Precision interventions targeting the maternal metabolic milieu for healthy pregnancies in obesity

Abstract

Purpose of Review:

Entering pregnancy with obesity increases the risk of adverse health outcomes for parent and child. As such, research interventions are largely focused on limiting excess gestational weight gain during pregnancy, especially in those with obesity. Yet, while many lifestyle interventions are successful in reducing GWG, few affect pregnancy outcomes. Here we review work targeting the metabolic milieu instead of focusing solely on weight.

Recent findings:

Work done in non-pregnant populations suggests that specifically targeting glucose, triglyceride, and leptin levels or inflammatory makers improves the metabolic milieu and overall health. We posit that precision interventions that include strategies such as time restricted eating, following the 24h movement guidelines, or reducing sedentary behavior during pregnancy can be successful approaches benefiting the maternal metabolic milieu and minimize the risk of adverse pregnancy outcomes.

Summary:

Personalized tools such as continuous glucose monitors or community-based approaches play an important role in pre-conception health and should be extrapolated to pregnancy interventions to directly benefit the metabolic milieu optimizing health outcomes for both parent and child.

Introduction

Obesity affects 29% of pregnant individuals in the United States (US), making it the most common disease in obstetrics [1]. Maternal morbidity and mortality rates in the US are on the rise and in large part due to obesity related complications affecting the metabolic milieu [2,3]. Adverse outcomes during pregnancy, delivery, and for offspring are worsened in those who enter pregnancy with obesity and are amplified when presented alongside pre-existing comorbidities such as hypertension, dyslipidemia, insulin resistance, and chronic inflammation [4]. Thus, the management of obesity and its comorbidities during the reproductive years and specifically in pregnancy is of critical importance to lessen obesity-related risks in both the pregnant individual and baby.

Adverse pregnancy outcomes (APOs) worsened with maternal obesity include gestational hypertension, preeclampsia, gestational diabetes mellitus (GDM), and unscheduled cesarean delivery. For the infant, there is heightened risk for being born large for gestational age (LGA), small for gestational age (SGA), fetal death, and NICU admission, among others [5]. The long-term and multi-generational risks of obesity are also evident. In individuals with obesity, 17% develop new-onset long-term cardiometabolic disease after pregnancy, 23% have infants born with adverse health outcomes, and the risk of having a child develop obesity increases exponentially [6] – thus contributing to the intergenerational transmission of metabolic disease. In the general population, evidence-based options for obesity treatment and prevention are available across the lifespan and include behavioral lifestyle intervention, anti-obesity medications, and surgery. Arguably, the opportune intervention period for optimal maternal and infant health is pre-conception defined as time females are nonpregnant during their reproductive years (often defined as 18-44 years).

Preconception health is associated with improved maternal health and birth outcomes [7-9] and interventions introduced prior to conception are needed for optimization of the maternal milieu during pregnancy. Yet this approach is often not feasible, given high rates of unintended pregnancies and how the time of preconception varies between individuals [10-12] and between pregnancies. Notably, highly efficacious treatments for obesity including anti-obesity medications and surgical approaches are not appropriate for use during pregnancy and also currently contraindicated for one year prior to pregnancy. As such intensive behavioral lifestyle intervention is the first line of therapy for obesity management during pregnancy (Figure 1).

Fig. 1.

Obesity prevention, treatment and management options throughout the reproductive cycle.

Lifestyle interventions almost exclusively commence around 16 to 20 weeks gestation and focus on the prevention of excess gestational weight gain (GWG) or worsening of maternal obesity. This approach relies on the Institute of Medicine’s, now National Academy of Science, Engineering, and Medicine (NASEM) recommendation of limiting GWG to 5-9 kg for obesity and is widely accepted. However, a growing body of evidence suggests that overall maternal metabolic health [13,14] is more important than body mass index (BMI) and GWG for APOs and to the developing fetus.

The aim of this review is to discuss the current evidence and controversies of using GWG as a gauge for successful prenatal interventions and propose new strategies to manage obesity during pregnancy for optimal maternal and infant outcomes.

The controversy – GWG as the focus of pregnancy interventions

In pregnant individuals, maternal obesity is associated with excess GWG, which leads to greater risk of postpartum weight retention, [15] in turn increasing the probability of initiating a subsequent pregnancy with worsened obesity and reinforcing the vicious cycle [16]. Nearly two out of three pregnant individuals who enter pregnancy with overweight or obesity experience excess GWG [17]. Results from the LifeCycle Project, an individual participant level meta-analysis compiling data from more than 1 million pregnancies in the US, Canada, and Europe, suggest that the risk for APOs concordantly increases per 1 standard deviation increase in GWG in individuals with obesity, at an odds ratio of 1.04 [8].

To combat the effects of excess GWG, the US Preventative Services Task Force suggested intensive (≥12 sessions) behavioral interventions when targeting weight gain during pregnancy [18]. In pregnant individuals with obesity, multicomponent interventions combining dietary and physical activity modifications improve diet quality and Healthy Eating Index and increased time spent exercising [19]. Yet, prenatal lifestyle interventions show moderate success in lowering GWG and improving outcomes [18,20,21]. For example, in the largest cluster of trials in the U.S., the LIFE-Moms consortium, multi-component interventions tested in pregnant individuals with overweight or obesity at seven clinical centers produced a 1.6 kg reduction in GWG compared to usual care. Despite this effect size, there were no observed differences in APOs including preeclampsia, gestational diabetes, cesarean delivery, or birth weight between groups [22]. A similar multicenter study comparing APOs between standard of care and three lifestyle interventions; a healthy eating intervention, a physical activity intervention, and a combined healthy eating and physical activity intervention in pregnant individuals with obesity, observed limited changes in GWG (average difference between interventions and standard of care: 0.3kg) with no improvements in glucose profiles across pregnancy [23]. Even among pregnant individuals with GDM, the most common APO and patient group targeted for lifestyle interventions, dietary and/or physical activity-based interventions have been largely unsuccessful in significantly improving fetal and birth complications [24]. However, despite a difference of only 0.1kg in GWG, a Finnish study demonstrated a 7.7% decrease in GDM prevalence between the intervention and standard of care groups following a lifestyle intervention specifically targeting GDM in pregnant females [25].

We posit that this research implies more precise strategies beyond modification of GWG are needed for successful and timely interventions in pregnancy. An alternative approach is to focus interventions on improving the maternal metabolic milieu. Intervening directly on the pregnant individual’s biomarker levels such as circulating glucose, insulin, triglyceride, leptin, and inflammatory markers, that define the metabolic milieu, promotes favorable improvements in the offspring. Irrespective of the parent’s weight, the fetus is keenly attuned to changes in the circulating milieu. Below we describe the effects of the maternal milieu on offspring health and highlight interventional strategies targeting the maternal milieu during pregnancy to optimize health in parent and child.

Shifting the focus from GWG to the maternal metabolic milieu

Maternal GDM increases the risk of APOs such as pre-eclampsia, macrosomia, neonatal hypoglycemia, and impaired glucose tolerance and long-term risk of type 2 diabetes mellitus, and cardiovascular disease in both parent and child [26-28]. The metabolic milieu with GDM promotes elevated uterine glucose levels. In utero the fetus secretes insulin to adjust to this adverse maternal environment which at birth (when the maternal glycemia ceases) leads to neonatal hypoglycemia [29]. A dysregulated glycemic milieu in pregnancy thus affects pregnancy outcomes and is associated with abnormal glycemic regulation in the offspring across childhood [28]. A large prospective study of offspring (n=4,160) exposed to GDM demonstrated increased rates of impaired fasting glucose (+1.8%) and impaired glucose tolerance (+5.6%) at 10-14 years of age compared to age-matched unexposed children [30]. Furthermore, insulin sensitivity in young children is inversely correlated with maternal HbA1c levels during pregnancy, reinforcing evidence of the effects of the maternal metabolic milieu on offspring glucose-insulin homeostasis [31].

While maternal blood lipid concentrations during pregnancy often progress to hyperlipidemia, this is a normal physiological adaptation to ensure adequate energy stores are available. However, progression of triglyceride concentrations above those considered normal during pregnancy are associated with an increased risk of pregnancy-induced hypertension and pre-eclampsia [32]. In mothers with obesity (and GDM), maternal triglycerides are 40–50% higher on average compared to normal-weight mothers early in pregnancy and are sustained at a higher level throughout gestation [33]. Excess maternal lipids are predictors of neonate obesity, predisposing newborns to greater risks of obesity and metabolic disfunction [33]. Particularly, maternal triglycerides have been positively associated with fetal size, birth weight, and fat mass [34]. A longitudinal birth cohort study demonstrated mothers who had elevated triglyceride levels in late pregnancy were 1.5 times more likely to have a macrosomic baby and were 1.6 times more likely to have a large for gestational age infant [35]. As such, triglycerides are an important aspect of the maternal metabolic milieu affecting the intrauterine contribution towards childhood obesity and metabolic disease.

High levels of adiposity observed in obesity directly impact leptin levels, a hormone produced by adipocytes that regulates energy homeostasis by promoting energy expenditure and inhibiting food intake [36]. It has been postulated that leptin may mediate the link between the increased risk of APOs and pregnant individuals with obesity, yet many studies have small sample sizes. Data from available studies demonstrate that higher maternal leptin is associated with pre-eclampsia [37-41], GDM [42-44], and adverse neonatal outcomes [45,46]. A prospective cohort study nested within a large randomized controlled trial of 776 women found that higher preconception levels of leptin, regardless of BMI, were predictive of a greater likelihood of experiencing at least one APO [47]. In addition to the impact of overweight/obesity on hormones in the maternal milieu, maternal overweight and obesity promote a high inflammatory state. This has also been correlated with APOs and higher risk of complications during pregnancy [48]. Measuring inflammatory markers during pregnancy can be complicated as there are many etiological factors such as diet, microbiota, age, stress, infection, and comorbidities, that impact inflammation [49]. Current research focuses on measuring pro-inflammatory markers known to increase over the course of pregnancy such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF- α), and C-reactive proteins [50]. A recent review on inflammation during pregnancy by Zavatta and colleagues [49] showed that pro-inflammatory environments led to compensatory adaptations, metabolic reprogramming, and adverse embryo-fetal development. Therefore, inflammation should be considered as a crucial factor for healthy life span both of the mother and the fetus.

Distinguishing between metabolically healthy and unhealthy obesity in pregnancy can benefit strategies for the optimization of health outcomes in mothers and infants. Infants born to individuals diagnosed as metabolically unhealthy obesity (i.e., obesity with risk factors of cardiometabolic diseases) are 20% heavier and have 96% more fat mass compared to those born to individuals considered metabolically healthy [14] and this effect is independent of GWG. Others have shown that while maternal BMI preconception is strongly linked to APO, this relationship is seemingly not mediated by GWG [51]. In support, is translational research examining the association between umbilical cord mesenchymal stem cells (MSCs) and infant health outcomes. The umbilical cord is a fetal tissue and the MSCs are the developmental source of adipocytes, myocytes, and other cell types in fetal development. After birth, the MSCs can be harvested and grown in culture conditions for differentiation into adipocytes, myocytes and studied for their links to infant and child health and maternal exposures.

In elegant studies, MSCs differentiated to adipocytes in situ, show that those from infants of obese mothers have 30% greater adipogenesis than those born to normal weight mothers and increase lipid accumulation [52]. The excess lipid accumulation in adipocytes from MSCs are positively associated with percent fat at birth and in childhood at age 4 to 6 months and at 4 to 6 years [53]. Similarly, MSC-derived myocytes show reduced fatty acid and lipid oxidation and suppressed 5’ adenosine monophosphate-activated protein kinase, an enzyme facilitating glucose and fatty acid uptake, explaining the predisposition to obesity in postnatal life [54]. Furthermore, myocytes differentiated from infant MSCs born to mothers with obesity plus additional obesity related co-morbidities “metabolically unhealthy obesity” as opposed to a “healthy” obesity phenotype have a greater insulin response, lower myogenic potential, and impaired fatty acid oxidation limiting myogenesis and promoting lipid storage, irrespective of GWG [55,56]. These mechanisms of increased propensity for adipose tissue expansion, lipid storage and incomplete fat oxidation in MSCs are only evident when the cross-sectional comparisons involve maternal BMI or maternal metabolic health. They don’t hold for low and high GWG. The MSC model is also sensitive to maternal lifestyle intervention. Moderate maternal exercise during pregnancy improves myocyte insulin signaling and fat oxidation in infant MSCs, which is associated with leaner infants at one month of age [57]. As such, studies focusing on MSCs demonstrate that fetal tissues are programmed in response to maternal substrates in a particular manner that is linked with maternal BMI and also maternal interventions but not to GWG [57-60]. From a mechanistic perspective, the MSC model reinforces that GWG is not a strong influence on offspring phenotypes in metabolically active tissues and supports the need for more precise interventions that perturb the maternal metabolic milieu.

Answering the call! Targeting the maternal metabolic milieu with precision interventions

Precision health is an emerging area of research that focuses on the genetic, environmental, and personal aspects of individual health [61]. The use of precision health can maximize the critical window where interventions may mediate adverse maternal milieu outcomes. Successful interventions improving pregnancy outcomes have involved trials with one-on-one counseling and elicited approaches such as an intervention toolbox where topics are personalized to current barriers participants are facing and to adjust intervention intensity accordingly [62,63]. Techniques such as just-in-time adaptive interventions (JITAI) are adjusted over time to an individual’s changing status and context [64]. JITAI aim to provide the appropriate modality and quantity of support needed, at the right time, by promoting behavior changes associated with inactivity, smoking, and obesity [65]. Trials are only beginning to test this approach during pregnancy and show promising outcomes [66].

Novel interventions focused on optimizing maternal substrate availability and hence insulin regulation may produce profound results as there is a progressive increase in insulin resistance and lipid availability across gestation due to the need to deliver growth-promoting nutrients through the placenta [67]. Time-restricted eating is an effective therapeutic dietary pattern promoting metabolic flexibility and improving insulin sensitivity [68,69]. This approach limits the eating window to specific hours of the day to better align eating events with the circadian rhythm, without limiting caloric intake. This allows for prolonged fasting and increased substrate metabolism between day-to-day food intakes [70]. In pregnant individuals, a time-restricted eating pattern may be an advantageous strategy for enhancing metabolic health across gestation, particularly in those with risk of GDM [71]. In non-pregnant individuals, TRE significantly reduces glucose (62%), insulin (140%), triglycerides (64%), and C-reactive protein (85%), an inflammatory marker, levels compared to non-fasters [72]. While there are no randomized controlled trials testing the effects of this dietary pattern during gestation, 24% of pregnant individuals are willing to try time-restricted eating during pregnancy [73]. Yet, concerns of safety and feeling hungry remain, posing potential barriers to the implementation of time-restricted eating interventions. Indeed, there may be a risk of ketogenesis in pregnancy from fasting, yet evidence is conflicting and inconsistent [74]. The use of continuous glucose monitors (CGMs) has emerged as a promising technology assessing glucose substrate availability. Replacing self-monitoring of blood glucose (i.e., finger sticks), CGM can provide a more comprehensive evaluation of daily glycemic values. Using CGMs may be a novel and practical approach to implementing and monitoring a TRE intervention in pregnant individuals.

Women spend more than 50% of their time in sedentary behavior, which is linked to negative outcomes of the maternal milieu such as higher levels of inflammatory markers and lipids [75]. However, many intervention studies do not include reducing sedentary behavior as an outcome. Instead, many interventions involve lifestyle changes that combine diet and exercise. Individuals who follow diet and aerobic exercise interventions lasting a minimum of eight weeks see a reduction in fasting glucose (11%), insulin (15%), triglycerides (13%) and TNF- α (32%) levels compared to the control groups who neither exercise nor restrict their energy intake [76]. The American College of Obstetricians and Gynecologists’ most recent guidelines suggest 150 minutes of moderate intensity exercise per week with a mix of aerobic and strength training [77]. While pregnant individuals have reported desire to engage in physical activity at least twice a week, barriers such as feeling tired, being uncomfortable, and education on pregnancy safe exercise limit the execution of exercise across gestation [78]. Data from the US Preventive Services Task Force most recent Grade B recommendation for healthy weight and weight gain during pregnancy demonstrate that in-person behavioral counseling interventions with higher intensity physical activity (e.g. increased minutes per week or number of session) may provide the most beneficial maternal health effects regarding APOs [79]. Providing pregnant patients with activity trackers that provide real-time feedback (i.e., Fitbit) are desirable to participants and have been shown to promote daily physical activity [80,81]. Yet, previous exercise interventions in pregnancy have varied in their effectiveness, suggesting interventions that focus broadly on improving a single behavior see limited benefits [82]. Shifting towards recognizing and focusing on the reciprocal properties of activities across 24-hours (sleep, sedentary behavior, and physical activity) may provide a more holistic approach to maternal health and can better address barriers to physical activity [83,84]. Encouraging behavioral changes related to the 24-hour movement guidelines allows for more personalized interventions targeting individual areas of improvement. Similarly, guidelines for physical activity during the postpartum period aim to promote postpartum health and optimize the metabolic milieu for subsequent pregnancies, yet there remains a need to account for sedentary behavior, which could further impact the metabolic milieu [77,85].

Supporting the pregnant individual is multi-faceted and requires both a systematic and personalized approach (Figure 2). It can be done through prevention, monitoring, and interventions delivered by clinicians, registered dietitians, qualified fitness specialists, physiotherapists, and health coaches across an individual’s reproductive years creating better education and guidelines for maternal health [79]. Observational studies have demonstrated that habits formed during early conception are adhered to throughout pregnancy regardless of the potential effects on maternal health [86,87]. Among nonpregnant individuals, behavioral interventions using tailored and personalized approaches targeting health outcomes have high success rates highlighting the potential for similar success in precision interventions during preconception and gestation [88]. Technological advances over the past several years have greatly increased the ability for clinical real-time monitoring and greater personalized care. To be successful, precision obstetric care needs to be accessible. There is a need for prenatal interventions tailored specifically towards those at the greatest risk for maternal morbidity and obesity related complications – such as low-income families, underrepresented minorities, and rural populations. Intervention components including culturally sensitive messaging are urgently needed. Such interventions should be developed using feedback from focus groups and research participants [89]. Furthermore, system-level and community-based interventions for prenatal health are lacking.

Fig. 2.

Interventions targeting the maternal metabolic milieu are needed for greater success in healthy pregnancy and birth outcomes

Conclusions

The limited success of lifestyle interventions targeting GWG combined with growing evidence against the effects of excess GWG on APOs [20,90] highlights the need for a new direction among pregnancy interventions. Here we provide evidence of the benefits of precision interventions targeting the maternal metabolic milieu during pregnancy on maternal and child health outcomes and via plausible mechanisms which can be tested in translational studies involving umbilical cord MSCs. Targeting biomarkers such as glucose, insulin, triglycerides, leptin, and inflammatory markers that constitute the metabolic milieu are likely to have greater effects on parent and infant health than weight alone. Precision interventions, such as time restricted eating, or physical activity interventions can be tailored to individuals and provide personalized information contributing to timely and adequate adjustments across the relatively short gestation period. Such approaches improve participant involvement in their own care and results in greater and more equitable health outcomes across populations, irrespective of risk status at conception.