Association of Maternal History of Preterm Birth With Congenital Anomalies in Offspring.

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.