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Background: Vitamin C (500 mg·day -1 ) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported., Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age., Methods: This is a pre-specified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day -1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated-measures analysis of covariance., Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were 40.2 mL·s -1 for at FEF 75 (75% of forced vital capacity (FVC)) (adjusted 95% CI for difference 6.6-73.8; p=0.025); 58.3 mL·s -1 for FEF 50 (10.9-105.8; p=0.0081); and 55.1 mL·s -1 for FEF 25-75 (9.7-100.5; p=0.013)., Conclusions: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway., Competing Interests: Conflict of interest: C.T. McEvoy reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: L.E. Shorey-Kendrick reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: K. Milner reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: D. Schilling reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: C. Tiller reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: B. Vuylsteke reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: A. Scherman reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: K. Jackson reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: D.M. Haas reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: J. Harris reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: B.S. Park reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: A. Vu reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: D.F. Kraemer reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: D. Gonzales reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: C. Bunten has nothing to disclose. Conflict of interest: E.R. Spindel reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: C.D. Morris reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study. Conflict of interest: R.S. Tepper reports grants from NHLBI (R01HL105447 and R01 HL105460), Office of Dietary Supplements, P51 OD011092565, NIH (UH3 OD023288) and UL1TR000128, during the conduct of the study., (Copyright ©ERS 2020.)

Rationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF 75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF 50 and FEF 25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C ( n  = 113) had the following FEFs at 3 months of age compared with those randomized to placebo ( n  =  109) as measured by FEF 75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P  = 0.10), FEF 50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P  = 0.02), and FEF 25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P  = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF 75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF 50 and FEF 25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF 50 and FEF 25-75 ) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

Importance: Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function., Objective: To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo., Design, Setting, and Participants: Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year., Interventions: Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90)., Main Outcomes and Measures: The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed., Results: Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P < .001 for interaction)., Conclusions and Relevance: Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities., Trial Registration: clinicaltrials.gov Identifier: NCT00632476.

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and maintenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3-year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre- and perimenopausal women who were part of the Michigan Bone Health Study, a population-based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone-related serum protein measurements, and life-style characteristics were also available on each woman. Based on evaluation of women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.05) and total body BMD level, but not their change over the 3-year period examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone-related serum and body composition measurements in the 372 women in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene x gene interaction effect (p < 0.05) for the VDR locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD levels. Women who had the (-/-) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (-/-) PvuII ER and BB VDR genotype had significantly lower BMD levels. This contrast was not explained by differences in serum levels of osteocalcin, parathyroid hormone, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D. These data suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.