Impact of a package of health, nutrition, psychosocial support, and WaSH interventions delivered during preconception, pregnancy, and early childhood periods on birth outcomes and on linear growth at 24 months of age: factorial, individually randomised controlled trial

Abstract Objective To determine the effect of integrated and concurrent delivery of health, nutrition, water, sanitation and hygiene (WaSH), and psychosocial care interventions during the preconception period alone, during pregnancy and early childhood, and throughout preconception, pregnancy, and early childhood on birth outcomes and linear growth at 24 months of age compared with routine care. Design Individually randomised factorial trial. Setting Low and middle income neighbourhoods of Delhi, India. Participants 13 500 women were randomised to receive preconception interventions (n=6722) or routine care (n=6778). 2652 and 2269 pregnant women were randomised again to receive pregnancy and early childhood interventions or routine care. The analysis of birth outcomes included 1290 live births for the preconception, pregnancy, and early childhood interventions (group A), 1276 for the preconception intervention (group B), 1093 for the pregnancy and early childhood interventions (group C), and 1093 for the control (group D). Children aged 24 months by 30 June 2021 were included in the 24 month outcome analysis (453 in group A, 439 in B, 293 in C, and 271 in D). Interventions Health, nutrition, psychosocial care and support, and WaSH interventions were delivered during preconception, pregnancy, and early childhood periods. Main outcome measures The primary outcomes were low birth weight, small for gestational age, preterm, and mean birth weight. At 24 months, the outcomes were mean length-for-age z scores and proportion stunted. Three prespecified comparisons were made: preconception intervention groups (A+B) versus no preconception intervention groups (C+D); pregnancy and early childhood intervention groups (A+C) versus routine care during pregnancy and early childhood (B+D) and preconception, pregnancy, and early childhood interventions groups (A) versus control group (D). Results The proportion with low birth weight was lower in the preconception intervention groups (506/2235) than in the no preconception intervention groups (502/1889; incidence rate ratio 0.85, 98.3% confidence interval 0.75 to 0.97; absolute risk reduction −3.80%, 98.3% confidence interval −6.99% to −0.60%). The proportion with low birth weight was lower in the pregnancy intervention groups (502/2096) than in the no pregnancy intervention groups (506/2028) but the upper limit of the confidence interval crossed null effect (0.87, 0.76 to 1.01; −1.71%, −4.96% to 1.54%). There was a larger effect on proportion with low birth weight in the group that received interventions in the preconception and pregnancy periods (267/1141) compared with the control group (267/934; 0.76, 0.62 to 0.91; −5.59%, −10.32% to −0.85%). The proportion stunted at 24 months of age was substantially lower in the pregnancy and early childhood intervention groups (79/746) compared with the groups that did not receive these interventions (136/710; 0.51, 0.38 to 0.70; −8.32%, −12.31% to −4.32%), and in the group that received preconception, pregnancy, and early childhood interventions (47/453) compared with the control group (51/271; 0.49, 0.32 to 0.75; −7.98%, −14.24% to −1.71%). No effect on stunting at 24 months was observed in the preconception intervention groups (132/892) compared with the no preconception intervention groups (83/564). Conclusions An intervention package delivered during preconception, pregnancy, and early childhood substantially reduced low birth weight and stunting at 24 months. Pregnancy and early childhood interventions alone had lower but important effects on birth outcomes and 24 month outcomes. Preconception interventions alone had an important effect on birth outcomes but not on 24 month outcomes. Trial registration Clinical Trial Registry—India CTRI/2017/06/008908.


WaSH
Provision of water filters, hand washing stations, water storage bottles, soap and disinfectants and counselling

PSYCHOSOCIAL SUPPORT
Screen for depressive symptoms using PHQ-9 questionnaire Counselling by study psychologist if PHQ score 10. Refer to psychiatrist if PHQ-9 score 15 and/or suicidal ideation.
Promotion of positive thinking and problem-solving skills Screen for substance abuse and exposure to second-hand smoke and alcohol use in husbands and counsel *Composition given at the end † Observed intake Electronic monitoring system for tracking women with problems to support them for achieving intervention compliance across all domains.

0-6 months: Mothers
*Composition given at the end † Observed intake Electronic monitoring system for tracking women with problems to support them for achieving intervention compliance across all domains.

HEALTH
Facilitate hospital visit at 6 weeks postpartum and encourage compliance to supplements.
Routine postnatal and early childhood care

NUTRITION
Locally-prepared snacks daily and milk † 6 days a week (600 kcal, 20 g protein).

WaSH
Continuation of all the WaSH interventions provided during pregnancy (water filters, water storage bottles, hand washing station, soap and disinfectants) and counselling on handwashing and hygiene practices (bathing the infant regularly, keeping the infant's surroundings clean, safe disposal of infant's feces, and handwashing before handling the baby).

PSYCHOSOCIAL CARE
Promotion of positive thinking and problem-solving skills Screening mothers for depressive symptoms and management as required Counselling by study psychologist if PHQ score 10. Referral to psychiatrist if PHQ-9 score 15 and/or suicidal ideation.

0-6 months: Infants
Electronic monitoring system for tracking infants with problems to support them for achieving intervention compliance across all domains.

6-24 months: Children Intervention group Control ‡ NUTRITION
Effective counselling on initiation of complementary feeding by preparing the mother and family 1-2 weeks prior to 6 months of infant's age Initiation of complementary feeding at 6 months of age and teaching the mother by demonstrations on how to prepare foods at home which can be fed easily to the child 6 Routine early childhood care

NUTRITION
Initiation of breastfeeding (BF) within the first hour of birth.
Early lactation counselling for all mothers to prevent BF problems, resolution anytime during the first 6 months.
Counsel on exclusive BF till 6 months of age emphasizing exclusivity of BF from 3 up to 6 months of age.
Growth monitoring and management of IWG Weight measurement on day 14 and thereafter monthly to identify IWG (<15 th centile as per WHO Growth Velocity Standards, i.e. weight gain <20 g/day between ages day 14 to month 2; <15 g/d for months 3 and 4; <10 g/d for months 5 to 6) for all term infants. Management through: lactation counselling, screening and treatment of infections, facility based management of IWG by senior paediatrician at Safdarjung Hospital after 15 days of continued efforts of lactation support and no medical cause is identified Additional support for LBW babies and preterm babies (even if not LBW). BF support by lactation counselling through home visits in the first three months (biweekly in first month, weekly in second and third month, monthly from fourth to sixth month).
Offer expressed breastmilk feeding for preterm babies only after a breastfeed.
Extended support for preterms (through assessment of feeding, growth and investigations within 4-6 weeks after birth) after discharge and ensuring that the advice given at the hospital is followed at home.

Support kangaroo mother care at home
Vitamin D 400 IU daily for all infants up to 6 months Iron supplementation up to 6 months: VLBW from 2 weeks, LBW from 6 weeks Routine postnatal and early childhood care

HEALTH
Educating mother and other family members to identify danger signs and in early care seeking for illness.
Facilitating referral to health facility for infants with any danger signs or illness requiring facility-based management.
Counselling on timely immunisation

PSYCHOSOCIAL CARE
Counselling, demonstration and practice sessions for mothers at each home visit on early child play and responsive care.
Identification of delayed development and timely referral for further management months onwards. Provision of daily food supplement with 125 kcal, 2.5 g protein up to 12 months and 250 kcal energy and 5 g protein from 12 to 24 months that includes 80 to 100% RDA of micronutrients Counselling for intake of home-based food Counselling and demonstration of responsive feeding to mother and family members IFA (10 mg iron and 100 mcg folic acid) supplementation daily up to 24 months Lactation counselling for supporting continued BF till 24 months of age Growth monitoring (weight and length monthly); management of IWG (<25 th centile as per WHO Growth Velocity Standards) by providing additional food supplements in form of snacks (125 kcal and 2.5 g protein up to 12 months, and 250 kcal energy and 5 g protein from 12 to 24 months) till child has adequate weight gain for 2 consecutive months; nutritional counselling; screening and treatment of infections Home based management of moderate acute malnutrition through counselling, on preparation of augmented home-based foods. Facilitating facility-based management of severe acute malnutrition.

HEALTH
Educating mother and other family members to identify danger signs, and in early care seeking. Facilitating medical management. Counselling on feeding the child during and after illness. Counselling on timely immunization Provision of Albendazole (200 mg) for deworming starting 12 months of age and then 6 monthly

WaSH
Continuation of all the WaSH interventions provided during pregnancy (water filters, water storage bottles, hand washing stations, soap, disinfectants) and counselling on hygiene practices (safe preparation of food, storage and feeding of the child utilizing clean utensils and clean water for cooking and drinking). Clean play area for children; provide play mat. Safe disposal of child's faeces; provide potty.

PSYCHOSOCIAL SUPPORT CHILDREN
Counselling on early child development. Demonstration and practice session for mother at each home visit on early child play and responsive care. Identification of delayed development three-monthly or as response to parental concerns and timely referral to developmental psychologist. MOTHERS Promotion of positive thinking and problem-solving skills. Screening mothers for depressive symptoms. Counselling by study psychologist if PHQ score 10. Referral to psychiatrist if PHQ-9 score 15 and/or suicidal ideation.
Electronic monitoring system for tracking children and mothers with problems to support them for achieving intervention compliance across all domains. ‡ National Programs for women of reproductive age, pregnant women and undertwos (

Figure S1. Subgroup analysis for low birth weight comparing Preconception interventions and No preconception interventions (Group A+B vs Group C+D)
Incidence Rate P-value for Ratio (98.3% CI) interaction

Figure S2. Subgroup analysis for low birth weight comparing Pregnancy and early childhood interventions and No pregnancy and early childhood interventions (Group A+C vs Group B+D)
Incidence Rate P-value for Ratio (98.3% CI) interaction

Figure S3. Subgroup analysis for low birth weight comparing Preconception and pregnancy and early childhood interventions and No preconception and pregnancy and early childhood interventions (Group A vs Group D)
Incidence Rate P-value for Ratio (98.3% CI) interaction

Figure S4. Subgroup analysis for stunting at 24 months comparing Preconception interventions and No preconception interventions (Group A+B vs Group C+D)
Incidence Rate P-value for Ratio (98.3% CI) interaction

Figure S5. Subgroup analysis for stunting at 24 months comparing Pregnancy and early childhood interventions and No pregnancy and early childhood interventions (Group A+C vs Group B+D)
Incidence Rate P-value for Ratio (98.3% CI) interaction

Figure S6. Subgroup analysis for stunting at 24 months comparing Preconception and pregnancy and early childhood interventions and No preconception and pregnancy and early childhood interventions (Group A vs Group D)
Incidence Rate P-value for Ratio (98.3% CI) interaction Group A+B vs Group C+D: Effect of preconception interventions: women who received interventions compared with those who did not receive preconception interventions; Group A+C vs Group B+D: Effect of pregnancy and early childhood interventions: women who received these interventions compared with those who did not receive these interventions; Group A vs Group D: Effect of preconception, pregnancy and early childhood interventions: women who received interventions in these periods compared with those who received routine care Adjusted mean difference, adjusted for place of birth, family possesses below poverty line card, woman's height, woman BMI as potential confounders and twins for clustering within a household; § Length on days 1-7 (up to +6 days); ** Significant (P values calculated using Holm-Bonferroni correction for multiple comparisons) Stunted: Length-for-age z score <-2 SD of the WHO Child Growth Standards Group A: Preconception, pregnancy and early childhood intervention; Group B: Only preconception intervention; Group C: Only pregnancy and early childhood intervention; Group D: Control Group A+B vs Group C+D: Effect of preconception interventions: women who received interventions compared with those who did not receive preconception interventions ; Group A+C vs Group B+D: Effect of pregnancy and early childhood interventions: women who received these interventions compared with those who did not receive these interventions ; Group A vs Group D: Effect of preconception, pregnancy and early childhood interventions: women who received interventions in these periods compared with those who received routine care. Anemia: Hb <12 g/dL, Hypothyroidism: TSH levels were >5.5 mIU/L or if TSH levels were between 4.0 and 5.5 mIU/L and Anti-TPO Ab positive, Prediabetes: HbA1c between 5.7% and 6.4%, Hypertension: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, Reproductive tract infection: Any symptoms of vaginal discharge, itching, burning, swelling, ulcer in genital region, swelling and pain lower abdomen

PSYCHOSOCIAL
Women screened for depressive symptoms (PHQ-9), n (%) 2370 (99.5) Women who received counselling on positive thinking and problem-solving skills, n (%) 2370 (99.5)  LAZ: length-for-age z score, WLZ: weight-for-length z score, WAZ: weight-for-age z score * Adjusted mean difference (98.3% CI), †Adjusted Incidence Rate Ratio (IRR), 98.3% CI, adjusted for place of birth, family possesses below poverty line card, woman's height, woman BMI as potential confounders and twins for clustering within a household. Not corrected for multiple outcomes or comparisons. Group A: Preconception, pregnancy and early childhood intervention; Group B: Only preconception intervention; Group C: Only pregnancy and early childhood intervention; Group D: Control Group A+B vs Group C+D: Effect of preconception interventions: women who received interventions compared with those who did not receive preconception interventions ; Group A+C vs Group B+D: Effect of pregnancy and early childhood interventions: women who received these interventions compared with those who did not receive these interventions ; Group A vs Group D: Effect of preconception, pregnancy and early childhood interventions: women who received interventions in these periods compared with those who received routine care. *Adjusted Incidence Rate Ratio (IRR), 98.3% CI, adjusted for place of birth, family possesses below poverty line card, woman's height, woman BMI as potential confounders and twins for clustering within a houseold. Not corrected for multiple outcomes or comparisons. Group A: Preconception, pregnancy and early childhood intervention; Group B: Only preconception intervention; Group C: Only pregnancy and early childhood intervention; Group D: Control Group A+B vs Group C+D: Effect of preconception interventions: women who received interventions compared with those who did not receive preconception interventions ; Group A+C vs Group B+D: Effect of pregnancy and early childhood interventions: women who received these interventions compared with those who did not receive these interventions ; Group A vs Group D: Effect of preconception, pregnancy and early childhood interventions: women who received interventions in these periods compared with those who received routine care. *Adjusted mean difference (98.3% CI), †Adjusted Incidence Rate Ratio (IRR), 98.3% CI, adjusted for place of birth, family possesses below poverty line card, woman's height, woman BMI as potential confounders and twins for clustering within a household. Not corrected for multiple outcomes or comparisons. Group A: Preconception, pregnancy and early childhood intervention; Group B: Only preconception intervention; Group C: Only pregnancy and early childhood intervention; Group D: Control Group A+B vs Group C+D: Effect of preconception interventions: women who received interventions compared with those who did not receive preconception interventions ; Group A+C vs Group B+D: Effect of pregnancy and early childhood interventions: women who received these interventions compared with those who did not receive these interventions ; Group A vs Group D: Effect of preconception, pregnancy and early childhood interventions: women who received interventions in these periods compared with those who received routine care.    Deaths during preconception period, n (%)* 10 (0.2) 6 (0.1) 1.77 (0.51 to 6.12) *Adjusted Incidence Rate Ratio (IRR, 98.3% CI) adjusted for family possesses below poverty line card, woman's height, woman BMI