Abstract
This study examines the prevalence of congenital anomalies in infants born to mothers with preterm birth occurring in a previous pregnancy.
Introduction
Congenital anomalies (CAs) are the leading cause of infant mortality, accounting for more than 20% of infant deaths in the US in 2017.1 Several parental risk factors of CAs, including diabetes before pregnancy and maternal smoking, have been identified.2,3 However, data on the associations of maternal history of previous pregnancy outcomes with the risk of CAs are sparse. To further elucidate potential risk factors, we evaluated maternal history of preterm birth (PTB) and offspring CAs.
Methods
This retrospective population-based cohort study used birth data from the US National Vital Statistics System from January 1, 2016, to December 31, 2019, including all women with a live singleton birth. Data analysis was conducted from February 1 to February 15, 2022. Because deidentified data are publicly available, ethics approval was not required by the institutional review board of Children’s Hospital of Fudan University. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Information on maternal history of PTB and 12 subtypes of CAs was retrieved from birth certificates. Because of low incidence of the outcome, proportions are expressed in parts per thousand (‰). The associations of maternal history of PTB with neonatal CAs were estimated as risk differences, crude odds ratios (ORs), and adjusted ORs (aOR) with 95% CIs. Stratified analyses according to baseline characteristics were performed. Adjustments were made for potential confounders, including maternal age, race and ethnicity, educational levels, marital status, parity, smoking before and during pregnancy, prepregnancy body mass index categories, timing of initiation of prenatal care, prepregnancy hypertension, prepregnancy diabetes, gestational hypertension, gestational diabetes, and infant sex. A description of methods and potential confounders is available in the eMethods in the Supplement. All P values were 2-sided, and P < .05 was considered statistically significant. Statistical analyses were performed using Stata, version 15.0 (StataCorp LLC).
Results
A total of 14 774 946 mother-neonate pairs with live singleton birth were included in the final analysis; the mean (SD) age of the mothers was 28.86 (5.81) years. The prevalence of CAs was 3.19‰ (47 205 of 14 774 946). Neonates born to mothers with a history of PTB had a higher prevalence in parts per thousand of CAs than did neonates born to mothers without a PTB history (5.25‰ [2554 of 486 894] vs 3.13‰ [44 651 of 14 288 052]; risk difference, 2.12; 95% CI, 1.91-2.33; crude OR, 1.68; 95% CI, 1.62-1.75). After full adjustment, the OR of CAs was 1.47 (95% CI, 1.42-1.54) for maternal history of PTB. For specific subtypes of CAs, maternal history of PTB was associated with an increased risk of nearly all subtypes except anencephaly (aOR, 1.25; 95% CI, 0.87-1.79). For example, the aOR of cyanotic congenital heart disease was 1.76 (95% CI, 1.60-1.93) for maternal history of PTB (Table 1).
Table 1. Association of Maternal History of PTB With Congenital Anomalies in Offspring.
| Congenital anomalies | No maternal history of PTB (n = 14 288 052) | Maternal history of PTB (n = 486 894) |
|---|---|---|
| Congenital anomaliesa | ||
| Cases, No. (‰) | 44 651 (3.13) | 2 554 (5.25) |
| RD (95% CI), ‰ | 1 [Reference] | 2.12 (1.91 to 2.33) |
| Crude OR (95% CI) | 1 [Reference] | 1.68 (1.62 to 1.75) |
| aOR (95% CI)b | 1 [Reference] | 1.47 (1.42 to 1.54) |
| Cyanotic congenital heart disease | ||
| Cases, No. (‰) | 6 959 (0.49) | 527 (1.08) |
| RD (95% CI), ‰ | 1 [Reference] | 0.60 (0.50 to 0.69) |
| Crude OR (95% CI) | 1 [Reference] | 2.22 (2.04 to 2.43) |
| aOR (95% CI)b | 1 [Reference] | 1.76 (1.60 to 1.93) |
| Congenital diaphragmatic hernia | ||
| Cases, No. (‰) | 1 414 (0.10) | 87 (0.18) |
| RD (95% CI), ‰ | 1 [Reference] | 0.08 (0.04 to 0.12) |
| Crude OR (95% CI) | 1 [Reference] | 1.81 (1.45 to 2.24) |
| aOR (95% CI)b | 1 [Reference] | 1.76 (1.41 to 2.21) |
| Omphalocele | ||
| Cases, No. (‰) | 1 185 (0.08) | 63 (0.13) |
| RD (95% CI), ‰ | 1 [Reference] | 0.05 (0.01 to 0.08) |
| Crude OR (95% CI) | 1 [Reference] | 1.56 (1.21 to 2.01) |
| aOR (95% CI)b | 1 [Reference] | 1.60 (1.23 to 2.08) |
| Gastroschisis | ||
| Cases, No. (‰) | 3 130 (0.22) | 121 (0.25) |
| RD (95% CI), ‰ | 1 [Reference] | 0.03 (−0.02 to 0.07) |
| Crude OR (95% CI) | 1 [Reference] | 1.13 (0.95 to 1.36) |
| aOR (95% CI)b | 1 [Reference] | 1.76 (1.46 to 2.13) |
| Limb reduction defect | ||
| Cases, No. (‰) | 1 650 (0.12) | 89 (0.18) |
| RD (95% CI), ‰ | 1 [Reference] | 0.07 (0.03 to 0.01) |
| Crude OR (95% CI) | 1 [Reference] | 1.58 (1.28 to 1.96) |
| aOR (95% CI)b | 1 [Reference] | 1.43 (1.14 to 1.78) |
| Cleft lip with or without cleft palate | ||
| Cases, No. (‰) | 6 938 (0.49) | 349 (0.72) |
| RD (95% CI), ‰ | 1 [Reference] | 0.23 (0.16 to 0.31) |
| Crude OR (95% CI) | 1.00 [Reference] | 1.48 (1.33 to 1.64) |
| aOR (95% CI)b | 1.00 [Reference] | 1.32 (1.18 to 1.47) |
| Cleft palate alone | ||
| Cases, No. (‰) | 3 161 (0.22) | 177 (0.36) |
| RD (95% CI), ‰ | 1 [Reference] | 0.14 (0.09 to 0.20) |
| Crude OR (95% CI) | 1 [Reference] | 1.64 (1.41 to 1.91) |
| aOR (95% CI)b | 1 [Reference] | 1.41 (1.20 to 1.65) |
| Hypospadias | ||
| Cases, No. (‰) | 8 136 (1.11) | 394 (1.59) |
| RD (95% CI), ‰ | 1 [Reference] | 0.48 (0.32 to 0.63) |
| Crude OR (95% CI) | 1 [Reference] | 1.43 (1.29 to 1.58) |
| aOR (95% CI)b | 1 [Reference] | 1.45 (1.30 to 1.61) |
| Anencephaly | ||
| Cases, No. (‰) | 684 (0.05) | 33 (0.07) |
| RD (95% CI), ‰ | 1 [Reference] | 0.02 (−0.004 to 0.04) |
| Crude OR (95% CI) | 1 [Reference] | 1.42 (1.00 to 2.01) |
| aOR (95% CI)b | 1 [Reference] | 1.25 (0.87-1.79) |
| Meningomyelocele/spina bifida | ||
| Cases, No. (‰) | 1 848 (0.13) | 109 (0.22) |
| RD (95% CI), ‰ | 1 [Reference] | 0.09 (0.05 to 0.14) |
| Crude OR (95% CI) | 1 [Reference] | 1.73 (1.43 to 2.10) |
| aOR (95% CI)b | 1 [Reference] | 1.55 (1.27 to 1.90) |
| Down syndrome | ||
| Cases, No. (‰) | 7 319 (0.51) | 473 (0.97) |
| RD (95% CI), ‰ | 1 [Reference] | 0.46 (0.37 to 0.55) |
| Crude OR (95% CI) | 1 [Reference] | 1.90 (1.73 to 2.08) |
| aOR (95% CI)b | 1 [Reference] | 1.30 (1.18 to 1.43) |
| Suspected chromosomal disorder | ||
| Cases, No. (‰) | 5 137 (0.36) | 356 (0.73) |
| RD (95% CI), ‰ | 1 [Reference] | 0.37 (0.30 to 0.45) |
| Crude OR (95% CI) | 1 [Reference] | 2.03 (1.83 to 2.57) |
| aOR (95% CI)b | 1 [Reference] | 1.66 (1.48 to 1.95) |
Abbreviations: aOR, adjusted odds ratio; PTB, preterm birth; RD, risk difference.
Congenital anomalies defined as any specific subtype of congenital anomalies in the data set.
Adjusted for maternal age group, race and ethnicity, educational levels, marital status, parity, smoking before pregnancy and during pregnancy, prepregnancy body mass index categories, timing of initiation of prenatal care, prepregnancy hypertension, prepregnancy diabetes, gestational hypertension, gestational diabetes, and infant sex (except for hypospadias).
Subgroup analyses by maternal age, race and ethnicity, educational level, parity, smoking before and during pregnancy, time of initiation of prenatal care, prepregnancy body mass index, prepregnancy hypertension, prepregnancy diabetes, gestational hypertension, gestational diabetes, and neonate sex were conducted. The neonates who were born to mothers with a history of PTB had a higher risk of CAs in all subgroups after full adjustment (Table 2).
Table 2. Subgroup Analyses of Associations Between Maternal History of PTB and Risk of Congenital Anomalies in Offspring.
| Variable | No history of PTB | Maternal history of PTBa | |||
|---|---|---|---|---|---|
| No. cases/No. total | No. cases/No. total | RD vs reference (95% CI), ‰ | Crude OR (95% CI) | aOR (95% CI)b | |
| Maternal age group, y | |||||
| <30 | 23 122/7 741 276 | 1 042/220 660 | 1.74 (1.45-2.02) | 1.58 (1.49-1.69) | 1.59 (1.49-1.69) |
| 30-34 | 11 103/4 054 751 | 700/150 651 | 1.91 (1.56-2.26) | 1.70 (1.57-1.84) | 1.48 (1.37-1.61) |
| 35-39 | 7 297/2 041 220 | 541/92 699 | 2.26 (1.76-2.76) | 1.64 (1.50-1.79) | 1.37 (1.25-1.50) |
| ≥40 | 3 129/450 805 | 271/22 884 | 4.90 (3.48-6.32) | 1.71 (1.51-1.94) | 1.38 (1.22-1.57) |
| Race and ethnicityc | |||||
| Hispanic | 9 016/3 402 006 | 514/106 969 | 2.15 (1.74-2.57) | 1.82 (1.66-1.99) | 1.49 (1.36-1.64) |
| Non-Hispanic Black | 4 916/2 010 484 | 404/101 911 | 1.52 (1.13-1.91) | 1.62 (1.47-1.80) | 1.46 (1.31-1.62) |
| Non-Hispanic White | 26 952/7 368 270 | 1 426/236 111 | 2.38 (2.07-2.70) | 1.66 (1.57-1.75) | 1.47 (1.40-1.56) |
| Otherd | 3 425/1 383 200 | 190/38 259 | 2.49 (1.78-3.20) | 2.01 (1.74-2.33) | 1.49 (1.28-1.73) |
| Missing data | 342/124 092 | 20/3 544 | 2.73 (0.32-5.15) | 2.00 (1.27-3.14) | 1.37 (0.86-2.19) |
| Educational level | |||||
| <High school diploma | 6 448/1 833 168 | 472/83 178 | 2.16 (1.64-2.67) | 1.62 (1.47-1.78) | 1.46 (1.32-1.60) |
| High school diploma | 11 800/3 613 829 | 710/140 464 | 1.79 (1.41-2.16) | 1.55 (1.44-1.67) | 1.45 (1.34-1.57) |
| >High school diploma | 25 910/8 657 434 | 1 338/258 050 | 2.19 (1.91-2.47) | 1.74 (1.64-1.83) | 1.50 (1.42-1.59) |
| Missing data | 493/183 621 | 34/5 202 | 3.85 (1.65-6.05) | 2.44 (1.72-3.46) | 1.68 (1.17-2.42) |
| Parity | |||||
| 1 | 12 739/4 543 797 | 771/166 601 | 1.82 (1.49-2.15) | 1.65 (1.54-1.78) | 1.47 (1.37-1.59) |
| 2 | 7 410/2 355 674 | 743/146 467 | 1.93 (1.56-2.30) | 1.62 (1.50-1.74) | 1.49 (1.38-1.61) |
| 3 | 3 407/989 607 | 497/87 745 | 2.22 (1.71-2.73) | 1.65 (1.50-1.81) | 1.56 (1.41-1.71) |
| ≥4 | 2 917/680 685 | 539/84 704 | 2.08 (1.52-2.64) | 1.45 (1.36-1.63) | 1.49 (1.36-1.64) |
| Missing data | 85/37 446 | 4/1 318 | 0.77 (−2.24-3.77) | 1.34 (0.49-3.65) | 1.21 (0.44-3.33) |
| Smoking before pregnancy | |||||
| No | 38 981/13 026 560 | 2 058/410 724 | 2.02 (1.80-2.24) | 1.68 (1.60-1.75) | 1.48 (1.41-1.55) |
| Yes | 5 425/1 195 369 | 472/72 683 | 1.96 (1.36-2.55) | 1.43 (1.30-1.58) | 1.46 (1.32-1.61) |
| Missing data | 245/66 123 | 24/3 487 | 3.18 (0.39-5.96) | 1.86 (1.22-2.83) | 1.91 (1.23-2,97) |
| Smoking during pregnancy | |||||
| No | 40 041/13 292 525 | 2 113/419 453 | 2.03 (1.81-2.24) | 1.68 (1.60-1.75) | 1.49 (1.42-1.56) |
| Yes | 4 255/913 305 | 404/61 968 | 1.86 (1.21-2.51) | 1.40 (1.27-1.55) | 1.45 (1.30-1.61) |
| Missing data | 355/82 222 | 37/5 473 | 2.44 (0.23-4.66) | 1.57 (1.12-2.20) | 1.37 (0.96-1.97) |
| Time of initiation of prenatal care | |||||
| First to third mo | 30 883/10 785 358 | 1 644/346 936 | 1.88 (1.64-2.11) | 1.66 (1.58-1.74) | 1.44 (1.37-1.52) |
| Fourth to sixth mo | 8 604/2 274 797 | 573/90 735 | 2.53 (2.01-3.05) | 1.67 (1.54-1.82) | 1.55 (1.42-1.70) |
| Seventh to ninth mo | 2 781/641 303 | 162/24 156 | 2.37 (1.33-3.41) | 1.55 (1.32-1.82) | 1.48 (1.26-1.74) |
| No prenatal care | 849/234 780 | 70/11 969 | 2.23 (0.84-3.62) | 1.62 (1.27-2.07) | 1.44 (1.12-1.85) |
| Missing data | 1 534/351 814 | 105/12 993 | 3.66 (2.11-5.20) | 1.85 (1.51-2.25) | 1.62 (1.32-1.99) |
| Prepregnancy BMI | |||||
| 18.5-24.9 | 18 030/6 010 519 | 937/174 759 | 2.36 (2.02-2.71) | 1.79 (1.68-1.92) | 1.56 (1.45-1.66) |
| <18.5 | 1 430/461 232 | 91/15 979 | 2.59 (1.42-3.77) | 1.84 (1.49-2.28) | 1.67 (1.33-2.09) |
| 25.0-29.9 | 11 375/3 689 966 | 601/125 146 | 1.72 (1.33-2.10) | 1.56 (1.44-1.69) | 1.37 (1.26-1.49) |
| ≥30 | 12 628/3 783 718 | 845/158 615 | 1.99 (1.63-2.35) | 1.60 (1.49-1.72) | 1.44 (1.34-1.54) |
| Missing data | 1 188/342 617 | 80/12 395 | 2.99 (1.56-4.41) | 1.87 (1.49-2.34) | 1.51 (1.19-1.91) |
| Prepregnancy hypertension | |||||
| No | 43 322/14 027 747 | 2 360/462 419 | 2.02 (1.81-2.22) | 1.66 (1.59-1.73) | 1.47 (1.41-1.54) |
| Yes | 1 329/260 305 | 194/24 475 | 2.82 (1.68-3.97) | 1.56 (1.34-1.81) | 1.51 (1.29-1.77) |
| Gestational hypertension | |||||
| No | 40 756/13 361 262 | 2 255/438 335 | 2.09 (1.88-2.31) | 1.69 (1.62-1.76) | 1.49 (1.43-1.56) |
| Yes | 3 895/926 790 | 299/48 559 | 1.96 (1.25-2.66) | 1.47 (1.30-1.65) | 1.33 (1.17-1.50) |
| Prepregnancy diabetes | |||||
| No | 43 734/14 165 096 | 2 394/474 947 | 1.95 (1.75-2.16) | 1.64 (1.57-1.70) | 1.46 (1.40-1.53) |
| Yes | 917/122 956 | 160/11 947 | 5.93 (3.82-8.05) | 1.81 (1.53-2.14) | 1.69 (1.41-2.02) |
| Gestational diabetes | |||||
| No | 41 057/13 391 043 | 2 275/440 708 | 2.10 (1.88-2.31) | 1.69 (1.62-1.76) | 1.49 (1.43-1.56) |
| Yes | 3 594/897 009 | 279/46 186 | 2.03 (1.32-2.75) | 1.51 (1.34-1.71) | 1.33 (1.17-1.51) |
| Neonate sex | |||||
| Male | 27 692/7 310 500 | 1 539/248 117 | 2.41 (2.10-2.73) | 1.64 (1.56-1.73) | 1.48 (1.40-1.56) |
| Female | 16 959/6 977 552 | 1 015/238 777 | 1.82 (1.55-2.08) | 1.75 (1.64-1.87) | 1.47 (1.38-1.57) |
Abbreviations: aOR, adjusted odds ratio; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); OR, odds ratio; PTB, preterm birth.
Neonates born to mothers with no history of PTB were the reference group.
Adjusted for maternal age group, race and ethnicity, educational levels, marital status, parity, smoking before pregnancy and during pregnancy, prepregnancy BMI categories, timing of initiation of prenatal care, prepregnancy hypertension, prepregnancy diabetes, gestational hypertension, gestational diabetes, and infant sex were adjusted, except when the variable was stratified.
Self-reported.
Included individuals who were non-Hispanic Asian, non-Hispanic Native American or Alaskan, non-Hispanic Native Hawaiian or other Pacific Islanders, non-Hispanic people of more than 1 race, of unknown racial or ethnic origin, or not stated.
Discussion
The findings of this study suggest that maternal history of PTB increased the risk of birth CAs in offspring. The mechanisms underlying the association between maternal history of PTB and birth CAs are yet to be elucidated. Previous PTB may be related to defects of the placenta and metabolic disorders of the mothers,4,5 which may involve the development of CAs. Limitations of this study include potential unmeasured confounding factors. Neonates born to mothers with a history of PTB may have an increased risk of CAs. These findings may help to identify neonates at high risk of CAs.
eMethods. Detailed Methods
Reference
- 1.Ely DM, Driscoll AK. Infant mortality in the United States, 2017: data From the Period Linked Birth/Infant Death File. Natl Vital Stat Rep. 2019;68(10):1-20. [PubMed] [Google Scholar]
- 2.Wu Y, Liu B, Sun Y, et al. Association of maternal prepregnancy diabetes and gestational diabetes mellitus with congenital anomalies of the newborn. Diabetes Care. 2020;43(12):2983-2990. doi: 10.2337/dc20-0261 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Yang L, Wang H, Yang L, et al. Maternal cigarette smoking before or during pregnancy increases the risk of birth congenital anomalies: a population-based retrospective cohort study of 12 million mother-infant pairs. BMC Med. 2022;20(1):4. doi: 10.1186/s12916-021-02196-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Auger N, Potter BJ, He S, Healy-Profitós J, Schnitzer ME, Paradis G. Maternal cardiovascular disease 3 decades after preterm birth: longitudinal cohort study of pregnancy vascular disorders. Hypertension. 2020;75(3):788-795. doi: 10.1161/HYPERTENSIONAHA.119.14221 [DOI] [PubMed] [Google Scholar]
- 5.Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-765. doi: 10.1126/science.1251816 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Detailed Methods