Accelerated Longitudinal Weight Gain Among Infants With In Utero COVID-19 Exposure.

CONTEXT: Since the initial outbreak of coronavirus disease 2019 (COVID-19), a novel population of children with in utero exposure to maternal infection has emerged whose health outcomes are largely unknown. OBJECTIVE: To compare longitudinal growth trajectories among infants with vs without in utero COVID-19 exposure. METHODS: We conducted a longitudinal cohort study leveraging a prospectively enrolled perinatal biorepository among 149 infants with in utero COVID-19 exposure and 127 unexposed controls. Weight, length, and body mass index (BMI) were abstracted from health records at 0, 2, 6, and 12 months and standardized using World Health Organization growth charts. Analyses were adjusted for maternal age, ethnicity, parity, insurance, and BMI as well as infant sex, birthdate, and breastfeeding. RESULTS: Infants with in utero COVID-19 exposure vs controls exhibited differential trajectories of weight and BMI, but not length, z-score over the first year of life (study group × time interaction, P < .0001 for weight and BMI). Infants born to mothers with prenatal COVID-19 had lower BMI z-score at birth (effect size: -0.35, 95% CI -0.66 to -0.03) and greater gain in BMI z-score from birth to 12 months (effect size: 0.53, 95% CI 0.06 to 0.99). Birth weight z-score mediated a significant proportion of the relationship between COVID-19 exposure and postnatal growth (estimate ± SE, 32 ± 14%, P = .02). CONCLUSION: Infants with in utero COVID-19 exposure exhibited lower birth weight and accelerated weight gain in the first year of life, which may be harbingers of downstream cardiometabolic pathology. Further studies are needed to delineate cardiometabolic sequelae among this emerging global population.

The Role of Prenatal Psychosocial Stress in the Associations of a Proinflammatory Diet in Pregnancy With Child Adiposity and Growth Trajectories.

Importance: Prenatal psychosocial stress and nutrition may each program offspring adiposity, an important predictor of lifelong cardiometabolic health. Although increased stress and poor nutrition have been found to co-occur in pregnancy, little is known about their combined longitudinal associations in the offspring. Objective: To investigate whether the associations of the Dietary Inflammatory Index (DII) with offspring adiposity differ by prenatal stress levels and whether these associations change with age. Design, Setting, and Participants: Project Viva, a prospective prebirth cohort study of mother-child dyads in Massachusetts, included singleton children of mothers enrolled between April 1999 and July 2002, with follow-up visits at early childhood, midchildhood, and early adolescence. Data analysis was performed from October 31, 2020, to October 31, 2022. Exposures: Food frequency-derived DII score in pregnancy was the exposure. Effect modifiers included stress-related measures in pregnancy; depressive symptoms assessed using the Edinburgh Postnatal Depression Scale (EPDS), dichotomized at scores greater than or equal to 13 vs less than 13; and census tract-level social vulnerability (overall Social Vulnerability Index and its 4 main subindices), dichotomized at the 75th percentile. Main Outcomes and Measures: Overall adiposity, comprising sex- and age-standardized body mass index (BMI z), sum of subscapular and triceps skinfolds, fat mass index (FMI), and body fat percentage estimated using bioelectrical impedance analysis (BIA) and dual x-ray absorptiometry (DXA); and central adiposity, comprising waist circumference, ratio of subscapular to triceps skinfolds, and DXA-derived trunk FMI. Results: Among 1060 mother-child dyads, mean (SD) maternal age was 32.6 (4.6) years, and 811 (77%) mothers were non-Hispanic White. Mean (SD) DII score was -2.7 (1.3) units, Social Vulnerability Index level was 38th (27th) percentile, and 8% of mothers had depressive symptoms. Mean (SD) age of the children was 3.3 (0.3) years at the early childhood visit, 7.9 (0.8) years at the midchildhood visit, and 13.2 (0.9) years at the early adolescence visit. In adjusted analyses, children born to mothers in the highest (vs lowest) quartile of DII had slower decrease in BMI z scores (ß, 0.03 SD units/y; 95% CI, 0.01-0.05 SD units/y), and faster adiposity gain (eg, BIA total FMI ß, 0.11 kg/m2/y; 95% CI, 0.03-0.19 kg/m2/y) over time. Associations of prenatal DII quartiles with childhood adiposity were stronger (eg, BIA total FMI quartile 4 vs quartile 1 change in ß, 1.40 kg/m2; 95% CI, 0.21-2.59 kg/m2) among children of mothers with high vs low EPDS scores in pregnancy, although EPDS scores did not modify the change over time. Associations of prenatal DII with adiposity change over time, however, were greater among children whose mothers lived in neighborhoods with a high (BIA percentage body fat: ß, 0.55% per year; 95% CI, 0.04%-1.07% per year) vs low (ß, 0.13% per year; 95% CI, -0.20 to 0.46% per year), percentage of racial and ethnic minorities, and residents with limited English-language proficiency. Conclusions and Relevance: The findings of this cohort study suggest that it may be useful to simultaneously evaluate prenatal diet and psychosocial stress in women as targets for interventions intended to prevent excess childhood adiposity.

Maternal diet in pregnancy is associated with differences in child body mass index trajectories from birth to adolescence.

BACKGROUND: Nutrition in pregnancy and accelerated childhood growth are important predictors of obesity risk. Yet, it is unknown which dietary patterns in pregnancy are associated with accelerated growth and whether there are specific periods from birth to adolescence that are most sensitive to these associations. OBJECTIVES: To examine the extent to which 3 dietary indices in pregnancy [Dietary Inflammatory Index (DII), Alternate Healthy Eating Index for Pregnancy (AHEI-P), and Mediterranean Diet Score (MDS)] are associated with child BMI z-score (BMI-z) trajectories from birth to adolescence. METHODS: We examined 1459 mother-child dyads from Project Viva that had FFQ data in pregnancy and ≥3 child BMI-z measurements between birth and adolescence. We used linear spline mixed-effects models to examine whether BMI-z growth rates and BMI z-scores differed by quartile of each dietary index from birth to 1 mo, 1-6 mo, 6 mo to 3 y, 3-10 y, and >10 y. RESULTS: The means ± SDs for DII (range, -9 to +8 units), AHEI-P (range, 0-90 points), and MDS (range, 0-9 points) were -2.6 ± 1.4 units, 61 ± 10 points, and 4.6 ± 2.0 points, respectively. In adjusted models, children of women in the highest (vs. lowest) DII quartile had higher BMI-z growth rates between 3-10 y (ß, 0.03 SD units/y; 95% CI: 0.00-0.06) and higher BMI z-scores from 7 y through 10 y. Children of women with low adherence to a Mediterranean diet had higher BMI z-scores from 3 y through 15 y. Associations of AHEI-P with growth rates and BMI z-scores from birth through adolescence were null. CONCLUSIONS: A higher DII and a lower MDS in pregnancy, but not AHEI-P results, are associated with higher BMI-z trajectories during distinct growth periods from birth through adolescence. Identifying the specific dietary patterns in pregnancy associated with rapid weight gain in children could inform strategies to reduce child obesity.

Effect of Omega-3 Supplementation in Pregnant Women with Obesity on Newborn Body Composition, Growth and Length of Gestation: A Randomized Controlled Pilot Study.

Maternal obesity, a state of chronic low-grade metabolic inflammation, is a growing health burden associated with offspring adiposity, abnormal fetal growth and prematurity, which are all linked to adverse offspring cardiometabolic health. Higher intake of anti-inflammatory omega-3 (n-3) polyunsaturated fatty acids (PUFA) in pregnancy has been associated with lower adiposity, higher birthweight and longer gestation. However, the effects of n-3 supplementation specifically in pregnant women with overweight and obesity (OWOB) have not been explored. We conducted a pilot double-blind randomized controlled trial of 72 pregnant women with first trimester body mass index (BMI) ≥ 25 kg/m2 to explore preliminary efficacy of n-3 supplementation. Participants were randomized to daily DHA plus EPA (2 g/d) or placebo (wheat germ oil) from 10-16 weeks gestation to delivery. Neonatal body composition, fetal growth and length of gestation were assessed. For the 48 dyads with outcome data, median (IQR) maternal BMI was 30.2 (28.2, 35.4) kg/m2. In sex-adjusted analyses, n-3 supplementation was associated with higher neonatal fat-free mass (ß: 218 g; 95% CI 49, 387) but not with % body fat or fat mass. Birthweight for gestational age z-score (-0.17 ± 0.67 vs. -0.61 ± 0.61 SD unit, p = 0.02) was higher, and gestation longer (40 (38.5, 40.1) vs. 39 (38, 39.4) weeks, p = 0.02), in the treatment vs. placebo group. Supplementation with n-3 PUFA in women with OWOB led to higher lean mass accrual at birth as well as improved fetal growth and longer gestation. Larger well-powered trials of n-3 PUFA supplementation specifically in pregnant women with OWOB should be conducted to confirm these findings and explore the long-term impact on offspring obesity and cardiometabolic health.

Maternal glucose tolerance in pregnancy and child cognitive and behavioural problems in early and mid-childhood.

BACKGROUND: Maternal abnormal glucose tolerance during pregnancy may adversely affect offspring cognition and behaviour, but few prospective studies investigated this association at multiple points throughout childhood. OBJECTIVES: We hypothesised that maternal abnormal glucose tolerance is associated with child cognitive and behavioural outcomes in early and mid-childhood. METHODS: We examined the associations of maternal abnormal glucose tolerance at 26-28 weeks of pregnancy with offspring cognitive and behavioural scores in 1421 children in the Project Viva pre-birth cohort. In early (mean 3.3 years) and mid-childhood (mean 7.9 years), we measured child cognition using validated instruments, the Kaufman Brief Intelligence Test, Wide Range Assessment of Memory and Learning, and the Wide Range Assessment of Visual Motor Abilities (WRAVMA); we assessed parent- and teacher-rated behavioural outcomes with the Strengths and Difficulties Questionnaire and the Behavioural Rating Inventory of Executive Function. We used linear regression models adjusted for potential confounders (maternal race/ethnicity, pre-pregnancy BMI, intelligence, age, parity, smoking status, education, and household income at enrolment, in addition to child's sex and age at assessment). RESULTS: Of 1421 mothers, 69 (4.9%) had gestational diabetes mellitus, 43 (3.0%) impaired glucose tolerance, 122 (8.6%) isolated hyperglycaemia, and 1187 (83.5%) normal glucose tolerance. Offspring born to women with gestational diabetes mellitus had lower total WRAVMA scores (-3.09 points; 95% CI -6.12, -0.05) in early childhood compared with offspring of women with normal glucose tolerance. None of the abnormal glucose tolerance categories during pregnancy were associated with any of the cognitive outcomes (verbal, non-verbal, and visual motor scores) or behavioural measures in mid-childhood. CONCLUSIONS: Children born to mothers who had gestational diabetes mellitus had slightly lower scores on one cognitive test in early childhood. We found no evidence to support that maternal abnormal glucose tolerance was associated with cognitive or behavioural development in mid-childhood.

A Graded Approach to Intravenous Dextrose for Neonatal Hypoglycemia Decreases Blood Glucose Variability, Time in the Neonatal Intensive Care Unit, and Cost of Stay.

OBJECTIVE: To determine associations between a graded approach to intravenous (IV) dextrose treatment for neonatal hypoglycemia and changes in blood glucose (BG), length of stay (LOS), and cost of care. STUDY DESIGN: Retrospective cohort study of 277 infants born at ≥35 weeks of gestation in an urban academic delivery hospital, comparing the change in BG after IV dextrose initiation, neonatal intensive care unit (NICU) LOS, and cost of care in epochs before and after a hospital protocol change. During epoch 1, all infants who needed IV dextrose for hypoglycemia were given a bolus and started on IV dextrose at 60 mL/kg/day. During epoch 2, infants received IV dextrose at 30 or 60 mL/kg/day based on the degree of hypoglycemia. Differences in BG outcomes, LOS, and cost of hospital care between epochs were compared using adjusted median regression. RESULTS: In epoch 2, the median (IQR) rise in BG after initiating IV dextrose (19 [10, 31] mg/dL) was significantly lower than in epoch 1 (24 [14,37] mg/dL; adjusted ß = -6.0 mg/dL, 95% CI -11.2, -0.8). Time to normoglycemia did not differ significantly between epochs. NICU days decreased from a median (IQR) of 4.5 (2.1, 11.0) to 3.0 (1.5, 6.5) (adjusted ß = -1.9, 95% CI -3.0, -0.7). Costs associated with NICU hospitalization decreased from a median (IQR) $14 030 ($5847, $30 753) to $8470 ($5650, $19 019) (adjusted ß = -$4417, 95% CI -$571, -$8263) after guideline implementation. CONCLUSIONS: A graded approach to IV dextrose was associated with decreased BG lability and length and cost of NICU stay for infants with neonatal hypoglycemia.

Role of maternal glucose metabolism in the association between maternal BMI and neonatal size and adiposity.

BACKGROUND/OBJECTIVE: One potential mechanism by which maternal obesity impacts fetal growth is through hyperglycemia below the threshold for gestational diabetes. Data regarding which measures of maternal glucose metabolism mediate this association is sparse. The objectives of this study were to (i) quantify the associations of maternal pre-pregnancy body mass index (BMI) with neonatal size and adiposity and (ii) examine the role of markers of maternal glucose metabolism as mediators in these associations. SUBJECTS/METHODS: This is a secondary analysis of 6,379 mother-infant dyads from the Hyperglycemia and Adverse Pregnancy Outcome cohort. Markers of glucose metabolism, including plasma glucose and c-peptide values, Stumvoll first-phase estimate, modified Matsuda index, and oral disposition index were measured and calculated from an oral glucose tolerance test (OGTT) between 24- and 32-weeks' gestation. We calculated the direct effect of maternal BMI category, measured at the time of the OGTT and regressed to estimate pre-pregnancy BMI, on neonatal (1) birth weight (BW), (2) fat mass (FM), (3) % body fat (BF%), and (4) sum of skinfold thickness (sSFT). We then calculated the indirect effect of BMI category on these measures through markers of glucose metabolism. RESULTS: Maternal BMI category was positively associated with neonatal BW, FM, BF%, and sSFT. Additionally, mothers who were overweight or obese had higher odds of delivering an infant with BW, FM, BF%, or sSFT >90th percentile. Fasting glucose and c-peptide values were the strongest mediators in the linear associations between maternal BMI category and neonatal size and adiposity. CONCLUSIONS: Maternal overweight and obesity were associated with higher odds of neonatal BW and adiposity >90th percentile. Fasting measures of glucose metabolism were the strongest mediators of these associations, suggesting that future studies should investigate whether incorporation of these markers in pregnant women with obesity may improve prediction of neonatal size and adiposity.

Type of feeding provided with dextrose gel impacts hypoglycemia outcomes: comparing donor milk, formula, and breastfeeding.

OBJECTIVE: Examine neonatal hypoglycemia (NH) outcomes based on type of feeding provided with first dextrose gel. STUDY DESIGN: Retrospective matched cohort study of 99 infants ≥35 weeks gestational age who received dextrose gel in combination with breastfeeding, formula feeding, or donor milk feeding for NH. The exposure was feeding type. The outcomes were: (1) median change in blood glucose (Δ BG) concentration after first gel, (2) odds of second gel, and (3) odds of recurrent NH. RESULTS: Median Δ BG was greater in formula (17.0 mg/dL) and donor milk (19.0 mg/dL) fed vs. breastfed infants (7.0 mg/dL). Donor milk and formula feeding were both associated with lower odds of second gel and recurrent NH. Associations remained significant in late-preterm infants, but only formula feeding remained significant in full-term infants. CONCLUSIONS: Formula and donor milk feedings both raised blood sugar concentrations, but the impact differed by gestational age.

Incorporating dextrose gel and feeding in the treatment of neonatal hypoglycaemia.

OBJECTIVES: To determine the impact of incorporating dextrose gel in the treatment of neonatal hypoglycaemia (NH) and the role of feeding type in NH outcomes. STUDY DESIGN: We conducted a retrospective analysis of 2688 infants >35 weeks' gestation who were screened for NH before and after implementation of a clinical guideline for NH evaluation and treatment. We analysed the proportion of infants who required intravenous dextrose for NH before and after guideline implementation, the change in blood glucose concentrations with gel by feeding type and the odds of successful NH treatment with gel and feeding by feeding type. RESULTS: Following implementation of the guideline, a lower proportion of infants required intravenous dextrose for NH treatment (8.6% (60 infants) before guideline vs. 5.6% (112 infants) after guideline (p=0.007)). The median rise in blood glucose concentration with gel administration in the entire cohort was 0.61 mmol/L (11 mg/dL) (IQR 0.28-1.06 mmol/L (5-19 mg/dL)). Blood glucose concentration of formula-fed infants rose more in response to feeding and gel than breastfed infants (p≤0.0001). Formula feeding was associated with a lower odds of recurrent hypoglycaemia, as defined by requiring a second gel, in a fully adjusted model. Specifically, in infants with a pregel blood glucose of 2.00-2.17 mmol/L (36-39 mg/dL), formula feeding with gel was associated with a lower odds of recurrent hypoglycaemia. CONCLUSIONS: Dextrose gel is an effective tool in the treatment of NH. An infant's pregel blood glucose concentration may be helpful in guiding decisions around type of feeding provided.

Maternal obesity and cesarean section delivery: additional risk factors for neonatal hypoglycemia?

OBJECTIVES: To determine (1) whether higher maternal body mass index (BMI) and Cesarean (C) Section mode of delivery are associated with neonatal hypoglycemia (NH) and (2) whether timing of NH onset differs by risk factors. STUDY DESIGN: Retrospective cohort study (n = 4602) to determine the odds of NH, NH requiring IV dextrose and timing of NH onset among infants with established and plausible (BMI and C-section) risk factors. RESULT: Infants born to class III obese mothers had higher odds of NH (OR 1.3, 95% CI 1.0-1.8) and of requiring IV dextrose (OR 2.2, 95% CI 1.2-3.9). Infants born via C-section had higher odds of requiring IV dextrose (OR 1.4, 95% CI 1.1-1.9). Infants who were delivered to high BMI mothers and by C-section developed NH earlier than the reference group. CONCLUSION: Determining the predictors and timing of NH onset may help develop tailored evaluation and management strategies for at-risk neonates.

Correction: Maternal obesity and offspring cognition: the role of inflammation.

Following publication of this article, the authors noted that the name of the last author was incorrectly displayed as 'Sen Sarbattama'. This authors name has now been corrected to 'Sarbattama Sen'. This has been corrected in both the PDF and HTML versions of the article.

Maternal obesity and offspring cognition: the role of inflammation.

BACKGROUND: High pre-pregnancy body mass index (ppBMI) has been linked to neurodevelopmental impairments in childhood. However, very few studies have investigated mechanisms in human cohorts. METHODS: Among 1361 mother-child pairs in Project Viva, we examined associations of ppBMI categories with the Peabody Picture Vocabulary Test III [PPVT] and Wide Range Assessment of Visual Motor Abilities [WRAVMA] in early childhood (median 3.2y); and with the Kaufman Brief Intelligence test (KBIT) and WRAVMA in mid-childhood (7.7y). We further examined the role of maternal inflammation in these associations using the following measures from the 2nd trimester of pregnancy: plasma C-reactive protein (CRP), dietary inflammatory index (DII), and plasma omega-6 (n-6): n-3 fatty acid ratio. RESULTS: Children of mothers with prenatal obesity (ppBMI ≥30 kg/m2) had WRAVMA scores that were 2.1 points lower (95% CI: -3.9, -0.2) in early childhood than children of normal weight mothers (ppBMI 18.5-<25 kg/m2), in a covariate adjusted model. This association was attenuated when we additionally adjusted for maternal CRP (ß -1.8 points; 95% CI: -3.8, 0.2) but not for other inflammatory markers. PpBMI was not associated with other cognitive outcomes. CONCLUSION: Maternal inflammation may modestly mediate the association between maternal obesity and offspring visual motor abilities.

Maternal Pre-Pregnancy Obesity Attenuates Response to Omega-3 Fatty Acids Supplementation During Pregnancy.

Maternal obesity is associated with adverse offspring outcomes. Inflammation and deficiency of anti-inflammatory nutrients like omega(n)-3 polyunsaturated fatty acids (PUFA) may contribute to these associations. Fetal supply of n-3 PUFA is dependent on maternal levels and studies have suggested that improved offspring outcomes are associated with higher maternal intake. However, little is known about how maternal obesity affects the response to n-3 supplementation during pregnancy. We sought to determine (1) the associations of obesity with PUFA concentrations and (2) if the systemic response to n-3 supplementation differs by body mass index (BMI). This was a secondary analysis of 556 participants (46% lean, 28% obese) in the Maternal-Fetal Medicine Units Network trial of n-3 (Docosahexaenoic acid (DHA) + Eicosapentaenoic acid (EPA)) supplementation, in which participants had 2g/day of n-3 (n = 278) or placebo (n = 278) from 19 to 22 weeks until delivery. At baseline, obese women had higher plasma n-6 arachidonic acid concentrations (ß: 0.96% total fatty acids; 95% Confidence Interval (CI): 0.13, 1.79) and n-6/n-3 ratio (ß: 0.26 unit; 95% CI: 0.05, 0.48) compared to lean women. In the adjusted analysis, women in all BMI groups had higher n-3 concentrations following supplementation, although obese women had attenuated changes (ß = -2.04%, CI: -3.19, -0.90, interaction p = 0.000) compared to lean women, resulting in a 50% difference in the effect size. Similarly, obese women also had an attenuated reduction (ß = 0.94 units, CI: 0.40, 1.47, interaction p = 0.046) in the n-6/n-3 ratio (marker of inflammatory status), which was 65% lower compared to lean women. Obesity is associated with higher inflammation and with an attenuated response to n-3 supplementation in pregnancy.

Maternal BMI, Mid-pregnancy Fatty Acid Concentrations,and Perinatal Outcomes.

PURPOSE: Maternal body mass index (BMI) and systemic fatty acid (FA) concentrations affect inflammatory balance in pregnancy and play a key role in fetal growth and well-being. Little is known about how maternal BMI may affect the association between key FA concentrations and neonatal outcomes. The objective of this study was to examine the associations between the maternal omega (n)6:n3 FA ratio and neonatal outcomes according to maternal pre-pregnancy BMI category. METHODS: This study is a secondary analysis of the Maternal-Fetal Medicine Units Network randomized controlled trial of omega-3 FA supplementation to prevent recurrent preterm birth. At consent (16-22 weeks of pregnancy), women were randomized to either the intervention arm (2g of n3 FAs) or the control arm (placebo). For the present analysis, the primary exposure was the ratio of proinflammatory to anti-inflammatory (n6:n3) FAs at 25 to 28 weeks of pregnancy. The primary outcome was fetal growth as measured by using birth-weight-for-gestational-age z score, birth-length-for-gestational-age z score, and head-circumference-for-gestational-age z score. BMI categories were defined as lean (18.5-24.9 kg/m²) and overweight/obese (OWOB) (≥25.0 kg/m²). Final analysis was stratified according to BMI and adjusted for education, race, parity, smoking status, total fish intake at the time of the blood draw, and number of days in the study at the time of delivery. FINDINGS: A total of 440 participants were included in this analysis; 49% were lean, and 51% were OWOB. After adjustment for covariates, a higher maternal n6:n3 FA ratio was associated with impaired fetal growth (birth-weight-for-gestational-age z score, ß = -0.04 per unit increase in n6:n3; 95% CI, -0.07 to -0.01), 1day shorter length of gestation (ß = -0.14 week; 95% CI, -0.27 to -0.01), higher incidence of neonatal respiratory distress syndrome (odds ratio, 1.37; 95% CI, 1.04 to 1.80), and increased length of neonatal hospital stay (ß = 0.29 day; 95% CI, 0.003 to 0.58) in OWOB, but not lean, participants. IMPLICATIONS: Higher maternal inflammation during pregnancy, as measured by using the n6:n3 FA ratio, may be a marker of adverse perinatal and neonatal outcomes, particularly among OWOB women.