Expanding the Massachusetts Birth Defects Monitoring Program to include additional pregnancy outcomes: Programmatic efforts and impacts on case ascertainment, 2012-2020.

BACKGROUND: Birth defects affect 1 in 33 infants in the United States and are a leading cause of infant mortality. Birth defects surveillance is crucial for informing public health action. The Massachusetts Birth Defects Monitoring Program (MBDMP) began collecting other pregnancy losses (OPLs) in 2011, including miscarriages (<20 weeks gestation) or elective terminations (any gestational age), in addition to live births and stillbirths (≥20 weeks gestation). We describe programmatic changes for adding OPLs and their impact on prevalence estimates. METHODS: Using population-based, statewide, data from the MBDMP (2012-2020), we assessed prevalence per 10,000 live births and 95% confidence intervals (CIs) with and without OPLs overall and for specific birth defects by time period, maternal age, and race/ethnicity. RESULTS: Including OPLs required amending a state statute and promulgating regulations, new data sources, and additional data processing, cleaning, and verification. Overall prevalence with OPLs increased from 257.4 (95% CI: 253.5-261.4) to 333.9 (95% CI: 329.4-338.4) per 10,000; increases were observed in all time periods, age, and race/ethnicity groups. After including OPLs, the prevalence increased for neural tube defects [3.2 (2.7-3.6) to 8.3 (7.6-9.0)], and trisomies 13 [0.5 (0.3-0.7) to 4.1 (3.6-4.6)], 18 [1.5 (1.2-1.9) to 8.2 (7.5-8.9)], and 21 [12.3 (11.4-13.2) to 28.9 (27.6-30.2)]. Cardiovascular defects increased slightly, while prevalence of eye/ear, respiratory, and gastrointestinal defects remained similar. CONCLUSIONS: Adding OPLs required substantial programmatic efforts and resulted in more complete case ascertainment, particularly for certain birth defects. More complete case ascertainment will allow for improved research, screening, and resource allocation.

Preconception dietary glycemic index and risk for large-for-gestational age births.

OBJECTIVES: Diets with a high glycemic index (GI) leading to elevated postprandial glucose levels and hyperinsulinemia during pregnancy have been inconsistently linked to an increased risk for large-for-gestational-age (LGA) births. The effects of prepregnancy dietary GI on LGA risk are, to our knowledge, unknown. We examined the association of prepregnancy dietary GI with LGA births and joint associations of GI and maternal overweight/obesity and infant sex with LGA births among 10 188 infants born without congenital anomalies from 1997 to 2011, using data from the National Birth Defects Prevention Study (NBDPS). The aim of this study was to investigate this association among infants without major congenital anomalies (controls) who participated in the NBDPS and to evaluate how prepregnancy BMI and infant sex may modify this association on the additive scale. METHODS: Dietary intake was ascertained using a 58-item food frequency questionnaire. We dichotomized dietary GI into high and low categories using spline regression models. Infants with a birth weight at or above the 90th percentile for gestational age and sex, according to a U.S. population reference, were considered LGA. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of the infants, 859 (9%) had a high dietary GI (cut-point: 59), and 1244 infants (12%) were born LGA. Unadjusted analysis suggested an inverse association between high dietary GI and LGA (OR, 0.79; 95% CI, 0.62-0.99). No association was observed in multivariable models when comparing high dietary GI intake between LGA births and all other births (OR, 0.94; 95% CI, 0.74-1.20) or when excluding small-for-gestational-age (SGA) births (OR, 0.94; 95% CI, 0.73-1.19). No joint associations with maternal overweight/obesity or infant sex were observed. CONCLUSION: High prepregnancy maternal GI was not associated with LGA births independently of or jointly with other factors.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.

BACKGROUND: Neural tube defects (NTDs) still occur among some women who consume 400 µg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. OBJECTIVES: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. METHODS: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 µg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. RESULTS: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. CONCLUSIONS: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

Inequities in COVID-19 Vaccination Coverage Among Pregnant Persons, by Disaggregated Race and Ethnicity - Massachusetts, May 2021-October 2022.

National estimates suggest that COVID-19 vaccination coverage among pregnant persons is lower among those identifying as Hispanic or Latino (Hispanic) and non-Hispanic Black or African American. When examining COVID-19 vaccination coverage during pregnancy by race and ethnicity, however, data are typically limited to large, aggregate categories that might obscure within-group inequities. To address this, Massachusetts examined COVID-19 vaccination coverage among pregnant persons by combinations of 12 racial and 34 ethnic groupings. Among 102,275 persons with a live birth in Massachusetts during May 1, 2021-October 31, 2022, receipt of ≥1 dose of a COVID-19 vaccine before or during pregnancy was 41.6% overall and was highest among persons who identified as Asian (55.0%) and lowest among those who identified as Hispanic (26.7%). However, within all broad racial and ethnic groupings, disparities in COVID-19 vaccination coverage were identified when the data were disaggregated into more granular categories; for example, COVID-19 vaccination coverage ranged from 10.8%-61.1% among pregnant persons who identified as Hispanic. Disaggregated analyses reveal diverse experiences within broad racial and ethnic groupings. This information can be used to guide outreach to pregnant persons in communities with lower rates of COVID-19 vaccination coverage during pregnancy.

Neighborhood Deprivation and Neural Tube Defects.

BACKGROUND: Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk. METHODS: The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery. RESULTS: Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity. CONCLUSIONS: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.

Associations between birth defects with neural crest cell origins and pediatric embryonal tumors.

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education. RESULTS: The risk of embryonal tumors among those with BDNCOs was 0.09% (co-occurring n = 105) compared to 0.03% (95% CI, 0.03%-0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5-5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3-22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3-4.2) and nephroblastoma (2.9; 95% CI, 1.9-4.4) were elevated. There was no notable HRM by the aforementioned factors. CONCLUSIONS: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions.

Trends in Delayed Diagnosis of Critical Congenital Heart Defects in an Era of Enhanced Screening, 2004-2018.

OBJECTIVE: To describe trends in delayed diagnosis of critical congenital heart defects (CCHDs) with prenatal and postnatal screening advances. STUDY DESIGN: We evaluated a retrospective cohort of live births with CCHD delivered between 2004 and 2018 from a statewide, population-based birth defects surveillance system in Massachusetts. Demographic information were obtained from vital records. We estimated timely (prenatal or birth/transfer hospital) and delayed diagnosis (after discharge) proportions by year and time periods coinciding with the transition to mandatory pulse oximetry in 2015. RESULTS: We identified 1524 eligible CCHD cases among 1 087 027 live births. By 2018, 92% of cases received a timely diagnosis, most prenatally. From 2004 to 2018, prenatal diagnosis increased from 46% to 76% of cases, while hospital diagnosis decreased from 38% to 17%, and delayed diagnosis declined from 16% to 7%. These trends were consistent across all characteristics evaluated. Among cases without a prenatal diagnosis, the proportion with delayed diagnosis did not change over time, even after implementation of mandatory pulse oximetry screening. Prenatal detection increased the most among severe cases (treated or died in first month of life). Well-appearing newborns without prenatal diagnosis made up 79% of delayed diagnosis cases by 2015-2018. Delayed diagnosis was most common for coarctation. CONCLUSIONS: While prenatal diagnosis of CCHD increased dramatically, there was no reduction in delayed diagnosis among postnatally diagnosed infants, even after pulse oximetry screening became mandatory. Pulse oximetry may not reduce delayed diagnosis in settings with high prenatal detection, and other strategies are needed to ensure timely diagnosis of well-appearing newborns.

Early pregnancy vitamin D status and risk of select congenital anomalies in the National Birth Defects Prevention Study.

INTRODUCTION: Vitamin D deficiency is associated with adverse pregnancy events. However, its role in the etiology of congenital anomalies remains unclear. We examined the association between vitamin D status, measured through prepregnancy diet, UV exposure, season of conception, and congenital anomalies. METHODS: We used data from the National Birth Defects Prevention Study, a U.S. population-based case-control study (1997-2011). Prepregnancy dietary vitamin D was calculated from food frequency questionnaires and evaluated using tertiles, based on the distribution in controls. We used the National Oceanic and Atmospheric Administration Weather Service to assign UV indices based on location and estimated date of conception, then dichotomized UV exposure (low vs. high). Seasons of conception was categorized as fall/winter spring/summer. We used logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS: Lower prepregnancy dietary vitamin D intake (<65.21 IU/d vs. >107.55 IU/d) was associated with increased odds of anencephaly (aOR = 1.28, 95% CI 1.01, 1.63), hypospadias (aOR = 1.21, 95% CI 1.04, 1.40), septal defects (aOR = 1.16, 95% CI 1.05, 1.30), diaphragmatic hernia (aOR = 1.42, 95% CI 1.13, 1.79), and gastroschisis (aOR = 1.27, 95% CI 1.07, 1.52). Findings were consistent when we stratified by UV exposure and season of conception. CONCLUSIONS: Our findings suggest lower dietary intake of vitamin D may be associated with increased risk of select congenital anomalies. Further investigations are warranted to evaluate the effects of other nutrients and appropriate thresholds and sources of vitamin D using serum.

SARS-CoV-2 infection during pregnancy and preterm birth in Massachusetts from March 2020 through March 2021.

BACKGROUND: SARS-CoV-2 infection during pregnancy has been linked to preterm birth, but this association is not well understood. OBJECTIVES: To examine the association between SARS-CoV-2 infection and spontaneous and provider-initiated preterm birth (PTB), and how timing of infection, and race/ethnicity as a marker of structural inequality, may modify this association. METHODS: We conducted a retrospective cohort study among pregnant people who delivered singleton, liveborn infants (22-44 weeks gestation) from 1 March 2020 to 31 March 2021 (n = 68,288). We used Cox proportional hazards models to compare the hazard of PTB between pregnant people with and without laboratory-confirmed SARS-CoV-2 infection during pregnancy. We evaluated this association according to the trimester of infection, timing from infection to birth, and timing of PTB. We also examined the joint associations of SARS-CoV-2 infection and race/ethnicity with PTB using the relative excess risk due to interaction (RERI). RESULTS: Positive SARS-CoV-2 tests were identified for 2195 pregnant people (3.2%). The prevalence of PTB was 7.2% (3.8% spontaneous, 3.6% provider-initiated). SARS-CoV-2 infection during pregnancy was associated with an increased risk of PTB overall (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.34, 1.74), and provider-initiated PTB (HR 1.79, 95% CI 1.50, 2.12) but not spontaneous PTB (HR 1.09, 95% CI 0.89, 1.36). Second trimester infections were associated with an increased risk of provider-initiated PTB, and third trimester infections were associated with an increased risk of both PTB subtypes. A joint inverse association between White non-Hispanic race/ethnicity and SARS-CoV-2 infection and spontaneous PTB (HR 0.56, 95% CI 0.34, 0.94; RERI -0.6, 95% CI -1.0, -0.2) was also observed. CONCLUSIONS: SARS-CoV-2 infections were primarily associated with an increased risk for provider-initiated PTB in this study. These findings highlight the importance of promoting infection-prevention strategies among pregnant people.

Assessing associations between residential proximity to greenspace and birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Residential proximity to greenspace is associated with various health outcomes. OBJECTIVES: We estimated associations between maternal residential proximity to greenspace (based on an index of vegetation) and selected structural birth defects, including effect modification by neighborhood-level factors. METHODS: Data were from the National Birth Defects Prevention Study (1997-2011) and included 19,065 infants with at least one eligible birth defect (cases) and 8925 without birth defects (controls) from eight Centers throughout the United States. Maternal participants reported their addresses throughout pregnancy. Each address was systematically geocoded and residences around conception were linked to greenspace, US Census, and US Department of Agriculture data. Greenspace was estimated using the normalized difference vegetation index (NDVI); average maximum NDVI was estimated within 100 m and 500 m concentric buffers surrounding geocoded addresses to estimate residential NDVI. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals comparing those in the highest and lowest quartiles of residential NDVI and stratifying by rural/urban residence and neighborhood median income. RESULTS: After multivariable adjustment, for the 500 m buffer, inverse associations were observed for tetralogy of Fallot, secundum atrial septal defects, anencephaly, anotia/microtia, cleft lip ± cleft palate, transverse limb deficiency, and omphalocele, (aORs: 0.54-0.86). Results were similar for 100 m buffer analyses and similar patterns were observed for other defects, though results were not significant. Significant heterogeneity was observed after stratification by rural/urban for hypoplastic left heart, coarctation of the aorta, and cleft palate, with inverse associations only among participants residing in rural areas. Stratification by median income showed heterogeneity for atrioventricular and secundum atrial septal defects, anencephaly, and anorectal atresia, with inverse associations only among participants residing in a high-income neighborhood (aORs: 0.45-0.81). DISCUSSION: Our results suggest that perinatal residential proximity to more greenspace may contribute to a reduced risk of certain birth defects, especially among those living in rural or high-income neighborhoods.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Characteristics of People With and Without Laboratory-Confirmed SARS-CoV-2 Infection During Pregnancy, Massachusetts, March 2020-March 2021.

OBJECTIVES: Pregnant people infected with SARS-CoV-2, the virus that causes COVID-19, are at increased risk for severe illness and death compared with nonpregnant people. However, population-based information comparing characteristics of people with and without laboratory-confirmed SARS-CoV-2 infection during pregnancy is limited. We compared the characteristics of people with and without SARS-CoV-2 infection during pregnancy in Massachusetts. METHODS: We compared maternal demographic characteristics, pre-pregnancy conditions, and pregnancy complications of people with and without SARS-CoV-2 infection during pregnancy with completed pregnancies resulting in a live birth in Massachusetts during March 1, 2020-March 31, 2021. We tested for significant differences in the distribution of characteristics of pregnant people by SARS-CoV-2 infection status overall and stratified by race and ethnicity. We used modified Poisson regression analyses to examine the association between race and ethnicity and SARS-CoV-2 infection during pregnancy. RESULTS: Of 69 960 completed pregnancies identified during the study period, 3119 (4.5%) had laboratory-confirmed SARS-CoV-2 infection during pregnancy. Risk for SARS-CoV-2 infection was higher among Hispanic (adjusted risk ratio [aRR] = 2.3; 95% CI, 2.1-2.6) and non-Hispanic Black (aRR = 1.9; 95% CI, 1.7-2.1) pregnant people compared with non-Hispanic White pregnant people. CONCLUSIONS: This study demonstrates the disproportionate impact of SARS-CoV-2 infection on Hispanic and non-Hispanic Black pregnant people in Massachusetts, which may widen existent inequities in maternal morbidity and mortality. Future research is needed to elucidate the structural factors leading to these inequities.

Use of vasoactive medications in pregnancy and the risk of stillbirth among birth defect cases.

BACKGROUND: Many previous studies have identified risk factors for stillbirth, but few examine stillbirth among pregnancies affected with birth defects. Because many hypothesized etiologies of stillbirth work through vascular pathologies of the placenta, we examined maternal use of vasoactive medications in relation to stillbirth among pregnancies affected with birth defects. METHODS: Data were analyzed from the National Birth Defects Prevention Study (1997-2011). We examined use of nonsteroidal anti-inflammatory drugs (NSAIDs), decongestants, short- or long-acting beta-agonists (SABA/LABA), and antihypertensive medications in relation to pregnancies affected by birth defects ending in stillbirth compared to live birth. Associations were measured with odds ratios (ORs) for early pregnancy use and hazard ratios (HRs) for time-varying late pregnancy use. RESULTS: Among all birth defects (n = 12,394), the risk of stillbirth was associated with use of antihypertensive medications in early (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.0, 3.1) and late pregnancy (HR: 2.0; 95% CI: 1.1, 3.6). Other vasoactive medications were not associated with increased risk of stillbirth. Of 27 specific defect groups, increased risks were observed for only one medication/defect pair: early decongestant use was more common among mothers of stillbirth versus live birth cases with spina bifida (OR: 2.4; 95% CI: 0.9, 6.5). CONCLUSION: This exploratory analysis of vasoactive medication use suggests that use of NSAIDs, decongestants, and SABA/LABA is not associated with increased risk of stillbirth among pregnancies affected with birth defects. Our finding of increased risks associated with antihypertensive medication use raises questions of confounding by indication, which we were not able to fully address.

The Massachusetts Racial Equity Data Road Map: Data as a Tool Toward Ending Structural Racism.

BACKGROUND: In 2015, the Massachusetts Department of Public Health (MDPH) adopted a Title V maternal and child health priority to "promote health and racial equity by addressing racial justice and reducing disparities." A survey assessing staff capacity to support this priority identified data collection and use as opportunities for improvement. In response, MDPH initiated a quality improvement project to improve use of data for action to promote racial equity. METHODS: MDPH conducted value stream mapping to understand existing processes for using data to inform racial equity work. Key informant interviews and a survey of program directors identified challenges to using data to promote racial equity. MDPH used a cause-and-effect diagram to identify and organize challenges to using data to inform racial equity work and better understand opportunities for improvement and potential solutions. RESULTS: Key informants highlighted the need to consider structural factors and historical and community contexts when interpreting data. Program directors noted limited staff time, lack of performance metrics, competing priorities, low data quality, and unclear expectations as challenges. To address the identified challenges, the team identified potential solutions and prioritized development and piloting of the MDPH Racial Equity Data Road Map (Road Map). CONCLUSIONS: The Road Map framework provides strategies for data collection and use that support the direction of actionable data-driven resources to racial inequities. The Road Map is a resource to support programs to authentically engage communities; frame data in the broader contexts that impact health; and design solutions that address root causes. With this starting point, public health systems can work toward creating data-driven programs and policies to improve racial equity.

Interpregnancy interval and prevalence of selected birth defects: A multistate study.

BACKGROUND: Both short and long interpregnancy intervals (IPIs) have been associated with adverse birth outcomes. We undertook a multistate study to describe the prevalence of selected birth defects by IPI. METHODS: We obtained data from nine population-based state birth defects registries for singleton live births in 2000-2009 among mothers with a previous live birth identified through birth certificates. IPI was calculated as the difference between prior birthdate and start of the current pregnancy (conception date). We estimated prevalence of selected defects per 10,000 live births and prevalence ratios (PRs) with 95% confidence intervals (CIs) overall and stratified by maternal age at previous birth and race/ethnicity. Primary analyses focused on short IPI < 6 months and long IPI ≥ 60 months compared to 18-23 months (referent). Sensitivity analyses limited to active-surveillance states and those with<10% missing IPI. RESULTS: Among 5,147,962 eligible births, 6.3% had short IPI while 19.8% had long IPI. Compared to referent, prevalence with short IPI was elevated for gastroschisis (3.7, CI: 3.0-4.5 vs. 2.0, CI: 1.6-2.4) and with both short and long IPI for tetralogy of Fallot (short: 3.4, 2.8-4.2 long: 3.8, 3.4-4.3 vs. 2.7, 2.3-3.2) and cleft lip ± palate (short: 9.9, 8.8-11.2 long: 9.2, 8.5-9.8 vs. 8.4, 7.6-9.2). Stratified analyses identified additional associations, including elevated prevalence of anencephaly with short IPI in younger mothers and limb defects with long IPI in those ages 25-34 at prior birth. Sensitivity analyses showed similar results. CONCLUSION: In this population-based study, we observed increased prevalence of several birth defects with short and long IPI.

Short interpregnancy intervals and risks for birth defects: support for the nutritional depletion hypothesis.

BACKGROUND: Research suggests short interpregnancy intervals increase risks for adverse perinatal outcomes, including some birth defects. A hypothesized cause is nutritional depletion, including folic acid (FA). OBJECTIVES: We evaluated associations between short interpregnancy intervals, alone and in combination with FA intake, and the occurrence of select malformations. METHODS: Data were from the National Birth Defects Prevention Study (US case-control, 1997-2011). Participants included multiparous women whose prior pregnancy resulted in live birth. Cases included 8 noncardiac and 6 cardiac defect groups (n = 3219); controls were nonmalformed live-borns (n = 2508). We categorized interpregnancy interval (<6, 6-11, 12-17, and 18-23 mo) and periconceptional FA intake [no FA supplement use and dietary folate equivalents (DFE) <400 µg/d, no FA supplement use and DFE ≥400 µg/d, or any FA supplement use]. We controlled for age, race/ethnicity, income, pregnancy intention, and study center. ORs <0.8 or >1.2 were considered to represent potentially meaningful associations. RESULTS: ORs for <6 compared with 18-23 mo were >1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing <6 with 6-23 mo were <1.2 for most defects. Conversely, most ORs were >1.2 for <6 mo + no FA supplement use and DFE <400 µg/d compared with 6-23 mo + any FA supplement use. Magnitude and precision varied by defect. CONCLUSIONS: Short interpregnancy intervals were associated with a trend of higher risks for several defects, notably in the absence of FA supplement use. To our knowledge, our study is the first to provide preliminary empirical support that these etiologies may be related to shorter interpregnancy intervals and possible nutritional deficiencies. Because FA intake is highly correlated with other nutrients, and because our estimates were generally imprecise, more research with larger sample sizes is needed to better understand the role of FA compared with other nutrients in each defect-specific etiology.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

The risk of birth defects with conception by ART.

STUDY QUESTION: What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER: N/A.

Maternal Exposure to Disinfection By-Products and Risk of Hypospadias in the National Birth Defects Prevention Study (2000-2005).

The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias.

Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy - SET-NET, 16 Jurisdictions, March 29-October 14, 2020.

Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness and might be at risk for preterm birth (1-3). The full impact of infection with SARS-CoV-2, the virus that causes COVID-19, in pregnancy is unknown. Public health jurisdictions report information, including pregnancy status, on confirmed and probable COVID-19 cases to CDC through the National Notifiable Diseases Surveillance System.* Through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET), 16 jurisdictions collected supplementary information on pregnancy and infant outcomes among 5,252 women with laboratory-confirmed SARS-CoV-2 infection reported during March 29-October 14, 2020. Among 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019 (4). Among 610 infants (21.3%) with reported SARS-CoV-2 test results, perinatal infection was infrequent (2.6%) and occurred primarily among infants whose mother had SARS-CoV-2 infection identified within 1 week of delivery. Because the majority of pregnant women with COVID-19 reported thus far experienced infection in the third trimester, ongoing surveillance is needed to assess effects of infections in early pregnancy, as well the longer-term outcomes of exposed infants. These findings can inform neonatal testing recommendations, clinical practice, and public health action and can be used by health care providers to counsel pregnant women on the risks of SARS-CoV-2 infection, including preterm births. Pregnant women and their household members should follow recommended infection prevention measures, including wearing a mask, social distancing, and frequent handwashing when going out or interacting with others or if there is a person within the household who has had exposure to COVID-19.†.