capture the dynamic aspects of fetal growth.
We grouped 797 children into four growth groups, depending on whether they experienced fetal growth deceleration only (14.2%), rapid postnatal weight gain only (23.3%), both (the mismatch group; 10.7%) or neither (the reference group; 51.8%).
We found that children who experienced fetal growth deceleration only had elevated blood pressure trajectories without a corresponding increase in body fat percentage, arterial thickness or arterial stiffness. This is an interesting phenomenon because elevated blood pressure is often observed with elevated adiposity and changes in arterial structure. Our finding suggests that poor fetal growth might affect blood pressure through other pathways, such as poorer nephrogenesis, rather than through adiposity or changes in arterial structure.
We also found that children who experienced rapid postnatal weight gain as 0–2-year-olds, regardless of their fetal growth rates, had elevated abdominal fat and intramyocellular lipid levels, insulin resistance and blood pressure trajectories in early childhood (at ages 3–6 years). As childhood cardiometabolic markers have been reported to track to adulthood, these children are likely to face increased cardiometabolic risk.
Finally, we found that children who experienced the mismatch of fetal growth deceleration followed by rapid postnatal weight gain had the highest blood pressure trajectories and multiple elevated cardiometabolic risk biomarkers. However, the elevations in cardiometabolic risk markers in this group occurred without a corresponding increase in overall body fat percentage, unlike children who only experienced rapid postnatal weight gain.
This finding suggests that rapid postnatal weight gain might act as a “second hit” and increase cardiometabolic risk in children who had already experienced poor fetal growth. This increased risk in children with mismatch does not seem to be secondary to increased whole-body adiposity. We found that the results remained consistent even after removing small-for-gestational-age infants from analyses, suggesting the importance of dynamic changes in fetal growth over and above the effects of being born small-for-gestational age.
However, it is important to note the limitations of our study. As this is an observational cohort rather than a randomized controlled trial, there might be unmeasured confounders or selection bias, so caution must be used when trying to make causal inferences. It is also unknown how well these alterations in cardiometabolic risk markers at 6 years of age translate to cardiometabolic health in adulthood, so further follow-up would be valuable.
We believe this study provides an impetus for more intensive investigations into developmental mismatch. Our findings were consistent with earlier studies, where the mismatched group have increased cardiometabolic risk, but we progressed our understanding by using ultrasound-measured longitudinal fetal growth as an improved proxy of fetal undernutrition. Characterization of longitudinal fetal growth can be done from fetal anomaly ultrasound scans performed between 18 and 22 weeks and growth ultrasound scans performed between 32 and 36 weeks. We also measured an extensive panel of cardiometabolic risk markers to better capture subclinical changes in childhood cardiometabolic profiles in a contemporary well-nourished population.
Our findings suggest that developmental mismatch or a mismatch in fetal and postnatal growth patterns might be a prevalent and pertinent problem not just in poorer populations facing drastic undernutrition but also in well-nourished populations. Future research should identify modifiable risk factors of poor fetal growth and rapid postnatal weight gain.
It might be useful for clinicians and the public in both developing and developed countries to understand the potential benefits of reducing developmental mismatch, as well as to focus on the identified determinants of poor fetal growth and rapid postnatal weight gain to reduce the prevalence of these two growth patterns. Taking a life-course epidemiological approach and focusing on early life, which is more sensitive to environmental influences, might be a key to curbing the wave of obesity and cardiometabolic diseases worldwide.
Read more:
Ong YY, Sadananthan SA, Aris IM, et al. Mismatch between poor fetal growth and rapid postnatal weight gain in the first 2 years of life is associated with higher blood pressure and insulin resistance without increased adiposity in childhood: the GUSTO cohort study. Int J Epidemiol 2020; August 27. doi: 10.1093/ije/dyaa143.
Yi Ying Ong is a PhD candidate in the Department of Paediatrics at Yong Loo Lin School of Medicine, National University of Singapore. Her research interests centre on the early-life determinants of obesity and cardiometabolic diseases.
Yung Seng Lee is a Professor of Paediatrics at the Yong Long Lin School of Medicine, National University of Singapore (NUS), and a senior consultant paediatrician practising paediatric endocrinology at the National University Hospital (NUH), Singapore. His clinical and research interests are focused on obesity, insulin resistance and mediators of obesity-related morbidities.
Navin Michael is a research scientist at the Singapore Institute for Clinical Sciences, ASTAR. His research focuses on understanding the determinants and mechanisms of cardiometabolic and cardiorenal diseases, and his research interests include the developmental origins of health and disease, gestational diabetes, non-alcoholic fatty liver disease, fetal and postnatal growth trajectories, body fat partitioning and magnetic resonance imaging/spectroscopy.
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