A novel intervention combining supplementary food and infection control measures to improve birth outcomes in undernourished pregnant women in Sierra Leone: A randomized, controlled clinical effectiveness trial

Background Innovations for undernourished pregnant women that improve : newborn survival and anthropometry are needed to achieve the Sustainable Development Goals 1 and 3. This study tested the hypothesis that a combination of a nutritious supplementary food and several proven chemotherapeutic interventions to control common infections would increase newborn weight and length in undernourished pregnant women. Methods and findings This was a prospective, randomized, controlled clinical effectiveness trial of a ready-to-use supplementary food (RUSF) plus anti-infective therapies compared to standard therapy in undernourished pregnant women in rural Sierra Leone. Women with a mid-upper arm circumference (MUAC) ≤23.0 cm presenting for antenatal care at one of 43 government health clinics in Western Rural Area and Pujehun districts were eligible for participation. Standard of care included a blended corn/soy flour and intermittent preventive treatment for malaria in pregnancy (IPTp). The intervention replaced the blended flour with RUSF and added azithromycin and testing and treatment for vaginal dysbiosis. Since the study involved different foods and testing procedures for the intervention and control groups, no one except the authors conducting the data analyses were blinded. The primary outcome was birth length. Secondary outcomes included maternal weight gain, birth weight, and neonatal survival. Follow-up continued until 6 months postpartum. Modified intention to treat analyses was undertaken. Participants were enrolled and followed up from February 2017 until February 2020. Of the 1,489 women enrolled, 752 were allocated to the intervention and 737 to the standard of care. The median age of these women was 19.5 years, of which 42% were primigravid. Twenty-nine women receiving the intervention and 42 women receiving the standard of care were lost to follow-up before pregnancy outcomes were obtained. There were 687 singleton live births in the intervention group and 657 in the standard of care group. Newborns receiving the intervention were 0.3 cm longer (95% confidence interval (CI) 0.09 to 0.6; p = 0.007) and weighed 70 g more (95% CI 20 to 120; p = 0.005) than those receiving the standard of care. Those women receiving the intervention had greater weekly weight gain (mean difference 40 g; 95% CI 9.70 to 71.0, p = 0.010) than those receiving the standard of care. There were fewer neonatal deaths in the intervention (n = 13; 1.9%) than in the standard of care (n = 28; 4.3%) group (difference 2.4%; 95% CI 0.3 to 4.4), (HR 0.62 95% CI 0.41 to 0.94, p = 0.026). No differences in adverse events or symptoms between the groups was found, and no serious adverse events occurred. Key limitations of the study are lack of gestational age estimates and unblinded administration of the intervention. Conclusions In this study, we observed that the addition of RUSF, azithromycin, more frequent IPTp, and testing/treatment for vaginal dysbiosis in undernourished pregnant women resulted in modest improvements in anthropometric status of mother : and child at birth, and a reduction in neonatal death. Implementation of this combined intervention in rural, equatorial Africa may well be an important, practical measure to reduce infant mortality in this context. This was a prospective, randomized, controlled clinical effectiveness trial in undernourished pregnant women comparing the impact of a package of nutritional and anti-inflammatory interventions with the standard of care in Sierra Leone. The primary outcome was birth length in a liveborn singleton pregnancy. A sample size of 1,514 undernourished pregnant women, divided equally between intervention and the standard of care, was estimated to allow for a 20% lost to follow-up and/or exclusion rate, leaving a final sample size of 1,200 (600 per group) with a two-tailed significance of 0.05, power of 80% to detect a difference of 0.22 SD or 0.5 cm in birth length and a difference of 0.19 SD or 80 g in birth weight. Full details of the study design and interventions administered have been described previously [26]. The study is reported as per the Consolidated Standards of Reporting Trials (CONSORT) guideline (S1 Fig). All pregnant women with undernutrition defined by a MUAC ≤23 cm and a fundal height <35 cm as a proxy for duration of gestation were invited to participate from 43 antenatal clinics in Pujehun and Western Rural Area Districts of Sierra Leone. Exclusion criteria were known gestational diabetes, hypertension, or severe anemia. Informed consent was obtained for eligible and interested women, and this was documented by a signature or thumbprint if the participant was unable to write. Women older than 16 years of age were eligible to consent for themselves, and girls younger than the age of 16 desiring to participate required consent from a parent or guardian. Ethical approval was obtained from the Sierra Leone Ethics and Scientific Review Committee (SLESRC) and from the Human Research Protection Office at Washington University in St. Louis. The trial was registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT03079388","term_id":"NCT03079388"}}NCT03079388) on 14 March 2017, 16 days after the first participant was enrolled. Late trial registration was the result of very poor 2G internet access at the study site and a failure of those supporting the trial from abroad to perform this function while the first author was at the study site. Participants were randomized to intervention or standard of care using a numbered, computer-generated randomization list created for the entire study. A set of opaque envelopes containing each assignment was created from this list. The envelopes were placed in sets of 25, those numbered 1 to 25, 26 to 50, 51 to 75 and so forth constituted a set, and eligible women then selected an envelope from the set to determine their group assignment. No participant was allowed to choose a second envelope or exchange her envelope after initial selection. All envelopes in the set currently in use were chosen to assign a participant to a group before a second set was brought into use. Further details are available in S1 Text. The RUSF was visually distinct from flour, so neither the study participants nor the field research study team members were masked. Birth outcome assessor and study managers were masked to treatment during data collection and analysis. The study was conducted in conjunction with care at government-provided antenatal clinics. Upon enrollment, demographic information, time of last menses, and estimated date of delivery were recorded. A clinical symptom questionnaire was completed. Weight, height, MUAC, blood pressure, and fundal height were measured by trained study staff. Weight was measured with a Seca 803 digital scale (Hamburg, Germany). Height was measured with a Seca stadiometer (Hamburg, Germany). MUAC was measured on the left arm in centimeters to the nearest 10th of a centimeter with a flexible measuring tape (TALC), according to standard procedures. Fundal height was measured in the supine position with a nonelastic tape to the nearest 0.5 cm and used as a proxy for length of gestation [27]. Participants returned for follow-up every 2 weeks for anthropometric assessment and provision of the study foods and medications until delivery. Follow-up occurred at 6 weeks, at 3 months, and at 6 months after birth. Participants were considered lost to follow-up after missing 3 consecutive visits. Home visits were attempted for any patient lost to follow-up. Clinic staff and participants were provided a telephone number and credit to call the study coordinator at the time of delivery. A birth measurement team was dispatched to measure infants within 48 hours of delivery. Birth measurements were taken as soon as was feasible, but because of poor road conditions and flooding during rainy season, this was not always possible. Infant survival, weight, length, head circumference, MUAC, morbidity, and feeding practices were assessed at each visit. Nude weight was obtained using Seca 334 infant digital scale (Hamburg, Germany) accurate to 5g. Recumbent length was measured in triplicate using a Seca 417 rigid height board (Hamburg, Germany); if the measurements differed by 2 mm, a fourth measurement was taken and the 3 closest measurements were recorded and averaged. Head circumference and MUAC of the left arm was obtained using a standard tape following standard procedures to the nearest 1 mm. Maternal weight, MUAC, and morbidity were assessed at these visits as well. If an infant was identified as deceased, an attempt was made to identify the cause of death by interviewing the mother and review of the medical record. The RUSF development and production have been previously described [26]. Briefly, linear programming was used to optimize the RUSF for nutrient content, cost, and inclusion of indigenous ingredients. Four candidate formulations were tested for acceptability in antenatal clinics in Pujehun, Sierra Leone. The preferred formulation, named Mama Dutasi, contained skimmed milk powder, whey protein isolate, vegetable oil, sugar, peanut paste, and pearl millet. The daily RUSF ration provided 520 kcal, 18 g protein, and at least 100% of recommended daily allowance (RDA) for most micronutrients during pregnancy (S1–S3 Tables). The micronutrient premix included in the RUSF provided the same quantities of micronutrients as the UNICEF/WHO/United Nations multiple micronutrient supplement for pregnant and lactating women (UNIMMAP) with additional calcium and magnesium. The RUSF was produced by Project Peanut Butter, Sierra Leone. Each batch of food met UNICEF specifications for aflatoxin, Enterobacter sp., and Salmonella contamination. The standard of care group received 250 g/d of corn/soy blended flour (SuperCereal, World Food Programme) and 25 g palmolein oil daily. This provided 589 kcal, 17.5 g protein for the participant and as well as a ration for family sharing as is standard WFP practice. They also received 60 mg iron given as ferrous sulfate and 400 μg folic acid. Nutritional supplementation was initiated at the time of enrollment and continued until the time of delivery. Adherence with nutritional intervention was assessed at each visit using a standardized questionnaire. The intervention group received 1,500 mg/75 mg of SP given every 4 weeks beginning in the second trimester. The standard of care group received 3 doses of 1,500 mg/75 mg SP during second and third trimesters. The intervention group received 1 g of azithromycin at the beginning of the second trimester and in the third trimester. The intervention group was tested for vaginal dysbiosis upon enrollment and again in the third trimester using rapid sialidase testing (OSOM BVBLUE, Sekisui Diagnostics, Burlington, MA, USA). If dysbiosis was found, participants were treated with 500 mg metronidazole twice daily for 7 days. All participants received an insecticide-treated bednet and 400 mg of albendazole in the second trimester of pregnancy. Doses of SP for IPTp, azithromycin, and albendazole were given under direct observation during study visits. Only the first dose of metronidazole was administered under direct observation. The study assured uninterrupted access to study food and medicine for the duration of their pregnancy. The primary outcome was newborn length. Secondary outcomes were the total and average weekly maternal weight gain, fundal height at delivery, recovery from maternal undernutrition defined as a MUAC >23 cm, newborn weight and head circumference, infant linear and ponderal growth through 6 months, and infant survival at 1.5, 3, and 6 months. Data were first recorded on clinic management cards. Data from these cards were then double entered into a spreadsheet database (Microsoft Access) and cross checked for discrepancies. All discrepancies were resolved by examination of the original data card. Once the content of the database was determined, it was locked for analyses. Descriptive statistics were used to characterize the study population. Mothers with singleton live births were included in the modified intention-to-treat comparative analyses. All singleton live birth data were included in the primary comparison, regardless of maternal duration of participation or adherence. Those lost to follow-up prior to delivery could not be included. All anthropometric parameters were converted to z-scores using the 2006 WHO growth standards [28]. Two-sided independent samples Student t test was used to compare continuous outcomes (IBM SPSSS Statistics v. 25, IBM, Armonk, NY, USA). Mean differences with 95% confidence intervals (CIs) were calculated. A p-value of <0.05 was considered statistically significant for hypothesis testing. Fisher exact test was used to compare categorical outcomes, and Newcombe/Wilson score with continuity correction was used to calculate 95% CIs for differences in the proportions. Linear mixed effects analysis of the relationship of the intervention and maternal and infant anthropometrics over the study period was performed in R (version 3.6.0) and lme4 package. For maternal anthropometric analysis, fixed effects of study group, duration of enrollment, and their interaction were entered with individual participant variability accounted for as a random variable. For analysis of infant anthropometrics as fixed effects, we entered whether the mother/newborn dyad received the intervention or control, age at measurement, and sex, and their interaction with individual participant variability accounted for as a random variable. p-values were estimated via t tests using the Satterthwaite approximations to degrees of freedom. Time–event analysis was performed to compare infant survival up to 6 months of age between the groups. The Cochran–Mantel–Haenszel test was used to calculate hazard ratios (HRs). Statistical analysis was performed using IBM SPSS Statistics v. 25 (IBM, Armonk, NY, USA), R (version 3.6.0), and GraphPad Prism version 8.3.0 (GraphPad, San Diego, CA, USA).