Inflammation During Pregnancy and Growth of Early School‐Aged Children in Rural Nepal
Authors: Panjwani Anita A , Schulze Kerry , Wu Lee , West Keith P , Christian Parul 
Published: June 2021

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.

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‐value

Maternal 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 allocation

0.061

0.814

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‐value

Newborn

Sex (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)
0.0415

Length (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)
0.0184

Six weeks

Weight (kg)
4.31 (0.73)
4.19 (0.69)
0.0319
4.32 (0.7)
4.17 (0.74)
0.0118

Median 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)
0.0199

Micronutrient supplement allocation

0.903

0.607

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‐value

One 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

Caste

0.632

0.402

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 groups

Maternal Serum Inflammatory Markers in Nepalese Women During Pregnancy (N=533)

1st Trimester Mean (SD)
3rd 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)

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‐value

Weight (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 groups

Regression of Child Anthropometric Measurements on Maternal Serum High vs Low AGP and CRP (N=533)

Model 1
Model 2
Model 3
Model 4

beta
SE
p‐value
beta
SE
p‐value
beta
SE
p‐value
beta
SE
p‐value

High AGP

Delta 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
0.021

Delta weight
0.093
0.196
0.636
0.152
0.189
0.422
0.093
0.187
0.621
0.149
0.183
0.418

High CRP

Delta 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
0.923

Model 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