Radha Chari

Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months

Background: The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding. Methods: We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing. Results: We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity. Interpretation: These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.

Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.

Dysbiosis of the infant gut microbiota may have long‐term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut microbiota, and to explore whether breastfeeding modifies these effects.

The effect of supervised prenatal exercise on fetal growth: a meta-analysis

OBJECTIVE: To estimate the influence of structured prenatal exercise on newborn birth weight, macrosomia, and growth restriction. DATA SOURCES: A structured search of MEDLINE, EMBASE, CINAHL, Sport Discus, Ovids All EBM Reviews, and ClinicalTrials.gov databases up to January 13, 2015. The search combined keywords and MeSH-like terms including, but not limited, to “physical activity,” “exercise,” “pregnancy,” “gestation,” “neonatal,” and “randomized controlled trial.” METHODS OF STUDY SELECTION: Articles reporting randomized controlled trials comparing standard care with standard care plus supervised prenatal exercise for which birth size was available were included. Supervision was defined as at least one exercise session performed with study personnel every 2 weeks throughout the program. Interventions consisting solely of pelvic floor exercises, stretching, or relaxation were excluded. Our search yielded 1,036 publications of which 79 were assessed for eligibility. Twenty-eight studies reporting on 5,322 pregnancies were subsequently included in the analysis. TABULATION, INTEGRATION, AND RESULTS: Our meta-analysis demonstrated that prenatal exercise reduced the odds of having a large newborn (birth weight greater than 4,000 g or greater than the 90th percentile for gestational age and sex) by 31% (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55–0.86; I 2 25%) without altering the risk of having a small newborn (birth weight less than 2,500 g or less than the 10th percentile for gestational age and sex) (OR 1.02, 95% CI 0.72–1.46; I 2 0%) or gestational age at delivery (weighted mean difference −0.00 weeks, 95% CI −0.09 to 0.09; I 2 0%). Newborns of mothers assigned to exercise were lighter than those of nonexercising controls (weighted mean difference –31 g, 95% CI –57 to −4; I 2 0%). Maternal gestational weight gain (weighted mean difference −1.1 kg, 95% CI −1.5 to −0.6; I 2 53%) and odds of cesarean delivery (OR 0.80, 95% CI 0.69–0.94; I 2 0%) were also reduced. CONCLUSION: These data demonstrate that structured prenatal exercise reduces the risk of having a large newborn without a change in the risk of having a small newborn.

A systematic review of intentional delivery in women with preterm prelabor rupture of membranes

Objective. To evaluate the effect of intentional delivery versus expectant management in women with preterm prelabor rupture of membranes (PPROM). Methods. We searched electronic databases and trials registries, contacted experts, and checked reference lists of relevant studies. Studies were included if they were randomized controlled trials comparing intentional delivery versus expectant management after PPROM, the gestational age of participants was between 30 and 36 weeks, and the study reported one of several pre-determined outcomes. Results. Four studies were included in the meta-analysis. No difference was found between intentional delivery and expectant management in neonatal intensive care unit (NICU) length of stay (LOS) (weighted mean difference (WMD) −0.81 day, 95% confidence interval (CI) −1.66, 0.04), respiratory distress syndrome (risk difference (RD) −0.01, 95% CI −0.07, 0.06), and confirmed neonatal sepsis (RD −0.01, 95% CI −0.05, 0.04). One study found a significantly lower incidence of suspected neonatal sepsis among the intentional delivery group (RD −0.31, 95% CI −0.50, −0.12; number needed to treat (NNT) 3, 95% CI 2, 8). Maternal LOS was significantly shorter for the intentional delivery group (WMD −1.39 day, 95% CI −2.03, −0.75). There was a significant difference in the incidence of clinical chorioamnionitis favoring intentional delivery (RD −0.16, 95% CI −0.23, −0.10; NNT 6, 95% CI 5, 11). There was no significant difference in the incidence of other maternal outcomes, including cesarean section (RD 0.05, 95% CI −0.01, 0.11). Conclusions. Intentional delivery may be favorable to expectant management for some maternal outcomes (chorioamnionitis and LOS). There is insufficient evidence to suggest that either strategy is beneficial or harmful for the baby. Large multicenter trials with primary neonatal outcomes are required to assess whether intentional delivery is associated with less neonatal morbidity.

Perinatal antibiotic exposure of neonates in Canada and associated risk factors: a population-based study

Abstract Objective: To describe neonatal antibiotic exposures occurring immediately before and after birth and their associated risk factors. Methods: A retrospective review of the hospital charts of 449 mother–neonate pairs enrolled in the Canadian Healthy Infant Longitudinal Development national birth-cohort study was conducted at two tertiary hospitals and one rural hospital in Manitoba, Canada. The main outcome measures included the following: maternal and neonatal antibiotic use during the perinatal period; indications for antibiotic use, including suspected neonatal sepsis, maternal group B Streptococcus (GBS), premature rupture of membranes and caesarean-section; maternal health status, focusing on gestational hypertension, gestational diabetes, obesity and primigravida pregnancies. Results: During the perinatal period, 45.0% of neonates were exposed to antibiotics. Intravenous penicillin G (17%) and cefazolin (16%) were the most commonly administered intrapartum antibiotics. Colonization with GBS was confirmed in 21.2% of women and treated with antibiotics in 86% of cases. Overweight women and women with hypertension were significantly more likely to receive intrapartum antibiotics for caesarean section or GBS prophylaxis. Antibiotic treatment of the neonate was highest following emergency caesarean section (12%) or unknown maternal GBS status (20%). Conclusions: Neonates in Canada are routinely exposed to antibiotics during the perinatal period.

Is fetal neurologic and physical development accelerated in preeclampsia

OBJECTIVE Our objective was to determine whether the Ballard score, a maturity score for neonatal neuromuscular and physical development, is more advanced in preterm infants of preeclamptic women than in controls. STUDY DESIGN A matched cohort study design was used. One hundred women with strictly defined preeclampsia (new-onset hypertension, proteinuria, and hyperuricemia) were matched for gestational age, race, and gender to 100 normotensive women with preterm delivery. All patients had an assigned antenatal gestational age based on ultrasonography before 24 weeks. The gestational age, based on antenatal ultrasonography and last menstrual period, was compared with the Ballard score given at the time of neonatal physical examination within the first 12 hours after delivery. The difference in gestational age between the Ballard score and antenatal ultrasonography (Ballard score - ultrasonography) was calculated for each patient. Results are expressed as median and range and are compared with a Student t test. RESULTS The mean gestational age at delivery by antenatal ultrasonography in patients with severe preeclampsia was 32.06 +/- 2.74 and 32.03 +/- 2.70 weeks, respectively. The median difference between scores in patients with severe preeclampsia and normal patient were 1.3 +/- 1.8 and 1.5 +/- 1.6 weeks, respectively (p = 0.41). CONCLUSION On the basis of criteria defined by the Ballard score, preeclampsia was not associated with accelerated fetal neurologic and physical development.

Regulation of Sympathetic Nerve Activity During the Cold Pressor Test in Normotensive Pregnant and Nonpregnant Women

Baseline neurovascular transduction is reduced in normotensive pregnancy; however, little is known about changes to neurovascular transduction during periods of heightened sympathetic activation. We tested the hypothesis that, despite an exacerbated muscle sympathetic nerve activity (microneurography) response to cold pressor stimulation, the blunting of neurovascular transduction in normotensive pregnant women would result in similar changes in vascular resistance and mean arterial pressure (Finometer) relative to nonpregnant controls. Baseline neurovascular transduction was reduced in pregnant women relative to controls when expressed as the quotient of both total resistance and mean arterial pressure and sympathetic burst frequency (0.32±0.07 versus 0.58±0.16 mm Hg/L/min/bursts/min, P<0.001 and 2.4±0.7 versus 3.6±0.8 mm Hg/bursts/min, P=0.001). Sympathetic activation was greater across all 3 minutes of cold pressor stimulation in the pregnant women relative to the nonpregnant controls. Peak sympathoexcitation was also greater in pregnant than in nonpregnant women, whether expressed as sympathetic burst frequency (+17±13 versus +7±8 bursts/min, P=0.049), burst incidence (+17±9 versus +6±11 bursts/100 hb, P=0.03), or total activity (+950±660 versus +363±414 arbitrary units, P=0.04). However, neurovascular transduction during peak cold pressor–induced sympathoexcitation remained blunted in pregnant women (0.25±0.11 versus 0.45±0.08 mm Hg/L/min/bursts/min, P<0.001 and 1.9±1.0 versus 3.2±0.9 mm Hg/bursts/min, P=0.006). Therefore, mean arterial pressure (93±21 versus 99±6 mm Hg, P=0.4) and total peripheral resistance (12±3 versus 14±3 mm Hg/L/min) were not different between pregnant and nonpregnant women during peak sympathoexcitation. These data indicate that the third trimester of normotensive pregnancy is associated with reductions in neurovascular transduction, which result in the dissociation of sympathetic outflow from hemodynamic outcomes, even during cold pressor–induced sympathoexcitation.

Sympathetic baroreflex gain in normotensive pregnant women

Muscle sympathetic nerve activity is increased during normotensive pregnancy while mean arterial pressure is maintained or reduced, suggesting baroreflex resetting. We hypothesized spontaneous sympathetic baroreflex gain would be reduced in normotensive pregnant women relative to nonpregnant matched controls. Integrated muscle sympathetic burst incidence and total sympathetic activity (microneurography), blood pressure (Finometer), and R-R interval (ECG) were assessed at rest in 11 pregnant women (33 ± 1 wk gestation, 31 ± 1 yr, prepregnancy BMI: 23.5 ± 0.9 kg/m(2)) and 11 nonpregnant controls (29 ± 1 yr; BMI: 25.2 ± 1.7 kg/m(2)). Pregnant women had elevated baseline sympathetic burst incidence (43 ± 2 vs. 33 ± 2 bursts/100 heart beats, P = 0.01) and total sympathetic activity (1,811 ± 148 vs. 1,140 ± 55 au, P < 0.01) relative to controls. Both mean (88 ± 3 vs. 91 ± 2 mmHg, P = 0.4) and diastolic (DBP) (72 ± 3 vs. 73 ± 2 mmHg, P = 0.7) pressures were similar between pregnant and nonpregnant women, respectively, indicating an upward resetting of the baroreflex set point with pregnancy. Baroreflex gain, calculated as the linear relationship between sympathetic burst incidence and DBP, was reduced in pregnant women relative to controls (-3.7 ± 0.5 vs. -5.4 ± 0.5 bursts·100 heart beats(-1)·mmHg(-1), P = 0.03), as was baroreflex gain calculated with total sympathetic activity (-294 ± 24 vs. -210 ± 24 au·100 heart beats(-1)·mmHg(-1); P = 0.03). Cardiovagal baroreflex gain (sequence method) was not different between nonpregnant controls and pregnant women (49 ± 8 vs. 36 ± 8 ms/mmHg; P = 0.2). However, sympathetic (burst incidence) and cardiovagal gains were negatively correlated in pregnant women (R = -0.7; P = 0.02). Together, these data indicate that the influence of the sympathetic nervous system over arterial blood pressure is reduced in normotensive pregnancy, in terms of both long-term and beat-to-beat regulation of arterial pressure, likely through a baroreceptor-dependent mechanism.

Roles of Birth Mode and Infant Gut Microbiota in Intergenerational Transmission of Overweight and Obesity From Mother to Offspring

Importance Maternal overweight, which often results in cesarean delivery, is a strong risk factor for child overweight. Little is known about the joint contribution of birth mode and microbiota in the infant gut to the association between maternal prepregnancy overweight and child overweight. Objective To investigate the association of birth mode with microbiota in the infant gut, and whether this mediates the association between maternal and child overweight. Design, Setting, and Participants An observational study was conducted of 935 full-term infants born between January 1, 2009, and December 31, 2012, in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Maternal prepregnancy body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared using height and weight data taken from medical records or maternal report. Infant gut microbiota were profiled with 16S ribosomal RNA sequencing in fecal samples collected at a mean (SD) age of 3.7 (1.0) months. At ages 1 and 3 years, BMI z scores adjusted for age and sex were generated according to World Health Organization criteria. Statistical analysis was conducted from January 29 to June 15, 2017. Exposures Mothers of normal weight (BMI, 18.5-24.9) and overweight or obese (BMI, ≥25.0) mothers. Main Outcome and Measures Risk of overweight and obesity (>97th percentile BMI z scores) among children at ages 1 and 3 years. Results Of the 935 mother-infant pairs in the study (mean [SD] age, 32.5 [4.5] years) 382 (40.9%) were overweight, 69 of 926 infants (7.5%) were overweight at age 1 year, and 90 of 866 infants (10.4%) were overweight at age 3 years. Compared with being born vaginally to a mother of normal weight, infants born vaginally to overweight or obese mothers were 3 times more likely to become overweight at age 1 year (adjusted odds ratio [OR], 3.33; 95% CI, 1.49-7.41), while cesarean-delivered infants of overweight mothers had a 5-fold risk of overweight at age 1 year (adjusted OR, 5.02; 95% CI, 2.04-12.38). Similar risks were also observed at age 3 years. Multiple mediator path modeling revealed that birth mode and infant gut microbiota (Firmicutes species richness, especially of the Lachnospiraceae family) sequentially mediated the association between maternal prepregnancy overweight and childhood overweight at ages 1 and 3 years. Bacterial genera belonging to the Lachnospiraceae family were more abundant in infants of overweight mothers; however, the participating genera of Lachnospiraceae differed between infants delivered vaginally and those delivered via cesarean birth. Conclusions and Relevance This study found evidence of a novel sequential mediator pathway involving birth mode and Firmicutes species richness (especially higher abundance of Lachnospiraceae) for the intergenerational transmission of overweight.

Cesarean Section, Formula Feeding, and Infant Antibiotic Exposure: Separate and Combined Impacts on Gut Microbial Changes in Later Infancy

Established during infancy, our complex gut microbial community is shaped by medical interventions and societal preferences, such as cesarean section, formula feeding, and antibiotic use. We undertook this study to apply the significance analysis of microarrays (SAM) method to quantify changes in gut microbial composition during later infancy following the most common birth and postnatal exposures affecting infant gut microbial composition. Gut microbiota of 166 full-term infants in the Canadian Healthy Infant Longitudinal Development birth cohort were profiled using 16S high-throughput gene sequencing. Infants were placed into groups according to mutually exclusive combinations of birth mode (vaginal/cesarean birth), breastfeeding status (yes/no), and antibiotic use (yes/no) by 3 months of age. Based on repeated permutations of data and adjustment for the false discovery rate, the SAM statistic identified statistically significant changes in gut microbial abundance between 3 months and 1 year of age within each infant group. We observed well-known patterns of microbial phyla succession in later infancy (declining Proteobacteria; increasing Firmicutes and Bacteroidetes) following vaginal birth, breastfeeding, and no antibiotic exposure. Genus Lactobacillus, Roseburia, and Faecalibacterium species appeared in the top 10 increases to microbial abundance in these infants. Deviations from this pattern were evident among infants with other perinatal co-exposures; notably, the largest number of microbial species with unchanged abundance was seen in gut microbiota following early cessation of breastfeeding in infants. With and without antibiotic exposure, the absence of a breast milk diet by 3 months of age following vaginal birth yielded a higher proportion of unchanged abundance of Bacteroidaceae and Enterobacteriaceae in later infancy, and a higher ratio of unchanged Enterobacteriaceae to Alcaligenaceae microbiota. Gut microbiota of infants born vaginally and exclusively formula fed became less enriched with family Veillonellaceae and Clostridiaceae, showed unchanging levels of Ruminococcaceae, and exhibited a greater decline in the Rikenellaceae/Bacteroidaceae ratio compared to their breastfed, vaginally delivered counterparts. These changes were also evident in cesarean-delivered infants to a lesser extent. The clinical relevance of these trajectories of microbial change is that they culminate in taxon-specific abundances in the gut microbiota of later infancy, which we and others have observed to be associated with food sensitization.