Impact of maternal nutritional interventions on short and long

term health, survival, and function

Parul Christian, DrPH, MSc Johns Hopkins Bloomberg School of Public Health, Baltimore, USA

CORE Workshop Baltimore, Apr 24, 2013

Short-term Outcomes

Birth outcomes ◦ Birth weight/size; fetal growth ◦ Gestational age ◦ Stillbirth and perinatal mortality

Neonatal and infant morbidity and mortality

Birth weight, FGR and preterm birth

Birth weight is a cumulative measure of intrauterine growth and gestational age ◦ Low birth weight defined as <2500 g ◦ Birth weight is one of the leading factors

influencing subsequent health and survival in low income countries where 90% of the 250 million low birth weight babies are born each year

Underlying causes of LBW are ◦ FGR - Fetal growth restriction (small-for-gestational

age, SGA defined as weight < 10th percentile of standard for a given GA) ◦ Preterm birth (GA< 37 wk)

4

Systematic literature review & Meta-analysis - Included 5 LMIC studies - 126,176 pregnant women Apparent dose response LIMITATIONS -No indication of etiology of anemia (iron deficiency, malaria, HIV, etc) - Timing of anemia in pregnancy

Moderate-Severe Anemia RR of SGA 1.53 (1.24-1.87)

LBW and preterm among adolescents

Gibbs et al, Pediatr Perinatal Epi 2012

Preg

Non-preg

Baseline

1y follow-up

(∆)

Baseline

1y follow-up

(∆)

Between group difference in ∆, p-value

Height (cm) MUAC (cm) Mean ± SD

149.2 ± 5.4

149.2 ± 5.3

-0.05 ± 0.72

149.4 ± 5.1

149.7 ± 5.0

0.29 ± 0.82a

<0.001

a. Baseline and follow-up measurements being significantly different with p<0.001 using a paired t-test

<0.001

23.4 ± 1.8

22.7 ± 1.8

-0.65 ± 1.11a

23.2 ± 2.0

23.5 ± 2.0

0.28 ± 0.90a

<0.001

BMI (kg/m2)

19.3 ± 1.7

19.0 ± 1.7

-0.35 ± 1.17a

19.0 ± 2.0

19.3 ± 2.0

0.29 ± 0.98a

Rah et al; J Nutr 2008

Influence of early pregnancy on growth and adolescent nutritional status in rural Bangladesh

Subramanian et al; PlosOne 2011

Height of Nations: Patterns among women in 54 LMIC

Maternal supplementation in pregnancy to reduce SGA and LBW

Balanced energy and protein (food) (Imdad & Bhutta, Pediatr Peri Epi 2012)

◦ 74 g overall increase in birth weight; 100 g in malnourished women ◦ 44% reduction in SGA

Iron w/wo folic acid (Imdad & Bhutta, Pediatr Peri Epi 2012)

◦ 20% reduction in LBW

Prevalence of micronutrients deficiencies in early pregnancy in rural Nepal

61.1

39.8

0.7

11.1

28.3

40.3

31.8

37.432.8

13.9

40.2

0

20

40

60

%

(Jiang et al; J Nutr 2005)

Multiple micronutrient supplementation and birth weight

Ramakrishnan et al; Pediatr Peri Epi 2012

Multiple micronutrient supplementation and risk of SGA

Ramakrishnan et al; Pediatr Peri Epi 2012

Long-term Outcomes

Linear and ponderal growth in childhood Long term survival Cardiometabolic health ◦ Metabolic syndrome

Cognition and motor function

Developmental Origins of Health and Disease - DOHaD

Previously known as the “Barker’s” or “Early/Fetal Origins” Hypothesis

Early life nutritional and environmental factors may impact later life disease risk

Most of the focus has been on the association between size at birth and the risk of cardiovascular disease and type 2 diabetes in adulthood

Risk of CHD by birth weight

Gluckman and Hanson; 2005

Odds ratios for impaired glucose tolerance or Type II diabetes among 64 yr old men in Hertfordshire (adjusted for adult BMI)

Odds ratios for metabolic syndrome among men in Hertfordshire (adjusted for adult BMI)

Hales & Barker, 2001

DOHaD Concepts

Thrifty Genotype (Neel, 1962)

Thrifty Phenotype (Hales & Barker, 1992)

Developmental plasticity Programming or Developmental Induction (Nathanielsz

1999) Predictive adaptive response (Gluckman & Hanson, 2005)

Not just “fetal” but postnatal environment is important

Birth weight is an inadequate marker of prenatal etiologic pathways

Hales & Barker, 2001

“The Thrifty Phenotype”

Match-Mismatch theory of metabolic disease

Gluckman et al, Am J Hum Biol, 2007

Long term Consequences - Growth and body composition - Child survival - Child cardiometabolic risk

Maternal food supplementation and CVD risk in 11-17 y old Gambian offspring

Hawkesworth et al; AJCN 2011

Maternal calcium supplementation and CVD risk in11-17 y old Gambian offspring

Hawkesworth et al; AJCN 2011

Antenatal MMN supplementation effects on children’s weight and size at 2 years of age in Nepal

IFA (n=453) Mean (SD)

MMN (n=462) Mean (SD)

Difference (95% CI) p-value

WAZ -1.76 (0.98) -1.63 (1.08) 0.14 (0.001, 0.27) 0.048

HAZ -2.28 (1.06) -2.20 (1.12) 0.08 (-0.06, 0.22) 0.048

WHZ -0.40 (1.05) -0.28 (1.12) 0.12 (-0.02, 0.26) 0.097

HC (cm) 46.40 (1.43) 46.64 (1.49) 0.24 (0.06, 0.43) <0.05

BP (mmHg) 101.9 (17.4) 99.4 (13.7) -2.5 (-0.5, -4.6) <0.05

Vaidya et al; Lancet 2008

Nepal Study and Interventions(1999-2001)

A double-masked, controlled, cluster randomized trial of antenatal and postnatal micronutrient supplementation to examine impact on birth outcomes and infant survival

5 supplement groups: ◦ C Vitamin A (Control) ◦ FA VA + Folic acid ◦ FAFe Folic Acid and Iron ◦ FAFeZn Folic acid, Iron and Zinc ◦ MM Multiple micronutrient

A cross-sectional follow-up was conducted in 2006-2008 to examine growth, survival, and biomarkers of cardiometabolic risk in the offspring at 6-8 y of age

Christian et al; AJE 2009

Impact of antenatal micronutrient supplementation on child survival through 7 y of age: Nepal

Anthropometry of children at birth and at follow-up

Measure Birth 6-8 y old Mean (SD)

Weight (kg) 2.64 (0.42) 18.05 (2.33)

Length / height (cm) 47.37 (2.26) 113.49 (5.50)

Weight for age z-score -1.52 (1.04) -2.09 (0.89)

Length for age z-score -1.19 (1.11) -1.90 (0.88)

Weight for length z-score -1.01 (1.11) --

BMI for age z-score -1.49 (1.11) -1.22 (0.86)

*Z-scores calculated using WHO growth standard for children <5 y (WHO 2006) and school-aged children (de Onis 2007)

Effect of maternal supplementation on child anthropometry at 6-8 y of age

Control FA FAFe FAFeZn MM

n=701 n=630 n=641 n=663 n=721

Mean (SD) Difference (95%CI)2

Height (cm) 113.3 (5.4) 0.3 (-0.3,0.9) -0.0 (-0.6,0.6) 0.6 (0.0, 1.3)* -0.1 (-0.7,0.5)

Weight (kg) 18.0 (2.2) 0.0 (-0.3, 0.3) -0.0 (-0.3, 0.3) 0.1 (-0.2, 0.4) -0.1 (-0.4, 0.2)

BMI (kg/m2) 14.0 (1.1) -0.0 (-0.2, 0.1) -0.0 (-0.2, 0.1) -0.1 (-0.2, 0.0) -0.1 (-0.2, 0.1)

Waist circ. (cm) 51.2 (3.0) -0.0 (-0.4, 0.4) 0.0 (-0.4, 0.4) -0.1 (-0.5, 0.3) -0.1 (-0.5, 0.3)

MUAC (cm) 15.4 (1.1) 0.0 (-0.1, 0.2) -0.0 (-0.2, 0.1) -0.0 (-0.2, 0.1) 0.0 (-0.1, 0.2)

Difference from control, adjusted for the age of the child at follow-up and the design effect using a GEE linear regression model. Height and weight models additionally adjusted for birth length and birth weight, respectively.* p<0.05, difference relative to the control.

Stewart et al; AJCN 2009

Differences in triceps and subscapular skinfolds and arm fat area among children 6-8 y by treatment

-.4

-.2

0

.2

Arm

fat a

rea

diffe

renc

e (c

m2)

-.4

-.2

0

.2

Ski

nfol

d th

ickn

ess

diffe

renc

e (m

m)

TSF SSF AFA.

Folic acidFolic acid-iron

Folic acid-iron-zincMultiple micronutrient

Maternal supplement group

-0.25 mm (-0.44, -0.06) -0.20 mm (-0.33, -0.06) -0.18 cm2 (-0.34, -0.01)

Stewart et al; AJCN 2009

0

20

40

60

80

100

Mea

n bl

ood

pres

sure

(mm

Hg)

Control FA FAFe FAFeZn MM

4

4.5

5

5.5

Mea

n H

bA1c

(%)

Control FA FAFe FAFeZn MM0

.1

.2

.3

.4

.5

Med

ian

HO

MA

-IR

Control FA FAFe FAFeZn MM

HbA1c

Blood Pressure

Insulin resistance (HOMA)

▬▬ Systolic

▬ Diastolic

The risk of metabolic syndrome by maternal supplement group

Control FA FAFe FAFeZn MM

n (%) 75 (11.7) 47 (8.1) 74 (12.2) 70 (11.4) 80 (11.9)

OR (95% CI)1 1.00 0.63*

(0.41,0.97) 1.02

(0.70,1.49) 0.95

(0.65,1.40) 1.00

(0.69,1.45)

1 Adjusted for child age at follow-up, and the design effect and for fasting status

Stewart et al; J Nutr 2009

1.2

0.4

0.6

0.8

1.0

Odd

s ra

tio

FA FAFe FAFeZn MM

The risk of microalbuminuria (MA/CR≥30 mg/g) by maternal supplement group

The risk of microalbuminuria (microalbumin/creatinine ratio ≥30 mg/g. Odds ratios and 95% CI calculated adjusting for the design effect and child age at follow-up using a GEE logistic model.

0.56 (0.33, 0.93)

0.77 (0.49, 1.22)

0.53 (0.32, 0.89)

0.70 (0.44, 1.11)

Stewart et al; J Nutr 2009

Long term Consequences - Child cognition and motor function

1Using multivariate regression with boot strapping to estimate 95% confidence interval adjusted for design effect; 2Bonferroni adjusted p-values to adjust for multiple comparisons; 3Using multivariate regression with boot strapping to estimate 95% confidence interval adjusted for design effect and adjusted for child age, sex, ever sent to school, asset score, milk and dairy intake, meat, chicken and fish intake, lower respiratory infection, diarrhea/dysentery in the past week 4 P-value for the overall treatment effect using Wilks’ lamda and Lawley-Hotelling trace test derived from the MANOVA with Bonferroni correction applied to the p-values

Differences in test scores in the maternal iron-folic acid group relative to control

Iron-folic acid Adj diff (95% CI)3

p-value3

UNIT 2.38 (0.06, 4.70) 0.04

Failure Stroop test -0.14 (-0.23, -0.04) 0.005

Backward digit test 0.36 (0.01, 0.71) 0.02

% correct no_go -0.54 (-7.44, 6.35) 0.88

MABC -1.47 (-3.06, 0.12) 0.07

Finger tapping test 2.05 (0.87, 3.24) 0.001

P-value4 0.002

Christian et al; JAMA 2010

Discussion

Nutritional interventions during pregnancy such as food and micronutrient supplementation have been shown to impact fetal growth although evidence for an effect on gestational duration is limited

Evidence of benefit of preconceptional and early pregnancy interventions is limited – future research is urgently needed

The need for a life-course approach for intervening is reflected in the emphasis on the first 1000 days, but should be expanded perhaps to -365 days

Discussion In LMICs increasing rates of overweight and

obesity among pregnant women and associated risks of pregnancy complications and adverse birth outcomes are of concern

In countries undergoing rapid nutrition transition, the impact of nutritional advice and counseling for appropriate weight gain, activity levels and other life style factors, and adequate nutrient intakes during pregnancy need further evaluation

Long term cohort follow-ups are needed to evaluate the impact of early life interventions on long term cognitive function and cardiometabolic health