| Summary: | Summary: Background: Association of timing and intensity of maternal smoking during pregnancy with all-cause and cause-specific infant death remains inconclusive. We aimed to examine the dose–response association of maternal smoking during each of the three trimesters of pregnancy with all-cause and cause-specific infant death. Methods: In this nationwide, population-based, retrospective cohort study, data were extracted from the U.S. National Vital Statistics System, 2015–2019. We included mother–infant pairs after excluding twin or multiple births, newborns with gestation age <37 weeks and those with low birthweight, mothers aged <18 years or ≥50 years, mothers with pre-existing hypertension or diabetes, and those with missing values for variables of interest. Poisson regression models were used to examine the association of different intensities and doses of maternal smoking during each of the three trimesters of pregnancy with all-cause and cause-specific infant death attributed to congenital anomalies, preterm birth, other perinatal conditions, sudden unexpected infant death, and infection. Findings: A total of 13,524,204 mother–infant pairs were included in our analyses. Maternal smoking during the entire pregnancy was associated with infant all-cause death (relative risk [RR] 1.88, 95% confidence interval [95% CI] 1.79–1.97), cause-specific death due to preterm birth (1.57, 1.25–1.98), perinatal conditions excluding preterm birth (1.35, 1.10–1.65), sudden unexpected infant death (2.56, 2.40–2.73), and infection (1.51, 1.20–1.88). The risk of infant all-cause death (RR values from 1.80 to 2.15) and cause-specific infant death by preterm birth (RR values from 1.42 to 1.74), perinatal conditions excluding preterm birth (RR values from 1.46 to 1.53), sudden unexpected infant death (RR values from 2.37 to 3.04), and infection (RR values from 1.48 to 2.69) increased with the intensity of maternal cigarette use during the entire pregnancy from 1–5 to ≥11 cigarettes. Compared with mothers who smoked during their entire pregnancy, those who smoked in the first trimester and then quit smoking in the second or third trimesters of pregnancy had a reduced risk of infant all-cause death (0.71, 0.65–0.78) and sudden unexpected infant death (0.64, 0.57–0.72). Interpretation: There was a dose–response association of maternal cigarette use during each of the three trimesters of pregnancy with all-cause and cause-specific infant death. In addition, mothers who are smokers in the first trimester and then quit smoking in the subsequent two trimesters are at decreased risk of infant all-cause mortality and sudden unexpected infant death compared with those who smoked during the entire pregnancy. These findings suggest that there is no safe level of maternal smoking in any trimester of pregnancy and maternal smokers should stop smoking during pregnancy to improve the survival of infants. Funding: Youth Team of Humanistic and Social Science and the Innovation Team of the “Climbing” Program of Shandong University (20820IFYT1902).
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