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Background: Adequate nutrition is essential during pregnancy and lactation to provide sufficient energy and nutrients to meet the nutritional requirements of the mother, fetus and infant. The primary objective of this study was to assess the effect of a maternal nutritional supplement enriched with probiotics during pregnancy and early lactation on the incidence of infant diarrhea. Methods: Healthy, pregnant (24–28 weeks gestation) women were randomized 1:1:1 to receive either no supplement or two servings per day of an oral supplement (140 kcal/serving) providing 7.9 g protein, multivitamin/ minerals, and enriched or not with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis, from the third trimester of pregnancy until at least 2 months post-delivery. Incidence of infant diarrhea until 12 months post- delivery was analyzed by Poisson regression. The effect on maternal health, fetal growth, and infant growth and morbidity were also evaluated and analyzed by ANOVA. Results: A total of 208 mother/infant pairs were included in the analysis. No significant difference in the incidence of infant diarrhea was observed between the three study groups. The mean maternal weight gains at delivery were similar among groups, despite an increase in caloric intake in the supplemented groups. No statistically significant differences between groups were observed in incidence of pregnancy-related or fetal adverse outcomes. Mean weight-, length-, BMI- and head circumference-for-age z-scores were below the WHO median value for all groups. Post-hoc analysis to compare the effect of the combined supplement groups versus the no supplement group on infant growth parameters showed, at 12 months, that thecombinedsupplementedgrouphadgainedstatistically significantmore weight(8.97 vs.8.61kg, p =0.001) and height (74.2 vs. 73.4 cm, p = 0.031), and had a higher weight-for-age z-score (− 0.62 vs. -0.88, p = 0.045) than the no supplement group. Conclusions: Maternal nutritional supplement with or without probiotics given during late pregnancy and early lactation was well tolerated and safe. Even though no difference in incidence of infant diarrhea was observed between the three groups, the analysis of the combined supplemented groups showed beneficial effects of maternal supplementation on infant weight and length gains at 12 months. Trial registration: ClinicalTrial.gov: NCT01073033. Registered 17.02.2010. Keywords: Maternal supplementation, Probiotics, Lactobacillus rhamnosus, Bifidobacterium lactis,Diarrhea,Safety,Infantgrowth * Correspondence: email@example.com Institute of Nutritional Science, Nestlé Research Center, Vers-chez-les-Blanc, 1000, 26 Lausanne, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 2 of 12 Background many factors, including diet and intake of nutritional bio- There is a substantial body of evidence showing that ma- actives such as probiotics . Probiotics can regulate gut ternal diet throughout pregnancy and during breastfeed- and vaginal microflora, and probiotic supplementation has ing could influence the infant growth, development and been used in some trials as a strategy to influence preg- health [1, 2]. Only a modest increase in energy intake is nancy and infancy outcomes . Maternal transfer of required during pregnancy compared to pre-pregnancy re- bacterial signals is possible during pregnancy and lactation quirements. Indeed, approximately 100 and 300 additional . This (as well as the mother’s diet and microbiota) kcal per day are needed in the first and second/third tri- can influence newborn microbial colonization and micro- mesters, respectively, with increased requirements during biota establishment which in turn may have an impact on breastfeeding of 450 kcal per day . Conversely, the rec- infant’s short and long-term development parameters, in- ommended intake during pregnancy for several nutrients cluding growth . such as iron, folate and vitamin B6 are up to 50% higher Prior to the initiation of our study, the safety and ef- than those for a non-pregnant state, which could prove fect of a maternal nutritional supplement containing a challenging . Geographic and sociodemographic differ- mix of probiotics for pregnant and breastfeeding women ences have been observed regarding nutrient deficiencies on fetal and infant growth was only partially addressed. in pregnancy. The World Health Organization (WHO) Safe use of probiotics has been documented. Indeed, in- has warned that some nutrient deficiencies (especially for fants born from mothers receiving Lactobacillus rham- vitamin A, iodine, vitamin D, calcium and zinc) are more nosus were shown to have a significantly reduced risk of common in pregnant women in low resource countries developing atopic eczema during the first two to compared to those with higher resources. Other micronu- seven  years of life and no adverse effects were re- trients (i.e., vitamin B12, iron, and folate) are commonly ported [12, 13]. Researchers also observed an improved deficient worldwide . This is of particular importance gut microbiota in babies born from women receiving considering that maternal undernutrition can lead to mis- probiotics during pregnancy  or during pregnancy carriage and major developmental issues such as intrauter- and lactation , and again, these studies did not re- ine growth restriction, low birth weight and premature port any adverse events [14, 15]. Some probiotic strains births [4, 5]. As many as 800,000 neonatal deaths per year have also been successfully used to improve the outcome are from small for gestational age births, many of which of gastrointestinal diseases, in particular diarrhea [16, are attributed to maternal undernutrition . It was esti- 17]. Diarrhea episodes are common infant infections and mated that stunting, wasting, and micronutrient deficien- are a major health concern in pediatrics. cies account for almost 3.1 million child deaths annually Among the probiotic strains, Bifidobacterium lactis and . Ultimately, maternal nutrition, especially micronu- Lactobacillus rhamnosus have been reported to improve trient intake, is an important determinant of health as an diarrheal outcomes in infants [18–23]. Therefore, we con- adult. This has been shown to have an impact on the de- ducted this study to assess the effect of an oral maternal velopment of cardiovascular diseases and obesity [7, 8]. nutritional supplement formulated with these two probio- In developing countries, with a high risk of under nutri- tics on the incidence of diarrhea in infants from birth to tion, the use of nutritional supplements during pregnancy one year, assessed as the primary endpoint of the trial. is encouraged to ensure adequate supply of nutrients for Secondary objectives included examining the effect of an both mother and fetus . In arecentCochranereview, oral maternal nutritional supplement on maternal health, Haider and Bhutta evaluated the benefits of oral fetal growth, and infant growth and morbidity up to one multiple-micronutrient supplementation during pregnancy year of age. Due to the overall low incidence of diarrhea on maternal, fetal and infant health outcomes. The analysis reported in this study, we conducted an additional of 15 clinical trials conductedinlow andmiddle-income post-hoc analysis. It evaluated the effect of the combined countries revealed that multiple-micronutrient supplemen- oral supplement groups (with and without probiotics) tation with iron and folic acid resulted in a significant compared to the no supplement group on maternal health decrease in the number of low birth weight or and fetal and infant growth. small-for-gestational age newborn infants, and a reduced rate of stillbirth . Methods Dramatic immune and physiological changes take place Study design during pregnancy to accommodate the growing fetus; A single center, randomized, double blind trial of three these include alterations in the gut and vaginal micro- parallel-groups (supplement, supplement plus probiotics, biome populations . These changes may influence the and no supplement) was conducted at the Community maternal metabolic profile and may contribute to the Hospital in Muntinlupa City, Philippines, between April metabolic and immunological health of the infant . 2010 and September 2012. The study protocol was ap- The composition of the microbiome is influenced by proved by the institution’s Ethics Committee (University of Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 3 of 12 the Philippines Manila – National Institutes of Health Table 1 Nutritional composition of the supplements Ethics Review Board; protocol number NIH 2009–027). Energy, kcal 140 The study was conducted in accordance with the Helsinki Fat, g 3.50 Declaration and complied with Good Clinical Practices as Linoleic acid, mg 73.2 laid out in the International Conference on Harmonization Alpha-linoleic acid, mg 80.9 guidelines. Written informed consent was obtained from all Docosahexaenoic acid, mg 43.8 study participants after the nature and possible conse- Protein, g 7.9 quences of the study had been fully explained. The primary objective of the trial was to examine the effect of an oral Carbohydrates, g 21 nutritional supplement containing a mix of probiotics Minerals, mg Lactobacillus rhamnosus and Bifidobacterium lactis, taken Sodium 87 during pregnancy and up to minimally 2 months Chloride 205 post-delivery on the incidenceof diarrhea ininfants from Calcium 254 birth to one year of age. The secondary objectives were (i) Magnesium 32 in mothers, to assess the effect of oral nutritional supple- ments on fetal growth and on maternal health (weight gain Iron 7 and pregnancy-related adverse events [AEs]) during the Zinc 2.6 third trimester of pregnancy and up to delivery; and (ii) in Vitamins infants, to investigate the impact of nutritional supplement Vitamin A, IU 438 beverages on infant growth and morbidity. Vitamin D, IU 35 Vitamin E, IU 4.60 Study population Healthy women at the beginning of the third trimester of Vitamin C, IU 19.6 pregnancy (24 to 28 weeks of gestation) who were willing Vitamin B1, μg 217 to exclusively breastfeed for at least the first 2 months Vitamin B6, μg 263 postpartum were recruited and enrolled in the study. The Niacin, μg 3045 study protocol encouraged exclusive breastfeeding up to Folic acid, μg 125 6 months of age. The infants born to study participants Panthotenic acid, μg 1295 were followed until one year of age. Pregnant women were excluded from the study if they had any of the following Biotin, μg 9.80 exclusion criteria: known allergy to cow’s milk, known his- The composition of the supplement plus probiotics is identical to the supplement alone except for the addition of L. rhamnosus (7 × 10 cfu) and B. tory of lactose intolerance, previous diagnosis of human Lactis (7 × 10 cfu) immunodeficiency virus (HIV) and hepatitis B, multiple pregnancy, high risk pregnancy (pre-eclampsia, diabetes, etc.), current or past participation in another clinical trial powder in 200 ml of water. Both products were blinded by during the last three months, consumption of pro- and/or the manufacturer. Thus, the identity of the specific prod- prebiotics-containing food/supplement in the month be- ucts was blinded to the subjects, support staff and investi- fore inclusion. gators. The reference group not taking the supplement was not blinded. Study supplements and blinding The supplement and supplement plus probiotics formula- Randomization tions consisted of proteins, carbohydrates, fats with vita- An in-house computer program (TrialSys) was used to mins and minerals in amounts intended for nutritional generate a randomization sequence to allocate expecting support during pregnancy. Each serving of 200 mL con- mothers to either the supplement, supplement plus pro- tained 140 kcal energy, 7.9 g of proteins, 21 g of carbohy- biotics, or no supplement groups. Eligible pregnant drates, and 3.5 g of fat. It also contained minerals and women were randomized into the three groups with a vitamins (Table 1). The supplement plus probiotics con- 1:1:1 ratio. The investigator accessed allocation numbers tained the mix of probiotics composed of 7 × 10 cfu of via a web-based application. Random allocation remained Bifidobacterium lactis CNCC I-3446 and 7 × 10 cfu of concealed until assigned by computer program and could Lactobacillus rhamnosus CGMCC 1.3724, per serving. Both not be predicted based on previous assignments. supplements were manufactured by the sponsor, Nestlé (Product technology center, Konolfingen, Switzerland). The Trial procedure two supplements were indistinguishable and were supplied Each supplemented group received 2 × 200 ml serving as powder, in sachets, with instructions to prepare 35 g of per day of the allocated nutritional supplement beverage Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 4 of 12 (to be taken in the morning and evening). The no sup- post-delivery. At birth, infants were examined, anthropo- plement group did not receive any nutritional supple- metric measurements were taken and AEs (any untoward ment beverage. For both supplemented groups, feeding birth defect) recorded. After birth, study investigators ex- with the assigned study product begun at 24–28 weeks amined the infants at 2 weeks and 1, 2, 4, 6, 7, and 12 (visit gestation and continued for two months (minimum) 10) months of age and took anthropometric measurements, after birth. Although optional, mothers were encouraged collected and reviewed parent/caregiver-reported 3-day to continue for six months after birth. When the mother feeding and gastrointestinal tolerance diaries, and assessed completely stopped breastfeeding, supplementation was the occurrence of any AEs and in particular episodes and also stopped. The infants continued in the study until duration of diarrhea, since last visit. one year of age. A total of 11 visits (from screening visit 0 to last visit 10) took place during the study, the major visits are illustrated Outcome measures in Fig. 1. Before birth, expecting mothers attended a screen- The primary outcome was the incidence of diarrhea in ing visit (at 24–28 weeks’ gestation, visit 0) during which infants from birth to one year (total count of diarrhea history and subjects’ data were collected, inclusion/exclu- per infant per year). The incidence and duration of diar- sion criteria were checked, health was assessed, and body rhea episode were clinically assessed by the pediatrician weight measured. A fetal ultrasound was performed and at each visit, starting 2 weeks post-delivery through women randomized to the supplemented groups started 12 months of age. Diarrhea was defined as at least three the supplements. At each visit, the physician inquired about or more watery stools in a 24-h period. An episode of the occurrence of AEs (especially nausea, vomiting, and diarrhea was considered to have ended after two con- diarrhea), assessed health, and measured body weight. At secutive non-watery stools or no stools for 24 h. delivery (visit 3), the same information was recorded along In mothers, secondary outcomes included health as- with completion of a delivery record, including mode of de- sessment (clinical examination, weight gain); documen- livery and gestational age. Mothers were followed and ex- tation of infections (genito-urinary tract infection); and amined (for AEs and health assessments) up to 2 months tolerance to study product (nausea, vomiting, diarrhea). Fig. 1 Disposition of study participants. FAS, full analysis set. *case report form did not distinguish between mothers/infants Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 5 of 12 Fetal growth (abdominal circumference, biparietal index [BMI]); anthropometric WHO z-scores over time diameter, and femoral length) was determined by ultra- (weight-, length-, BMI- and head circumference-for-age); sound at enrolment and just before delivery. and infant’s morbidity. All outcomes were analyzed both by In infants, secondary outcomes included anthropom- per protocol and by intention to treat data sets. etry and morbidity. Anthropometry was measured by weight, recumbent length/height and head circumfer- Results ence at each visit from birth to 12 months. Infants were Mothers and infants demographics and baseline weighed unclothed to the nearest 10 g on the same elec- characteristics tronic scales calibrated according to the manufacturer’s A total of 233 expecting mothers attending a single com- instructions. Recumbent length was measured on a stan- munity hospital were randomized to one of the three dardized length board to the nearest 1 mm with the study groups. Twenty-five women were not exposed to body fully extended and feet flexed. Head circumference the study supplement and/or withdrew from the study on was measured using a standard plastic-coated measuring or before delivery. The results described in this section are tape at approximately 2.5 cm above the eyebrows. Mor- based on the FAS population. Two hundred and eight bidity was inquired by the pediatrician at each visit and mothers and the same number of infants were included in recorded in the AEs form. the FAS: 70 in the supplement group, 70 in the supple- ment plus probiotics group, and 68 in the no supplement Adverse events and serious adverse events (SAEs) group. Eight, 10, and 7 mothers/infants were excluded The study investigator evaluated the seriousness of all AEs from the FAS in the supplement, supplement plus probio- and any potential relation to the study products. AEs and tics, and no supplement groups, respectively. A total of SAEs were collected from randomization of the mothers 183 infants completed the 12 months study visit (Fig. 1). up to the 12-month follow-up period, and coded using the The demographics and baseline characteristics of WHO Adverse Reactions Terminology (WHO-ART). A mothers and infants were similar across the three groups serious AE was defined as any untoward medical occur- (Table 2). All infants were in good health at birth with rence that at any dose: results in death; is life-threatening; similar APGAR scores measured at 1 and 5 min after requires inpatient hospitalization or prolongation of exist- birth. The mean body weights at birth were similar for ing hospitalization; results in persistent or significant dis- infants from the two supplemented groups (2.93 kg ability/incapacity; or is a congenital anomaly/birth defect. ±0.47 and 2.90 kg ±0.39, supplement and supplement plus probiotics, respectively) and for the no supplement Statistical methods group (2.88 kg ±0.44). At 4 months of age, 64.3% (sup- Thesamplesizewas calculatedbased on thearticlesof plement), 64.3% (supplement plus probiotics), and 72% Hengstermann et al.  and Ortiz-Andrellucchi et al. . (no supplement) of the infants were still on exclusive Based on these two reference articles, a two sample test on breastfeeding in their respective groups. proportion led to a number of 62 subjects per group in ordertoshowa50%decreaseinincidence of diarrhea with Maternal supplementation during pregnancy a significance of 0.05 and a statistical power of 80%. Con- Maternal and fetal anthropometrics during last trimester of sidering an estimated 20% of dropouts, a total number of pregnancy 234 infants (78 per randomized group) were planned to be recruited into the study, and a total of 62 infants per group Maternal weight gain Pre-pregnancy weight and BMI were supposed to be seen at 1 year of age. Those numbers were very similar across all study groups, reflecting a were achieved as indicated in Fig. 1.The primaryoutcome homogeneous study population (Table 3). Despite a daily was the total count of diarrhea per infant per year. The in- increase in calorie intake of about 280 kcal in the supple- cidence of diarrhea was analyzed by Poisson regression in ment and supplement plus probiotics groups, no signifi- the full analysis set (FAS). Secondary outcomes (anthropo- cant difference in median maternal weight gain was metric measurements and other continuous outcomes) observed between the supplemented groups and the no were analyzed by ANOVA correcting for sex and available supplement group (supplement plus probiotics vs. no sup- baseline, respectively. A post-hoc analysis comparing the plement, p = 0.945; supplement vs. no supplement, p = combined supplemented groups (oral nutritional supple- 0.892). Mean maternal weight gain at delivery was 10.6 kg, ments with and without probiotics) versus the no supple- 10.5 kg, and 10.3 kg, in the supplement, supplement plus ment group was performed. The aim of this post-hoc probiotics, and no supplement groups, respectively. Mean analysis was to assess the following outcomes in infants: BMI at delivery was similar among groups (Table 3). body weight gain up to one year of age (non-inferiority ana- lysis); anthropometric measurements at 12 months of age Fetal growth and development Infants were born at ap- (body weight, length, head circumference and body mass proximately 39 weeks gestation with no statistically Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 6 of 12 Table 2 Maternal and infants baseline characteristics Characteristics Supplement Supplement + probiotics No supplement Mothers, n 70 70 68 Age at randomization in years, mean (SD) 26.3 (5.5) 24.8 (5.3) 24.9 (5.4) Ethnic origin, % of Asian 100 100 100 First-time mothers, % 45.7 40.0 52.9 Type of delivery, % C-section 21.7 15.7 13.2 Education, % of secondary education 73.9 55.7 73.5 Infants at birth, n 62 60 61 Gestation age at birth in weeks, mean (SD) 38.8 (1.5) 38.8 (2.0) 38.8 (1.2) Sex, % of males 50 62.9 44.1 APGAR score at 1 min, median (min-max) 9.0 (4.0–9.0) 9.0 (6.0–9.0) 9.0 (6.0–9.0) APGAR score at 5 min, median (min-max) 9.0 (8.0–9.0) 9.0 (5.0–10.0) 9.0 (9.0–9.0) Length in cm, mean (SD) 50.1 (2.7) 49.9 (2.8) 49.7 (2.4) Weight in kg, mean (SD) 2.93 (0.47) 2.90 (0.39) 2.88 (0.44) Body mass index in kg/m , mean (SD) 11.6 (1.3) 11.6 (1.3) 11.6 (1.2) Head circumference in cm, mean (SD) 32.7 (1.3) 32.8 (1.7) 32.5 (1.6) SD Standard deviation significant differences between the three groups in mean Maternal supplementation during lactation birth weight, APGAR scores, and anthropometrics (Table 2). Infant outcome measures Similarly, no significant differences were observed between the three groups for abdominal circumference (mean values Incidence of diarrhea During the 12-month follow-up, of 32.64, 32.29, and 32.20 cm, in the supplement, supple- 12.9% (9/70), 14.3% (10/70), and 16.2% (11/68) of infants ment plus probiotics, and no supplement groups, respect- experienced diarrhea in the supplement, supplement ively), biparietal diameter (mean values of 8.85, 8.86, and plus probiotics, and no supplement groups, respectively. 8.82 cm in the supplement, supplement plus probiotics, and One serious case of diarrhea was reported in the supple- no supplement groups, respectively), or femoral length ment group. There was no statistically significant differ- (mean values of 6.88, 6.75, and 6.76 cm, in the supplement, ence in the incidence of diarrhea observed between the supplement plus probiotics, and no supplement groups, re- three groups. The incidence (95% confidence interval spectively) (Fig. 2). Overall, there were no statistically signifi- [CI]) was 0.17 (0.09–0.30) in the supplement group, 0.14 cant differences between the three groups for infant growth (0.07–0.27) in the supplement plus probiotics group, parameters during fetal development. and 0.19 (0.11–0.33) in the no supplement group (supplement plus probiotics group vs. supplement group, p = 0.692; supplement plus probiotics group vs. no sup- Pregnancy-related AEs and SAEs plement group, p = 0.509). When supplemented groups There were no statistically significant differences in the num- were combined, the incidence (adjusted mean [95% CI]) ber of pregnancy-related AEs and SAEs recorded during the was 0.15 (0.10–0.24) in the combined supplement study between the three groups (Table 4). None of the SAEs groups vs. 0.19 (0.11–0.33) in the no supplement group were considered as related to the study supplements. (p = 0.586). The mean product effect with combined Table 3 Maternal weight status until delivery Mean (SD) Supplement Supplement + probiotics No supplement (n = 70) (n = 70) (n = 68) Declared pre-pregnancy weight (kg) 49.1 (8.2) 49.2 (7.7) 49.1 (7.7) Pre-pregnancy BMI (kg/m ) 20.6 (2.9) 20.7 (2.7) 21.1 (3.3) Maternal weight gain from baseline (24–28 weeks of pregnancy) 5.00 (2.69) 4.55 (2.25) 4.62 (2.16) up to delivery (kg) Maternal weight gain at delivery (kg) 10.6 (5.8) 10.5 (4.0) 10.3 (7.0) Maternal BMI at delivery (kg/m ) 25.0 (3.2) 25.1 (3.0) 25.5 (3.4) BMI body mass index; SD, Standard deviation. Calculated from participant report pre-pregnancy weight Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 7 of 12 frequent vomiting cases in the combined supplemented group compared to no supplement group (0.0% vs. 5.9%, p = 0.011). In total, there were four infant deaths. Two deaths were reported in the supplement group, one in the supplement plus probiotics group, and one in the no supple- ment group (Table 5). None of these cases were considered related to product consumption in the medical records. Changes in anthropometric measurements over time In the three study groups, mean weight-for-age, length-for-age, BMI-for-age and head circumference-for-age z-scores were below the WHO median values. At birth, all anthropometric measurements were similar between the groups. Interestingly, at 2 months of age, i.e. at the end of the mandatory intake of maternal supplementation and breastfeeding, the combined supplemented group had higher weight-for-age (− 0.40, 95% CI: -0.54 to − 0.25 vs. -0.57, 95% CI: -0.77 to − 0.36), length-for-age (− 0.37, 95% CI: -0.55 to − 0.19 vs. -0.51, 95% CI: -0.77 to − 0.25), and BMI-for-age (− 0.25, 95% CI: -0.43 to − 0.07 vs. -0.39, 95% CI: -0.65 to − 0.14) z-scores than the no supplement group (Fig. 3a, b, c, ). However, these differences did not reach significance. This trend persisted throughout the study follow-up period, up to 12 months. At 12 months of age, the combined supplemented groups gained more weight (adjusted mean in kg, 95% CI: 8.97 [8.84–9.09] vs. 8.61 [8.43–8.78]; p = 0.001) and height (adjusted mean in cm, 95% CI: 74.2 [73.8–74.6] vs. 73.4 [72.8–74.0]; p =0.031) compared to the no supplement group (Table 6)andhada Fig. 2 Fetal development. Fetal abdominal circumference (a), fetal significantly higher weight-for-age z-score (− 0.88 vs. biparietal diameter (b), and fetal femoral length (c) -0.62, p = 0.045) (Fig. 3a). There was neither statistically significant difference nor trend for a higher head supplement was 0.82 (0.40–1.68) compared to no circumference-for-age z-score in the combined versus supplement. no supplement groups throughout the study (Fig. 3d). No statistically significant differences on growth outcome per Adverse events in infants Overall, infant morbidity was gender were observed between groups (data not shown). similar among groups. However, there was a trend towards more serious gastrointestinal infections in the no supple- Discussion ment group (10.3%) than in the combined supplemented In the present study, we assessed the effect of an oral groups (4.3%). Moreover, we noticed significantly less maternal nutritional supplement formulated with the Table 4 Pregnancy-related serious adverse events (SAEs) Supplement Supplement + probiotics No supplement (n = 70) (n = 70) (n = 68) Pregnancy, puerperium and perinatal conditions # Events # Mothers # Events # Mothers # Events # Mothers p- value* (%) (%) (%) Fetal growth restriction 0 0 (0.0%) 0 0 (0.0%) 1 1 (1.5%) – Gestational hypertension 1 1 (1.4%) 1 1 (1.4%) 0 0 (0.0%) 1.000 Pre-eclampsia 1 1 (1.4%) 1 1 (1.4%) 1 1 (1.5%) 1.000 Premature labor 3 3 (4.3%) 1 1 (1.4%) 1 1 (1.5%) 0.620 Genito-urinary tract infections 15 14 (20.0%) 9 7 (10.0%) 3 3 (4.4%) 0.154 Tolerance: nausea, vomiting and diarrhea 6 4 (5.7%) 11 7 (10.0%) 1 1 (1.5%) 0.532 Data are number (%) of mothers with at least one event; *Supplement + probiotics versus Supplement Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 8 of 12 Table 5 Adverse events in infants (combined supplemented groups versus non-supplemented group) Combined No Supplement p- value* Combined vs. (n = 140) (n = 68) No supplement # Events # Infants # Events # Infants (%) (%) Adverse events of diarrhea Serious diarrhea 1** 1 (0.7%) 0 0 (0.0%) 1.000 Diarrhea 21 19 (13.6%) 12 11 (16.2%) 0.675 Total 22 20 12 11 – Other serious adverse events of interest All respiratory infections/symptoms 309 119 (85.0%) 177 63 (92.6%) 0.179 Gastrointestinal infections 7 6 (4.3%) 7 7 (10.3%) 0.126 Allergies 11 7 (5.0%) 4 3 (4.4%) 1.000 Death 3 3 (2.4%) 1 1 (1,5%) Other adverse events of interest Vomiting 0 0 (0.0%) 5 4 (5.9%) 0.011 Data are number of infants with at least one event (%). Combined: supplement and supplement + probiotics groups.*Exact Fisher test p-value.**Event reported in the supplement group. As confirmed by clinicians, not related to product consumption probiotics Lactobacillus rhamnosus and Bifidobacterium containing a mix of probiotics for pregnant and breast- lactis on the incidence of diarrhea in infants from birth to feeding women on fetus and infant [12–15], but none have one year. The supplement was consumed by expecting fully examined the impact of oral nutritional supplements mothers during the third trimester of pregnancy and con- on fetal and infant growth. Our study provides preliminary tinued for at least two months post-partum while breast- evidence suggesting a beneficial effect of oral nutritional feeding. There was no significant difference in the supplements, with and without probiotics, during the incidence of infant diarrhea between treatment groups. third trimester of pregnancy on optimal maternal weight The incidence of diarrhea was also similar between the gain and infant growth at one year. supplemented groups and the no supplement group. In a Oral maternal nutritional supplements are formulated clinical trial setting, an overall lower incidence of infant to provide a balance of energy, protein and nutrients to diarrhea is often observed as compared to field data re- support a healthy pregnancy. However the consumption cords. It is likely that mothers involved in clinical trials of too many calories during pregnancy may increase a provide more care and attention to their infants than dur- woman’s risk for excessive weight gain which has been ing everyday life when infants do not undergo such a con- linked with gestational diabetes [26, 27] and hypertension stant growth and health monitoring. Nevertheless, in the , cesarean birth [26, 28], macrosomia [28–30]and present study the incidence rate of infant diarrhea was not large-for-gestational age infants [26, 28], later type 2 dia- dramatically lower than the estimates from the two refer- betes and obesity, along with childhood obesity ence articles used for sample size calculation [24, 25]. . During the third trimester of pregnancy, our study Even if the supplement plus probiotics group pointed to- showed that maternal weight gain among the three study wards a slight numerical trend compared to the supple- groups was equivalent despite an increase in calorie intake ment and no supplement groups, the expected 50% of 280 kcal per day in the supplemented groups. This is reduction in incidence of infant diarrhea was not achieved consistent with a recent report indicating a reduced occur- in the current clinical trial setting. In order to reach statis- rence of central adiposity (i.e. waist circumference ≥ 80 cm) tical significance more than 300 infants per group would at 6 months after birth when probiotics are given to have been required. In this context, one could consider pregnant women in combination with dietary counsel- that the study was underpowered to show such a dramatic ing . Moreover, our results are in agreement with impact on incidence of infant diarrhea. the findings of Luoto et al. who reported a reduction of Secondary endpoints were evaluated as planned, and an gestational diabetes in mothers fed probiotics Lactoba- additional post-hoc analysis was performed. It compared cillus rhamnosus and Bifidobacterium lactis together the combined groups receiving oral supplements (with with dietary counseling from the first trimester of preg- and without probiotics) with the no supplement group to nancy and adequate prenatal and postnatal growth rates evaluate the effect of maternal supplementation on mater- (body weight and length) of infants during the first two nal health and fetal and infant growth. Some studies have years of life . Additionally, our study showed no dif- described the safety and effect of a nutritional supplement ferences in the incidence of pregnancy-related AEs and Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 9 of 12 Fig. 3 Infant anthropometrics over the study period. Weight-for-age (a), length-for-age (b), BMI-for-age (c) and head circumference-for-age (d) z-scores (World Health Organization growth reference). *p = 0.045 Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 10 of 12 Table 6 Infant anthropometrics at 12 months of age Measurement, adjusted Supplement Supplement + Combined No supplement p-value mean (95% CI) (n = 62) probiotics (n = 60) (n = 122) (n = 61) Supplement + probiotics Combined vs. vs. supplement No supplement Weight (kg) 8.92 (8.75–9.09) 9.06 (8.88–9.24) 8.97 (8.84–9.09) 8.61 (8.43–8.78) 0.273 0.001 Length (cm) 73.8 (73.3–74.4) 74.6 (74.1–75.2) 74.2 (73.8–74.6) 73.4 (72.8–74.0) 0.057 0.031 Head circumference (cm) 44.0 (43.7–44.3) 44.1 (43.9–44.5) 44.1 (43.9–44.3) 44.2 (44.0–44.7) 0.413 0.317 Body mass index (kg/m ) 16.3 (16.0–16.7) 16.1 (15.8–16.5) 16.2 (16.0–16.5) 16.0 (15.7–16.4) 0.496 0.371 Analyzed by ANCOVA, correcting for sex and available baseline; Combined: supplement and supplement + probiotics groups; CI confidence interval SAEs, and adverse fetal outcomes between all study may often be of lower nutritional value than infant for- groups. Overall, the optimal maternal weight gain and mula, resulting in the consumption of a non-optimal positive tolerance data indicate that maternal feeding amount of calories, protein and essential micronutrients. with a supplement containing or not probiotics during the In the Philippines, among the lower socio economic last trimester of pregnancy is safe for the mother and the population, an increased risk of infection combined with fetus with respect to its energy density and nutritive value. inadequate nutrition may be contributing to the decline We further explored the effect of the supplementation in infant growth rate. This could explain what was ob- compared to the current nutrition practice, i.e. no sup- served at 6 months of age. plement. The two supplemented groups were thus sub- At 12 months of age, infants in the combined supple- sequently pooled and compared to the no supplement mented group had gained significantly more weight than group in a post-hoc analysis. No difference was observed the infants in the no supplement group. This suggests a between the two groups with respect to AEs or SAEs in potential long-term beneficial effect of the supplementa- infants, except for vomiting which appeared significantly tion. The GUSTO (Growing Up in Singapore Towards less frequent in the combined supplemented group than healthy Outcomes) study group recently showed that food in the no supplement group. Moreover, a trend for less consumption was altered during pregnancy and the post- serious gastrointestinal infections in the combined sup- partum period in a large number of women from a multi- plemented group was noticed. Altogether, these observa- ethnic Asian population who were heavily influenced by tions are suggestive of the potential beneficial effect of traditional beliefs surrounding these periods . This the maternal supplement on infant health, regardless of study group further investigated the association between the addition of probiotics. Additional studies would be maternal macronutrient intake during pregnancy and in- needed to confirm these observations. fant birth size in the same Asian population . Similar As giving nutritional supplements to breastfeeding to what was observed in the no supplement group of our mothers in developing countries could presumably im- study, the study concluded that maternal macronutrient prove infant growth, in the post-hoc analysis, we also ex- intake was not associated with infant birth weight . amined the effect of the combined supplemented group Additionally, Bhargava examined the effect of dietary in- on infant growth. In our study, all infant growth parame- take on growth and morbidity in Filipino infants from 2 to ters were below WHO median values, at all study time 24 months and reported calcium, protein to energy intake points (up to 12 months of age) and in both the combined ratio, and β-carotene were significantly correlated with supplemented and the no supplement groups. This finding height, weight, and morbidity indexes, respectively . In is consistent with the results from the Food and Nutrition western infants, clinically significant catch-up growth (de- Research Institute of the Department of Science and fined as a gain in weight z-scores > 0.67) between 0 and Technology, 8th National Nutrition Survey showing an es- 24 months was associated with greater weight, height, timated 19.9% of Filipino children aged 0 to 5 years are BMI and body fat at five years compared to similar aged underweight . Nevertheless, it should be noted that children without catch-up growth . In this study, the the growth curves of the combined supplemented group mean product effect on weight-for-age z-scores was only was higher (except for head circumference) compared equal to 0.211. Nevertheless, there is a need for a better with the no supplement group for all time points. understanding of the benefits and risks of greater weight Starting around 6–7 months of age, a negative break gain to promote improved health outcomes and the later in the infant growth curves was observed which prob- risk of adiposity and obesity . Further investigating of ably corresponds to the start of the weaning period. At these potential determinants of excess infant adiposity this time, complementary foods are introduced and the gain could lead to intervention strategies in clinical and infant is at an increased risk of being exposed to public health settings to prevent childhood obesity and its food-borne illness. Furthermore, complementary foods consequences. Mantaring et al. BMC Pregnancy and Childbirth (2018) 18:193 Page 11 of 12 We acknowledge some limitations in our study. First, Funding Nestec Ltd. sponsored the study. supplement consumption was not monitored beyond the 2-month postnatal period, and the impact of continued Availability of data and materials supplement consumption on breast-fed infant growth The study protocol as well as the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. was not examined. Second, the potential beneficial effect of the supplements on breast milk composition was not Authors’ contributions studied and compared between groups. This could have VG, JM, and JB conceived and designed the study. JB, KV, SP and SV developed the statistical analysis plan. VG, JM, SP, JB, KV and SV jointly provided insights on the effect observed on infant developed the structure and the arguments for the paper. RD performed growth. Third, the absence of increased weight gain in clinical samples laboratory analyses. All contributed to the writing of the pregnant women taking the supplement (with or without manuscript. All agreed with the manuscript results and conclusion. All made critical revisions and approved final version. All authors reviewed and probiotics) cannot be generalized to the whole popula- approved the final manuscript. tion as this observation may be linked to a genetic com- ponent specific to this sample of Filipino women. Ethics approval and consent to participate The study was performed in accordance with the Helsinki Declaration and Indeed, women’s weight in Western countries is gener- complied with Good Clinical Practices as laid out in the International ally higher and women tend to gain more weight during Conference on Harmonization guidelines. It was approved by the pregnancy (for women with a normal weight, i.e. a BMI institution’s Ethics Committee (University of the Philippines Manila – National Institutes of Health Ethics Review Board; protocol number NIH 2009–027). of 18.5–24.9, the recommended range of total weight Participants provided written informed consent to share data and gain during pregnancy is 11–16 kg ). Moreover, the participation was voluntary. mother’s diet and exercise during the third trimester of Competing interests pregnancy and the 2-month postnatal period was not VG and JM received a study grant from Nestlé Nutrition for this study. SP, JB, taken into account, as these data were not recorded dur- KV and SV are Nestlé employees. ing the trial. However, considering that all recruited mothers had comparable socioeconomic profiles and Publisher’sNote came from the same geographical area, one can assume Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. that their global calorie intake was similar. Nevertheless, a better monitoring of mothers’ diet and exercise should Author details be included in future nutritional intervention trials. Fi- Department of Pediatrics, Philippines General Hospital, City, Manila, Philippines. Institute of Nutritional Science, Nestlé Research Center, nally, limitations also include the study population of Vers-chez-les-Blanc, 1000, 26 Lausanne, Switzerland. Internal Medicine & women in the third trimester of pregnancy living in the 4 Infectious Diseases, Philippines General Hospital, Manila, Philippines. Clinical greater Manila region, limiting the generalizability of Research, Nestlé Nutrition, Vevey, Switzerland. Janssen R&D LLC, Welsh & McKean Roads, Springhouse, PA 19477, USA. Department of Obstetrics & these findings to all stages of pregnancy and all regions Gynecology, Philippines General Hospital, Manila, Philippines. of the Philippines. Received: 21 December 2017 Accepted: 15 May 2018 Conclusion Oral maternal nutritional supplements formulated with References 1. Ramakrishnan U, Grant F, Goldenberg T, Zongrone A, Martorell R. Effect of or without Lactobacillus rhamnosus and Bifidobacterium women's nutrition before and during early pregnancy on maternal and lactis during the last trimester of pregnancy and through infant outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012; the first two months of exclusive breastfeeding were well 26(Suppl 1):285–301. 2. Ramakrishnan U, Imhoff-Kunsch B, Martorell R. Maternal nutrition tolerated and safe for mothers, fetus and infants. 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