Inflammation During Pregnancy and Growth of Early School‐Aged Children in Rural Nepal

Objective We are showing a negative association between inflammation during pregnancy and birth size among mother‐infant pairs in rural Nepal. In the current study, we explored whether the association of inflammation in pregnancy with offspring anthropometry persisted to 6–8 years of age. Methods Our sample consisted of 533 children from the 4,130 children born to mothers in the Nepal Nutrition Intervention Project – Sarlahi (NNIPS‐3) study, a randomized controlled trial of prenatal micronutrient supplementation between 1999 and 2001. Children were measured at 6–8 years of age to examine long‐term health and nutritional outcomes. The main outcomes of this study were deltas of child growth measurements from birth to 6–8‐year follow‐up: change in height, change in HAZ, and change in weight. Linear regression was used to analyze the association of child anthropometry and maternal inflammation status during pregnancy comparing the highest vs the lower two tertiles of C‐reactive protein (CRP) and α1‐acid glycoprotein (AGP). Crude differences and those adjusted for supplement allocation and other potential confounders, including child and maternal characteristics and SES, are reported. We also assessed for interaction between birth length (and birth weight) and each inflammatory marker with the hypothesis that when children born into a possibly less inflammatory environment, they may demonstrate increased growth to “catch up” to their normally developing peers. Results There was no difference found in the anthropometric measurements in children at the 6–8‐year follow‐up by maternal pregnancy CRP or AGP status. However, there was a 0.26 increase in the mean change in HAZ score from birth to follow‐up among children born to mothers with high AGP compared to normal AGP. This association was significant in simple regression (p=0.010) and remained significant in the fully adjusted model accounting for gestational and follow‐up age, sex of the child, maternal supplementation arm from the original trial and child supplementation arm from a second trial, maternal characteristics, and socioeconomic status (beta: 0.23, SE: 0.10, p=0.021). Interaction between birth length and AGP was not significant in these models. Conclusions Inflammation during pregnancy was not substantially associated with child growth status at 6–8 years of age. However, change in HAZ score was positively associated with elevated maternal AGP, suggesting there may have been catch‐up growth among children born to Nepalese mothers with the highest AGP concentrations throughout pregnancy compared to those with lower in utero exposure to inflammation. Thus, our hypothesis that reduced size at birth due to an inflammatory fetal environment persists into childhood held true even after adjustment of potential confounders. It is still possible there may be residual confounding we could not account for as there are a myriad of factors that contribute to child growth. Support or Funding Information Funded through grant GH614 from the Bill and Melinda Gates Foundation, Seattle WA, USA the Office of Health, Infectious Diseases and Nutrition, the US Agency for International Development, Washington DC, USA and the Sight and Life Research Institute, Baltimore, MD, USA. 1 Characteristics of Nepalese Women in Early Pregnancy and Children at Birth and Six Weeks (N=533)Normal AGP (n=356) High AGP (n=177) Normal CRP (n=356) High CRP (n=177)Maternal Characteristics Mean (SD) * Mean (SD) * p‐value Mean (SD) * Mean (SD) * p‐valueMaternal Age 23.83 (5.58) 22.07 (5.46) 0.0003 22.91 (5.55) 23.92 (5.64) 0.9749 Maternal Parity 2.41 (2.18) 1.79 (1.95) 0.0009 2.12 (2.17) 2.37 (2.13) 0.8978 MUAC at 1st trimester 21.43 (1.82) 21.63 (1.75) 0.8821 21.49 (1.76) 21.52 (1.88) 0.5923 Micronutrient supplement allocation0.0610.814 Folic acid‐Iron, total (%) 67 (18.82) 30 (16.95) 65 (18.26) 32 (18.08)Multiple micronutrient, total (%) 59 (16.57) 37 (20.90) 65 (18.26) 31 (17.51)Folic acid‐Iron‐Zinc, total (%) 98 (27.53) 30 (16.95) 89 (25.00) 39 (22.03)Vitamin A (Control), total (%) 77 (21.63) 48 (27.12) 76 (21.35) 49 (27.68)Folic acid, total (%) 55 (15.45) 32 (18.08) 61 (17.13) 26 (14.69)Child Characteristics Mean (SD) * Mean (SD) * p‐value Mean (SD) * Mean (SD) * p‐valueNewbornSex (Female), total (%) 168 (47.19) 88 (49.72) 0.582 169 (47.47) 87 (49.15) 0.715 Gestational Age (wks) 39.14 (2.94) 38.9 (2.72) 0.2748 39.19 (2.82) 38.81 (2.94) 0.0777 Breastfed after birth, total (%) ** 197 (55.34) 85 (48.02) 0.207 199 (55.90) 83 (46.89) 0.060 Weight (kg) 2.74 (0.44) 2.61 (0.39) 0.0003 2.72 (0.43) 2.65 (0.43) 0.0415Length (cm) 47.95 (2.00) 47.43 (1.80) 0.0018 47.81 (1.96) 47.69 (1.94) 0.2546 Median head circum (cm) 32.83 (1.25) 32.69 (1.18) 0.1064 32.83 (1.24) 32.70 (1.20) 0.1317 Median chest circum (cm) 31 17 (1.78) 30.59 (1.61) 0.0002 31.09 (1 74) 30.75 (1.75) 0.0184Six weeksWeight (kg) 4.31 (0.73) 4.19 (0.69) 0.0319 4.32 (0.7) 4.17 (0.74) 0.0118Median head circum (cm) 37.16 (4.94) 36.63 (1.37) 0.2597 37.16 (4.93) 36.63 (1.46) 0.0799 Median chest circum (cm) 36.80 (5.24) 36.17 (2.11) 0.6450 36.87 (5.18) 36.03 (2.34) 0.0199Micronutrient supplement allocation0.9030.607 Iron, total (%) 84 (23.60) 47 (26.55) 91 (25.56) 40 (22.60)Iron‐Zinc, total (%) 87 (24.44) 42 (23.73) 89 (25.00) 40 (22.60)Zinc, total (%) 104 (29.21) 49 (27.68) 96 (26.97) 57 (32.20)Placebo control, total (%) 81 (22.75) 39 (22.03) 80 (22.47) 40 (22.60)SES Variables Total (%) Total (%) p‐value Total (%) Total (%) p‐valueOne or more radios in household 129 (36.24) 62 (35.03) 0.784 130 (36.52) 61 (34.46) 0.641 Mother literate 104 (29.21) 57 (32.20) 0.479 113 (31.74) 48 (27.12) 0.274 Caste0.6320.402 Brahmin 46 (12.92) 22 (12.43) 50 (14.04) 18 (10.17)Chhetri 41 (11.52) 16 (9.04) 36 (10.11) 21 (11.86)Vaiysha 197 (55.34) 99 (55.93) 201 (56.46) 95 (53.67)Shudra 30 (8.43) 12 (6.78) 28 (7.87) 14 (7.91)Non‐Hindu 42 (11.8) 28 (15.82) 41 (11.52) 29 (16.38)* Unless otherwise specified ** One missing in Normal AGP and High CRP groups2 Maternal Serum Inflammatory Markers in Nepalese Women During Pregnancy (N=533)1 st Trimester Mean (SD) 3 rd Trimester Mean (SD) Average of both Trimesters Mean (SD)CRP (mg/L) 1.35 (2.04) 1.86 (2.52) 1.60 (1.72) AGP (g/L) 0.67 (0.20) 0.44 (0.18) 0.55 (0.15)3 Anthropometric Measurements of Nepalese Children at Follow‐up (Ages 6–8 years) (N=533)Normal AGP (n=356) High AGP (n=177) Normal CRP (n=356) High CRP (n=177)Measurement Mean (SD) Mean (SD) p‐value Mean (SD) Mean (SD) p‐valueWeight (kg) 18.30 (2.31) 18.26 (2.07) 0.4233 18.36 (2.34) 18.15 (2.01) 0.1597 Height (cm) 114.15 (5.48) 114.02 (5.70) 0.3988 114.14 (5.84) 114.03 (4.92) 0.4149 BMI‐for‐age Z * −1.19 (0.88) −1.15 (0.89) 0.7052 −1.14 (0.91) −1.24 (0.82) 0.1116 Height‐for‐age Z −1.77 (0.87) −1.78 (0.99) 0.4502 −1.78 (0.95) −1.77 (0.83) 0.5435 MUAC (cm) 15.38 (1.10) 15.50 (1.07) 0.8813 15.41 (1.11) 15.44 (1.05) 0.6058 Waist circ (cm) 51.19 (3.17) 51.09 (2.90) 0.3482 51.25 (3.18) 50.97 (2.86) 0.1640 Triceps SF (cm) 5.90 (1.50) 6.02 (1.35) 0.8060 5.94 (1.53) 5.94 (1.29) 0.5116 Subscap SF (cm) 4.75 (0.85) 4.77 (0.82) 0.6065 4.75 (0.84) 4.77 (0.84) 0.6356* One missing in High AGP and Normal CRP groups4 Regression of Child Anthropometric Measurements on Maternal Serum High vs Low AGP and CRP (N=533)Model 1 Model 2 Model 3 Model 4beta SE p‐value beta SE p‐value beta SE p‐value beta SE p‐valueHigh AGPDelta height 0.389 0.485 0.423 0.488 0.436 0.264 0.272 0.443 0.540 0.418 0.428 0.329 Delta HAZ score 0.257 0.100 0.010 0.241 0.099 0.015 0.209 0.099 0.036 0.231 0.099 0.021Delta weight 0.093 0.196 0.636 0.152 0.189 0.422 0.093 0.187 0.621 0.149 0.183 0.418High CRPDelta height 0.009 0.486 0.986 0.192 0.436 0.660 0.282 0.432 0.514 0.371 0.421 0.379 Delta HAZ score 0.066 0.100 0.508 0.050 0.099 0.614 0.068 0.098 0.488 0.081 0.098 0.410 Delta weight −0.137 0.196 0.485 −0.072 0.189 0.705 −0.053 0.185 0.775 −0.017 0.181 0.923Model 1: inflammatorymarker only Model 2: model 1 + gestational age of the baby, biomarker collection dates during gestation, micronutrient supplement allocation codes for mother and child, and the age of the child at 6–8 year follow up Model 3: model 2 + baby's sex, along with the mother's parity, her age, and her middle upper arm circumference during the first trimester Model 4: model 3 + SES variables including mother's literacy, radio ownership, and caste