Abstract
We examined birth defects in offspring of adolescent and young adult (AYA) women with a history of cancer (age 15–39 years at diagnosis).
We identified AYA women diagnosed with cancer between January 1, 1999, and December 31, 2015 using population-based data from the Texas Cancer Registry; data were linked with live birth and fetal death certificates through December 31, 2016 to identify singleton births to AYA women after diagnosis. Birth defects in offspring through age 12 months were ascertained from the Texas Birth Defects Registry. We estimated risk of birth defects in offspring of AYA women and women without cancer (matched 3:1 by maternal race/ethnicity, maternal age, and offspring year of birth) and compared risk using log binomial regression models.
There were 6,882 singleton births to AYA women after diagnosis. Common cancer types were thyroid (28.9%), lymphoma (12.5%), and breast (10.7%). Risk of any birth defect was higher in offspring of AYA women (6.0%) compared with offspring of women without cancer [n = 20,646; 4.8%; risk ratio (RR) 1.24; 95% confidence interval (CI), 1.11–1.38]. Risk of eye or ear (RR, 1.39; 95% CI, 1.03–1.90), heart and circulatory (RR, 1.32; 95% CI, 1.09–1.60), genitourinary (RR, 1.38; 95% CI, 1.12–1.69), and musculoskeletal (RR, 1.37; 95% CI, 1.13–1.66) defects was also higher.
Risk of birth defects was elevated in liveborn and stillborn offspring of AYA women.
Although birth defects are rare, AYA women making decisions about pregnancy and prenatal care should receive appropriate counseling and surveillance.
Background
Cancer and its treatment may adversely affect the reproductive health of adolescent and young adult (AYA) women with a history of cancer (diagnosed at age 15–39 years; hereafter, “AYA women”). AYA women comprise a growing but understudied population (1, 2), and they often receive care across fragmented health systems (3, 4) at a time when they also experience many unmet reproductive health needs (5). Cancer treatment can have gonadotoxic effects (e.g., cytotoxic chemotherapy; refs. 6–8), and a large literature now demonstrates excess risk of infertility and adverse birth outcomes, including small for gestational age, preterm birth, low birth weight, and cesarean delivery, in AYA women (7–10).
Offspring of AYA women may also have higher risk of birth defects because women develop cancer and receive cancer treatment during childbearing years. However, reproductive decision-making for AYA women and counseling by their providers is limited by a lack of information on health-related consequences for offspring. Clinical practice guidelines (11) on counseling and surveillance of obstetric risks in AYA women instead rely on evidence from childhood cancer survivors (12–21), who are diagnosed with and receive different types of cancer and treatment (22), respectively, at an earlier life stage. To better inform the care of AYA women and their families, we examined birth defects among offspring of AYA women by linking population-based data from the Texas Cancer Registry to live birth and fetal death certificates and the Texas Birth Defects Registry. We addressed two aims: (i) to compare risk of any birth defect and specific types of birth defects in offspring of AYA women to women without cancer; and (ii) to estimate the association between birth defects and: (a) cancer type and (b) receipt of chemotherapy.
Materials and Methods
Study population
We identified all women diagnosed with cancer at age 15 to 39 years between January 1, 1999, and December 31, 2015 using population-based data from the Texas Cancer Registry. As of 2021, the Texas Cancer Registry is one of only 12 state registries participating in both the NCI's Surveillance, Epidemiology and End Results Program and the Center for Disease Control and Prevention's National Program of Cancer Registries.
The Texas Cancer Registry used Match*Pro (described in detail at: https://seer.cancer.gov/tools/matchpro/; accessed 2/20/2023) to link data to: (i) live birth and fetal death (gestational age ≥20 weeks or weight ≥350 grams) certificates from January 1, 1999, to December 31, 2016, to identify births to AYA women; and (ii) the Texas Birth Defects Registry, to identify birth defects in offspring of AYA women. Match*Pro links records using a probabilistic linkage framework based on the Fellegi and Sunter model (23). Blocking variables included maternal social security number, first name, last name, and date of birth, and matching variables included maternal social security number, first name, middle name, last name, date of birth, street address, city, and ZIP code. A pair must have matched exactly on at least two blocking variables to be eligible for manual review by matching variables. A staff member then independently reviewed all pairs eligible for manual review and determined true versus false matches, using guidance from the NAACCR's Virtual Pooled Registry Cancer Linkage System (described in detail at: https://www.naaccr.org/about-vpr-cls/). A second staff member was available to help determine true vs. false match for pairs that were unclear during manual review.
There were 11,066 live births and 76 stillbirths to AYA women after cancer diagnosis. To identify the first singleton birth after diagnosis, we applied the following exclusions: births missing gestational age (n = 13 live births and 3 stillbirths), multiple births (n = 582 live births and 4 stillbirths), births to AYA women diagnosed with cancer during pregnancy (n = 1,271 live births and 20 stillbirths; ref. 24), and second or later births after diagnosis (n = 2,360 live births and 7 stillbirths). Exclusion criteria were designed to maintain adequate sample size for analysis while avoiding violations of the assumption of independence (e.g., in the case of multiple births per pregnancy or AYA woman). The final analytic sample included 6,840 singleton live births and 42 stillbirths to 6,882 AYA women.
Statistical analysis
We described characteristics of AYA women, including age at cancer diagnosis, race/ethnicity, cancer type, receipt of surgery, chemotherapy, and radiotherapy, stage at diagnosis, and time from diagnosis to delivery (<2, 2–5, >5 years). We combined race and ethnicity to include Hispanic (of any race), non-Hispanic Asian or Pacific Islander, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Non-Hispanic Other included Alaska Native or American Indian and “some other race” as coded according to NAACCR item #160 (described in detail at: http://datadictionary.naaccr.org/; accessed 2/20/2023). We defined cancer types using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) site and histology codes and according to the AYA Site Recode ICD-O-3/WHO 2008 (described in detail at https://seer.cancer.gov/ayarecode/aya-who2008.html; accessed 2/20/2023). The Texas Cancer Registry collects information on first course of treatment, including surgery, chemotherapy, and radiotherapy.
We identified birth defects in liveborn and stillborn offspring of AYA women using data from the Texas Birth Defects Registry, one of the world's largest, population-based birth defects registries (25). The Texas Birth Defects Registry is an active surveillance system: staff members routinely visit all maternity hospitals, pediatric hospitals, birthing centers, and midwife facilities in Texas, as well as review diagnostic codes from discharge logs, to identify birth defects in infants through age 12 months (26). The Texas Birth Defects Registry participates in the National Birth Defects Prevention Network (27), and data have been previously linked with the Texas Cancer Registry to identify cancers diagnosed in children with birth defects (28–30).
We categorized birth defects using modified BPA codes 740.000 – 759.000, based on the British Pediatric Association Classification of Diseases and developed by the National Center on Birth Defects and Developmental Disabilities (31). We estimated risk of any birth defect and specific types of birth defects, including chromosomal anomalies (758.000 – 758.990), clefts (749.000 – 749.290), and structural defects of the central nervous system (740.000 – 742.990), eye or ear (743.000 – 744.910), heart and circulatory system (745.000 – 747.900), respiratory system (748.000 – 748.900), gastrointestinal system (750.000 – 751.900), genitourinary system (752.000 – 753.990), musculoskeletal system (754.000 – 756.990), and skin, hair, or nails (757.000 – 757.990). We also estimated risk of 12 critical congenital heart defects: coarctication of the aorta, double-outlet right ventricle, transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, total anomalous pulmonary venous return, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus (27).
We compared risk of any and specific types of birth defects in offspring of AYA women to offspring of women without cancer by randomly selecting singleton births from January 1, 1999, to December 31, 2016 to women without cancer. Separately for live births and stillbirths, comparison births were frequency matched 3:1 to births to AYA women by maternal age at delivery (15–19, 20–24, 25–29, 30–34, 35–39, 40–44, ≥45 years), maternal race/ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White, and non-Hispanic Asian or Pacific Islander, Other, and Unknown), and year of delivery. We compared risk using log binomial regression models and report risk ratios (RR) and 95% confidence intervals (CI). We also estimated risk of any birth defect by cancer type, receipt of chemotherapy, and time from diagnosis to delivery, comparing offspring of AYA women versus offspring of women without cancer. We did not estimate risk of any birth defect by receipt of radiotherapy because most AYA women (n = 5,167 or 75.1%) were missing information on radiotherapy.
The Institutional Review Board at the University of Texas Health Science Center at Houston and Texas Department of State Health Services approved this study. All analyses were conducted in SAS version 9.4 (SAS Institute, Cary, NC). Statistical tests were two-sided; P < 0.05 indicated statistical significance.
Data availability
Data underlying this study were provided by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, 1100 West 49th Street, Austin, TX 78756 (www.dshs.texas.gov/tcr); by the Center for Health Statistics, Texas Department of State Health Services, 1100 West 49th Street, Austin, TX 78756 (https://www.dshs.texas.gov/chs/); and by the Texas Birth Defects Registry, Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, 1100 West 49th Street, Austin, TX 78756 (https://www.dshs.texas.gov/birthdefects/). Derived, de-identified data supporting the findings are available from the corresponding author upon request.
Results
Characteristics of the study population
There were 6,840 singleton live births and 42 stillbirths to 6,882 AYA women after cancer diagnosis that met inclusion criteria. Table 1 shows characteristics of AYA women and women without cancer (n = 20,646). The population was racially and ethnically diverse: 29.8% Hispanic, 8.9% non-Hispanic Black, and 56.6% non-Hispanic White. The sex ratio of offspring of AYA women was similar to women without cancer, and as previously reported (9), a higher proportion of births to AYA women were preterm (< 37 weeks gestation; 12.6% vs. 9.0%).
Characteristics of 6,882 AYA women with a history of cancer (diagnosed at age 15–39 years) and 20,646 women without cancer.
. | AYA women . | Women without cancer . | ||
---|---|---|---|---|
. | (n = 6,882) . | (n = 20,646) . | ||
. | n . | (%) . | n . | (%) . |
Live birth | 6,840 | (99.4) | 20,520 | (99.4) |
Stillbirth | 42 | (0.6) | 126 | (0.6) |
Maternal age at delivery | ||||
15–19 | 126 | (1.8) | 378 | (1.8) |
20–24 | 812 | (11.8) | 2,435 | (11.8) |
25–29 | 1,757 | (25.5) | 5,272 | (25.5) |
30–34 | 2,272 | (33.0) | 6,821 | (33.0) |
35–39 | 1,532 | (22.7) | 4,682 | (22.7) |
≥40 | 353 | (5.1) | 1,058 | (5.1) |
Race and ethnicity | ||||
Non-Hispanic White | 3,894 | (56.6) | 11,683 | (56.6) |
Non-Hispanic Black | 611 | (8.9) | 1,831 | (8.9) |
Hispanic (any race) | 2,048 | (29.8) | 6,146 | (29.8) |
Non-Hispanic Other | 329 | (4.8) | 986 | (4.8) |
Year of delivery | ||||
1999–01 | 144 | (2.1) | 432 | (2.1) |
2002–04 | 515 | (7.5) | 1,545 | (7.5) |
2005–07 | 1,409 | (20.5) | 4,227 | (20.5) |
2008–10 | 1,472 | (21.4) | 4,416 | (21.4) |
2011–13 | 1,599 | (23.2) | 4,796 | (23.2) |
2014–16 | 1,743 | (25.3) | 5,230 | (25.3) |
Infant sex | ||||
Male | 3,527 | (51.3) | 10,544 | (51.1) |
Female | 3,355 | (48.8) | 10,102 | (48.9) |
Gestational age | ||||
<32 weeks | 168 | (2.4) | 337 | (1.6) |
32–<37 weeks | 702 | (10.2) | 1,525 | (7.4) |
>37 weeks | 6,012 | (87.4) | 18,784 | (91.0) |
Parity | ||||
Nulliparous | 2,866 | (41.8) | 6,456 | (31.4) |
Primiparous | 3,997 | (58.2) | 14,140 | (68.7) |
Missing | 19 | 50 | ||
Metropolitan statistical areaa | ||||
Dallas-Fort Worth-Arlington | 1,778 | (25.8) | 5,866 | (28.1) |
Houston-The Woodlands-Sugar Land | 1,702 | (24.7) | 5,151 | (24.7) |
San Antonio-New Braunfels | 585 | (8.5) | 1,519 | (7.3) |
Austin-Round Rock-Georgetown | 682 | (9.9) | 1,699 | (8.1) |
McAllen-Edinburg-Mission | 171 | (2.5) | 488 | (2.3) |
. | AYA women . | Women without cancer . | ||
---|---|---|---|---|
. | (n = 6,882) . | (n = 20,646) . | ||
. | n . | (%) . | n . | (%) . |
Live birth | 6,840 | (99.4) | 20,520 | (99.4) |
Stillbirth | 42 | (0.6) | 126 | (0.6) |
Maternal age at delivery | ||||
15–19 | 126 | (1.8) | 378 | (1.8) |
20–24 | 812 | (11.8) | 2,435 | (11.8) |
25–29 | 1,757 | (25.5) | 5,272 | (25.5) |
30–34 | 2,272 | (33.0) | 6,821 | (33.0) |
35–39 | 1,532 | (22.7) | 4,682 | (22.7) |
≥40 | 353 | (5.1) | 1,058 | (5.1) |
Race and ethnicity | ||||
Non-Hispanic White | 3,894 | (56.6) | 11,683 | (56.6) |
Non-Hispanic Black | 611 | (8.9) | 1,831 | (8.9) |
Hispanic (any race) | 2,048 | (29.8) | 6,146 | (29.8) |
Non-Hispanic Other | 329 | (4.8) | 986 | (4.8) |
Year of delivery | ||||
1999–01 | 144 | (2.1) | 432 | (2.1) |
2002–04 | 515 | (7.5) | 1,545 | (7.5) |
2005–07 | 1,409 | (20.5) | 4,227 | (20.5) |
2008–10 | 1,472 | (21.4) | 4,416 | (21.4) |
2011–13 | 1,599 | (23.2) | 4,796 | (23.2) |
2014–16 | 1,743 | (25.3) | 5,230 | (25.3) |
Infant sex | ||||
Male | 3,527 | (51.3) | 10,544 | (51.1) |
Female | 3,355 | (48.8) | 10,102 | (48.9) |
Gestational age | ||||
<32 weeks | 168 | (2.4) | 337 | (1.6) |
32–<37 weeks | 702 | (10.2) | 1,525 | (7.4) |
>37 weeks | 6,012 | (87.4) | 18,784 | (91.0) |
Parity | ||||
Nulliparous | 2,866 | (41.8) | 6,456 | (31.4) |
Primiparous | 3,997 | (58.2) | 14,140 | (68.7) |
Missing | 19 | 50 | ||
Metropolitan statistical areaa | ||||
Dallas-Fort Worth-Arlington | 1,778 | (25.8) | 5,866 | (28.1) |
Houston-The Woodlands-Sugar Land | 1,702 | (24.7) | 5,151 | (24.7) |
San Antonio-New Braunfels | 585 | (8.5) | 1,519 | (7.3) |
Austin-Round Rock-Georgetown | 682 | (9.9) | 1,699 | (8.1) |
McAllen-Edinburg-Mission | 171 | (2.5) | 488 | (2.3) |
aMetropolitan statistical area derived from county listed on live birth or fetal death certificate; five largest areas shown in table; see Supplementary Table S1 for distribution of all metropolitan statistical areas.
Among AYA women (Table 2), mean time from cancer diagnosis to delivery was 4.0 years (4.0 years for live birth and 3.8 years for stillbirth). Most women were diagnosed at age 25 to 29 (31.6%) or 30 to 34 (24.7%) years, and the most common cancer types were thyroid (28.9%), lymphoma (12.5%), and breast (10.7%). Twenty four percent (n = 1,622) received chemotherapy.
Cancer-related characteristics of 6,882 AYA women with a history of cancer.
. | n . | (%) . |
---|---|---|
Age at diagnosis | ||
15–19 | 803 | (11.7) |
20–24 | 1,542 | (22.4) |
25–29 | 2,176 | (31.6) |
30–34 | 1,700 | (24.7) |
35–39 | 661 | (9.6) |
Cancer type | ||
Breast | 738 | (10.7) |
Central nervous system | 247 | (3.6) |
Genitourinary | 146 | (2.1) |
Gastrointestinal | 207 | (3.0) |
Gynecologic | 651 | (9.5) |
Head and neck | 212 | (3.1) |
Leukemias | 215 | (3.1) |
Lymphomas | 861 | (12.5) |
Sarcomas | 316 | (4.6) |
Melanoma and skin | 574 | (8.3) |
Thyroid | 1,990 | (28.9) |
Other specified | 255 | (3.7) |
Unspecified | 470 | (6.8) |
Stage at diagnosis | ||
Local | 3,568 | (62.3) |
Regional | 1,464 | (25.6) |
Distant | 698 | (12.2) |
Missing | 1,152 | |
Year of diagnosis | ||
1999–01 | 1,328 | (19.3) |
2002–04 | 1,433 | (20.8) |
2005–07 | 1,490 | (21.7) |
2008–10 | 1,329 | (19.3) |
2011–13 | 1,027 | (14.9) |
2014–15 | 275 | (4.0) |
Received surgery | ||
Yes | 4,936 | (75.3) |
No | 1,622 | (24.7) |
Missing | 324 | |
Received chemotherapy | ||
Yes | 1,440 | (24.0) |
No | 4,550 | (76.0) |
Missing | 892 | |
Received radiotherapy | ||
Yes | 334 | (19.5) |
No | 1,381 | (80.5) |
Missing | 5,167 | |
Time from diagnosis to delivery | ||
<2 years | 1,033 | (15.0) |
2–5 years | 4,210 | (61.2) |
>5 years | 1,639 | (23.8) |
. | n . | (%) . |
---|---|---|
Age at diagnosis | ||
15–19 | 803 | (11.7) |
20–24 | 1,542 | (22.4) |
25–29 | 2,176 | (31.6) |
30–34 | 1,700 | (24.7) |
35–39 | 661 | (9.6) |
Cancer type | ||
Breast | 738 | (10.7) |
Central nervous system | 247 | (3.6) |
Genitourinary | 146 | (2.1) |
Gastrointestinal | 207 | (3.0) |
Gynecologic | 651 | (9.5) |
Head and neck | 212 | (3.1) |
Leukemias | 215 | (3.1) |
Lymphomas | 861 | (12.5) |
Sarcomas | 316 | (4.6) |
Melanoma and skin | 574 | (8.3) |
Thyroid | 1,990 | (28.9) |
Other specified | 255 | (3.7) |
Unspecified | 470 | (6.8) |
Stage at diagnosis | ||
Local | 3,568 | (62.3) |
Regional | 1,464 | (25.6) |
Distant | 698 | (12.2) |
Missing | 1,152 | |
Year of diagnosis | ||
1999–01 | 1,328 | (19.3) |
2002–04 | 1,433 | (20.8) |
2005–07 | 1,490 | (21.7) |
2008–10 | 1,329 | (19.3) |
2011–13 | 1,027 | (14.9) |
2014–15 | 275 | (4.0) |
Received surgery | ||
Yes | 4,936 | (75.3) |
No | 1,622 | (24.7) |
Missing | 324 | |
Received chemotherapy | ||
Yes | 1,440 | (24.0) |
No | 4,550 | (76.0) |
Missing | 892 | |
Received radiotherapy | ||
Yes | 334 | (19.5) |
No | 1,381 | (80.5) |
Missing | 5,167 | |
Time from diagnosis to delivery | ||
<2 years | 1,033 | (15.0) |
2–5 years | 4,210 | (61.2) |
>5 years | 1,639 | (23.8) |
Compared with offspring of women without cancer, a higher proportion of offspring of AYA women had any birth defect (6.0% vs. 4.8%; RR, 1.24; 95% CI, 1.11–1.38), as well as specific types of birth defects (Table 3). Specifically, risk of structural defects of the eye or ear (RR, 1.39; 95% CI, 1.03–1.90), heart and circulatory system (RR, 1.32; 95% CI, 1.09–1.60), genitourinary system (RR, 1.38; 95% CI, 1.12–1.69), and musculoskeletal system (RR, 1.37; 95% CI, 1.33–1.66) was higher in offspring of AYA women compared with women without cancer. There was no difference between the two groups in risk of chromosomal anomalies (0.3% vs. 0.3%) or critical congenital heart defects (0.3% vs. 0.2%).
Risk of birth defects among singleton liveborn and stillborn offspring of AYA women with a history of cancer and women without cancer.
. | AYA women (n = 6,882) . | Women without cancer (n = 20,646) . | . | ||
---|---|---|---|---|---|
. | n . | % . | n . | % . | RR (95% CI)a . |
Any birth defect | 410 | 6.0 | 994 | 4.8 | 1.24 (1.11–1.38) |
Structural birth defectb | |||||
Central nervous system | 44 | 0.6 | 105 | 0.5 | 1.26 (0.89–1.79) |
Eye or ear | 59 | 0.9 | 127 | 0.6 | 1.39 (1.03–1.90) |
Heart and circulatory system | 142 | 2.1 | 323 | 1.6 | 1.32 (1.09–1.60) |
Critical congenital heart defect | 20 | 0.3 | 50 | 0.2 | 1.02 (0.59–1.77) |
Respiratory system | 17 | 0.3 | 41 | 0.2 | 1.24 (0.71–2.19) |
Clefts | — | — | 30 | 0.2 | 0.90 (0.43–1.90) |
Gastrointestinal system | 42 | 0.6 | 111 | 0.5 | 1.14 (0.80–1.62) |
Genitourinary system | 128 | 1.9 | 279 | 1.4 | 1.38 (1.12–1.69) |
Hypospadiasc | 29 | 0.8 | 75 | 0.7 | 1.16 (0.75–1.77) |
Musculoskeletal system | 147 | 2.1 | 323 | 1.6 | 1.37 (1.13–1.66) |
Skin, hair, or nails | 26 | 0.4 | 67 | 0.3 | 1.16 (0.74–1.83) |
Other | 13 | 0.2 | 39 | 0.2 | 1.00 (0.53–1.87) |
Chromosomal anomaly | 22 | 0.3 | 56 | 0.3 | 1.18 (0.72–1.93) |
. | AYA women (n = 6,882) . | Women without cancer (n = 20,646) . | . | ||
---|---|---|---|---|---|
. | n . | % . | n . | % . | RR (95% CI)a . |
Any birth defect | 410 | 6.0 | 994 | 4.8 | 1.24 (1.11–1.38) |
Structural birth defectb | |||||
Central nervous system | 44 | 0.6 | 105 | 0.5 | 1.26 (0.89–1.79) |
Eye or ear | 59 | 0.9 | 127 | 0.6 | 1.39 (1.03–1.90) |
Heart and circulatory system | 142 | 2.1 | 323 | 1.6 | 1.32 (1.09–1.60) |
Critical congenital heart defect | 20 | 0.3 | 50 | 0.2 | 1.02 (0.59–1.77) |
Respiratory system | 17 | 0.3 | 41 | 0.2 | 1.24 (0.71–2.19) |
Clefts | — | — | 30 | 0.2 | 0.90 (0.43–1.90) |
Gastrointestinal system | 42 | 0.6 | 111 | 0.5 | 1.14 (0.80–1.62) |
Genitourinary system | 128 | 1.9 | 279 | 1.4 | 1.38 (1.12–1.69) |
Hypospadiasc | 29 | 0.8 | 75 | 0.7 | 1.16 (0.75–1.77) |
Musculoskeletal system | 147 | 2.1 | 323 | 1.6 | 1.37 (1.13–1.66) |
Skin, hair, or nails | 26 | 0.4 | 67 | 0.3 | 1.16 (0.74–1.83) |
Other | 13 | 0.2 | 39 | 0.2 | 1.00 (0.53–1.87) |
Chromosomal anomaly | 22 | 0.3 | 56 | 0.3 | 1.18 (0.72–1.93) |
Note: “–" denoted because Texas Department of State Health Services prohibits reporting small (n < 10) cells.
aUnadjusted risk ratio shown in table; in these models, cancer is the independent variable and each birth defect is the dependent variable.
bStructural defects include only those diagnosed in offspring without a chromosomal anomaly.
cIn male offspring only.
Table 4 summarizes risk of any and specific types of birth defects in offspring of AYA women and women without cancer, separately for preterm (<37 weeks gestation) and full term (≥37 weeks gestation). Among offspring born full term (n = 6,012 to AYA women and 18,784 to women without cancer), those of AYA women had higher risk of any birth defect (5.0% vs. 4.2%) and structural defects of the genitourinary system (1.6% vs. 1.2%) and musculoskeletal system (1.8% vs. 1.4%) compared with women without cancer (all P = 0.01), similar to the overall pattern. There was an elevated but not statistically significantly higher risk of any birth defects among preterm offspring of AYA women (12.4% of 870) compared with women without cancer (10.6% of 1,862; P = 0.16).
Birth defects among singleton liveborn and stillborn offspring of AYA women with a history of cancer and women without cancer, separately for preterm vs. full term.
. | Preterm (<37 weeks) . | . | Full term (≥37 weeks) . | . | ||||||
---|---|---|---|---|---|---|---|---|---|---|
. | AYA women (n = 870) . | Women without cancer (n = 1,862) . | . | AYA women (n = 6,012) . | Women without cancer (n = 18,784) . | . | ||||
. | n . | % . | n . | % . | P value . | n . | % . | n . | % . | P value . |
Any birth defect | 108 | 12.4 | 197 | 10.6 | 0.16 | 302 | 5.0 | 797 | 4.2 | 0.01 |
Structural birth defecta | ||||||||||
Central nervous system | 15 | 1.7 | 33 | 1.8 | 0.93 | 29 | 0.5 | 72 | 0.4 | 0.29 |
Eye or ear | 19 | 2.2 | 35 | 1.9 | 0.59 | 40 | 0.7 | 92 | 0.5 | 0.10 |
Heart and circulatory system | 50 | 5.8 | 83 | 4.5 | 0.14 | 92 | 1.5 | 240 | 1.3 | 0.14 |
Respiratory system | — | — | 14 | 0.8 | 0.88 | 10 | 0.2 | 27 | 0.1 | 0.69 |
Clefts | — | — | — | — | 0.44 | — | — | 24 | 0.1 | 0.92 |
Gastrointestinal system | 11 | 1.3 | 32 | 1.7 | 0.37 | 31 | 0.5 | 79 | 0.4 | 0.33 |
Genitourinary system | 30 | 3.5 | 57 | 3.1 | 0.59 | 98 | 1.6 | 222 | 1.2 | 0.01 |
Musculoskeletal system | 37 | 4.3 | 62 | 3.4 | 0.23 | 110 | 1.8 | 261 | 1.4 | 0.01 |
Skin, hair, or nails | — | — | — | — | 1.00 | 23 | 0.4 | 61 | 0.3 | 0.50 |
Other | — | — | 16 | 0.9 | 0.43 | — | — | 23 | 0.1 | 0.84 |
Chromosomal anomaly | — | — | 17 | 0.9 | 0.99 | 14 | 0.2 | 39 | 0.2 | 0.71 |
. | Preterm (<37 weeks) . | . | Full term (≥37 weeks) . | . | ||||||
---|---|---|---|---|---|---|---|---|---|---|
. | AYA women (n = 870) . | Women without cancer (n = 1,862) . | . | AYA women (n = 6,012) . | Women without cancer (n = 18,784) . | . | ||||
. | n . | % . | n . | % . | P value . | n . | % . | n . | % . | P value . |
Any birth defect | 108 | 12.4 | 197 | 10.6 | 0.16 | 302 | 5.0 | 797 | 4.2 | 0.01 |
Structural birth defecta | ||||||||||
Central nervous system | 15 | 1.7 | 33 | 1.8 | 0.93 | 29 | 0.5 | 72 | 0.4 | 0.29 |
Eye or ear | 19 | 2.2 | 35 | 1.9 | 0.59 | 40 | 0.7 | 92 | 0.5 | 0.10 |
Heart and circulatory system | 50 | 5.8 | 83 | 4.5 | 0.14 | 92 | 1.5 | 240 | 1.3 | 0.14 |
Respiratory system | — | — | 14 | 0.8 | 0.88 | 10 | 0.2 | 27 | 0.1 | 0.69 |
Clefts | — | — | — | — | 0.44 | — | — | 24 | 0.1 | 0.92 |
Gastrointestinal system | 11 | 1.3 | 32 | 1.7 | 0.37 | 31 | 0.5 | 79 | 0.4 | 0.33 |
Genitourinary system | 30 | 3.5 | 57 | 3.1 | 0.59 | 98 | 1.6 | 222 | 1.2 | 0.01 |
Musculoskeletal system | 37 | 4.3 | 62 | 3.4 | 0.23 | 110 | 1.8 | 261 | 1.4 | 0.01 |
Skin, hair, or nails | — | — | — | — | 1.00 | 23 | 0.4 | 61 | 0.3 | 0.50 |
Other | — | — | 16 | 0.9 | 0.43 | — | — | 23 | 0.1 | 0.84 |
Chromosomal anomaly | — | — | 17 | 0.9 | 0.99 | 14 | 0.2 | 39 | 0.2 | 0.71 |
Note: “–" denoted because Texas Department of State Health Services prohibits reporting small (n < 10) cells.
aStructural defects include only those diagnosed in offspring without a chromosomal anomaly.
Compared with offspring of women without cancer, risk of any birth defect in offspring of AYA women was similar by receipt of chemotherapy, stage at diagnosis, and time from diagnosis to delivery (Fig. 1). Specifically, there was no difference in risk of any birth defect by receipt of chemotherapy (received chemotherapy: RR, 1.28; 95% CI, 1.04–1.58; did not receive chemotherapy: RR, 1.23; 95% CI, 1.08–1.40), stage at diagnosis (local: RR, 1.32; 95% CI, 1.15–1.52; regional: RR, 1.21; 95% CI, 0.97–1.50; distant: RR, 1.25; 95% CI, 0.93–1.69), or time since diagnosis (<2 years: RR, 1.27; 95% CI, 0.99–1.62; 2–5 years: RR, 1.20; 95% CI, 1.05–1.37; >5 years: RR, 1.32; 95% CI, 1.08–1.60). Risk of any birth defect varied by cancer type but was elevated for all cancer types, with the exception of central nervous system (Fig. 1).
Forest plot illustrating risk of any birth defect among liveborn and stillborn offspring of AYA women by cancer type, receipt of chemotherapy, and time since cancer diagnosis compared with offspring of women without cancer
Forest plot illustrating risk of any birth defect among liveborn and stillborn offspring of AYA women by cancer type, receipt of chemotherapy, and time since cancer diagnosis compared with offspring of women without cancer
Discussion
In this population-based study spanning 17 years in Texas, risk of birth defects was higher in liveborn and stillborn offspring of AYA women with a history of cancer compared with offspring of age- and race/ethnicity-matched women without cancer, although birth defects were rare in both groups. Risk of structural defects of the heart and circulatory, genitourinary, and musculoskeletal systems was also higher in offspring of AYA women, and this pattern was not explained by differences in preterm birth. Importantly, birth defects are the leading cause of infant mortality (32), and children with birth defects have higher, lifetime risks of several adverse health conditions, including cancer (28). Given the large, diverse population of AYA women and the statewide, active surveillance system used to ascertain birth defects in Texas, these findings represent some of the most robust evidence to date on birth defects among offspring of AYA women and fill a critical gap in clinical practice.
Our findings contrast those reported in several studies of childhood cancer survivors that suggest no difference in risk of birth defects in their offspring compared with offspring of sibling- or age-matched controls (12–21, 33–36). The higher risk of birth defects among offspring of AYA women in our study may reflect childbearing years as the more relevant window of susceptibility, as well as the different types of cancers and treatment that AYA women and children with cancer experience. Limitations of prior studies of childhood cancer survivors may also preclude robust findings: many relied on self-reported outcomes several years after pregnancy and/or cancer diagnosis and include small samples. Although also small, a few studies suggest excess risk of birth defects in offspring of survivors of Wilms tumor (37), men and women of any age with a history of cancer (38, 39), and childhood cancer survivors diagnosed in the 1950s and 60s (40). Additional, well-conducted population-based studies will be critical to substantiate our findings and inform clinical guidelines for counseling and surveillance of obstetric risks in AYA women.
Offspring of AYA women with a history of gastrointestinal cancer had a particularly high risk of birth defects, consistent with excess risk of stillbirth, preterm birth, low birth weight, cesarean delivery, and low Apgar score associated with these cancers and demonstrated in our prior work (24, 41, 42). At the same time, incidence rates of gastrointestinal cancers in young (age 18–49 years) adults are increasing; for example, rates of colorectal have increased from 7.4 per 100,000 in 1992 to 11.5 per 100,000 in 2019 among young women (43), and although rare, rates of pancreas and gallbladder cancers are also increasing in this population (44). Together, these observations suggest counseling and surveillance for adverse birth outcomes—including birth defects—are particularly important for women with gastrointestinal cancers. Additional studies on mechanisms of adverse outcomes should prioritize these women.
Risk of birth defects was similar by time since cancer diagnosis and stage at diagnosis. Because most AYA women were missing information on radiotherapy, and population-based cancer registries do not systematically collect information on specific chemotherapy agents, we cannot rule out the possibility that certain types or doses of chemotherapy and/or radiotherapy increase risk. Alternatively, our findings may implicate factors contributing to the development of cancer, such as genetic syndromes characterized by both congenital anomalies and cancer in the same families. These syndromes can be inherited or sporadic, such as Gorlin syndrome (45), neurofibromatosis (46), and so-called “RASopathies,” (47) causing developmental defects and predisposing individuals to several cancers. For example, there are well-established relationships between chromosomal anomalies and specific types of childhood cancer (e.g., Down syndrome and acute lymphoblastic leukemia; ref. 48), and even among children with nonchromosomal defects, the number and type of birth defects is directly related to their cancer risk (28). Emerging evidence also suggests common genetic variants not implicated in syndromes may lead to birth defects and cancer, as demonstrated in a recent genome-wide association study of congenital heart defects and neuroblastoma (49).
Nongenetic risk factors may also explain our findings. A broad array of environmental chemicals demonstrates teratogenic (reviewed by Weinhold; ref. 50) and carcinogenic effects, including pesticides (51, 52), plastics and plasticizers (53), solvents, metals (54), and industrial by-products (55), as well as pharmaceuticals such as diethylstilbestrol (56–60). Many of these exhibit key characteristics of endocrine-disrupting compounds (61, 62) that have similarly been implicated in adverse reproductive outcomes and cancer (63). Obesity—often a consequence of environmental obesogens (64)—increases risk of cancer in young adulthood (65) and may also affect subsequent risk of birth defects in offspring (66).
An important strength of this study is the large, diverse population. We included singleton live births and stillbirths to AYA women over a 17-year period, and our findings reflect the diverse women of Texas. Cancers and birth defects were identified from population-based, statewide registries, and it is unlikely that differential ascertainment explains our findings. There are some limitations. As with all linkage-based studies, we could not identify births or birth defects in offspring of AYA women who moved away from Texas; however, we do not expect out-migration to differ by risk of birth defect. Birth defects were ascertained through 12 months, and some congenital anomalies may not manifest until early childhood. Most AYA women had missing information on radiotherapy, and we were not able to examine differences in risk by type or dose of chemotherapy received. Prepregnancy height and weight were not systematically collected on live birth and fetal death certificates until the mid-2000s (67), and examining the association between maternal obesity and birth defects in offspring of AYA is a promising area of future research. Finally, cancer and birth defects are heterogeneous diagnoses, and given the relative infrequency of both, we were not able to examine co-occurrence of specific types of cancer and specific types of birth defects.
In summary, we observed higher risk of birth defects in offspring of AYA women, in contrast to prior studies of childhood cancer survivors. Together with the growing evidence on risk of cancer among children with birth defects (28), our findings may reflect the shared genetic and environmental origins of birth defects and cancer and underscore the multigenerational consequences of cancer diagnosed in adolescence and young adulthood. Determining these shared origins may generate opportunities for prevention (68). Epigenetic mechanisms may also play a role (69). The impact of cancer and cancer treatment on the health of offspring remains a top reproductive concern of AYA women (70), and our study adds to the large literature on adverse birth outcomes they experience (7–10). Although birth defects are rare, AYA women making decisions about pregnancy and prenatal care should receive appropriate counseling and surveillance.
Authors' Disclosures
C.C. Murphy reports personal fees from Freenome outside the submitted work. A.C. Betts reports grants from U.S. Department of Defense; and grants from NIH during the conduct of the study. S.L. Pruitt reports grants from Department of Defense during the conduct of the study; personal fees from Pfizer outside the submitted work. B.A. Cohn reports grants from NIH, Department of Defense Breast Cancer Research Program, Department of Defense Prostate Cancer Research Program; and grants from California Breast Cancer Research Program during the conduct of the study. No disclosures were reported by the other authors.
Disclaimer
The sponsor had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Authors' Contributions
C.C. Murphy: Conceptualization, formal analysis, funding acquisition, writing–original draft, writing–review and editing. A.C. Betts: Conceptualization, writing–review and editing. S.L. Pruitt: Conceptualization, writing–review and editing. B.A. Cohn: Conceptualization, writing–review and editing. L.A. Shay: Conceptualization, writing–review and editing. M.A. Allicock: Conceptualization, writing–review and editing. J.S. Wang: Data curation, writing–review and editing. P.J. Lupo: Conceptualization, supervision, writing-review and editing.
Acknowledgments
Research reported in this publication was supported by the U.S. Department of Defense under award numbers CA181215 (to C.C. Murphy) and CA190214 (to P.J. Lupo), and by the UTHealth Houston Center for Clinical and Translational Sciences TL1 Program supported by the National Institutes of Health under award number TL1TR003169 (to A.C. Betts).
The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).