Trends and Associated Maternal Risk Factors for Cyanotic Congenital Heart Defects From 2016 To 2022 In the United States

Abstract

Cyanotic Congenital Heart Defects (CCHD) are major birth defects and a leading cause of infant deaths in the United States, with a 25% mortality rate. From 2016 to 2022, the CCHD rate increased 18%, yet few studies have identified causes for this increasing trend. This study assessed the influence of maternal risk factors and drinking water contaminants on CCHD and identified risk factors associated with this increasing trend. Odds ratios (ORs) from multivariate logistic regression analysis show significant association between CCHD and maternal age ≥35 (OR: 1.13, 95% CI: 1.02-1.25), pre-pregnancy diabetes (OR: 4.31, 95% CI: 3.53-5.27), and gestational diabetes (OR:1.23). Utah has the highest CCHD rate among 50 states, accounting for 10.4% of cases. Both drinking water nitrate concentration and CCHD rate show similar increasing trends in Utah. In addition, nitrate concentration is positively correlated with CCHD with a p-value <0.001, suggesting that nitrate concentration in drinking water might be a risk factor for the high CCHD rate in Utah. Thus, reducing nitrate in drinking water and these identified maternal risk factors may reduce the rate of CCHD.

Keywords: Cyanotic Congenital Heart Defects, Birth Defects, Maternal Age, BMI, Smoking, Prenatal Care, Pre-pregnancy Diabetes, and Gestational Diabetes

Introduction

The leading cause of infant deaths in the United States is birth defects, which account for 20% of all infant deaths¹. Among 12 major birth defects, Cyanotic Congenital Heart Defects (CCHD) has the highest rate of 60.7 cases per 100 000 live births and makes up 20% of all birth defects in the U.S.². In addition, CCHD has a mortality rate of 25%³. Thus, CCHD is one of severe birth defect issues in the United States. 

Birth defects are caused by a complex mix of genetic, behavioral, and environmental factors¹. Previous studies have reported many risk factors. For example, mother’s age, lifestyle such as smoking, and health issues such as diabetes, are identified as maternal risk factors. Although many risk factors have been identified as a potential cause of birth defects, the etiology remains unknown for about 70% of cases⁴. Moreover, the influence and magnitude of maternal risk factors varies across studies and over time, likely due to changes in human behavior, health issues, and environmental exposures^4,5,6,7.

Recent data from the Centers for Disease Control and Prevention (CDC) show that the national rate of CCHD has increased 18% from 55.6 in 2016 to 66.0 in 2022². During this period, national screening policies for CCHD remained the same^8,9, and the national abortion rate decreased by 0.3, from 11.5 in 2016 to 11.2 in 2022¹⁰. Therefore, the increase in CCHD cases is less likely due to changes in screening or termination practices. However, few studies have investigated causes for this CCHD increasing trend and the risk factors for this increasing trend are still unknown⁷.. Hence, this study conducts a systematic investigation on the influence of maternal risk factors, specifically maternal age, body mass index (BMI), pre-pregnancy and gestational diabetes, smoking, prenatal care, and trimester of prenatal care initiation, on CCHD from 2016 to 2022, based on the annual birth data provided by CDC.

Methods

Previous research has reported maternal age ≥35, pre-pregnancy diabetes, obesity, smoking, gestational diabetes, alcohol use, preeclampsia, and paternal smoking as important risk factors for CCHD for various US states during various time frames^3,5,6,7. To the best of our knowledge, no other study has conducted a systematic analysis of maternal risk factors associated with the CCHD increasing trend from 2016 to 2022. This study hypothesizes that maternal risk factors, specifically maternal age, BMI, pre-pregnancy and gestational diabetes, smoking, prenatal care access, and trimester of prenatal care initiation, may be associated with the CCHD increasing trend, and conducts a systematic investigation on the influence of these maternal risk factors on CCHD.

Data Source

Birth data were collected from the CDC National Center for Health Statistics (NCHS) live birth database². The CDC NCHS collects birth data from the standard certificate of birth, which is mandatory to be completed and published for every birth occurring in the United States. The birth data only includes births from US residents and non-residents inside the US. Births occurring to US citizens or residents outside of the US are not included. Data not reported by parents on birth certificates were labeled as “unknown” in the CDC NCHS dataset.

The CDC NCHS dataset provides the health status of pregnant women and infants, with the focus on the demographic, health, and risk factors of maternal and infant health. However, CDC restricts access to birth data with less than 10 live birth cases and individual case location due personal confidentiality². Thus, these data and unknown data were not used in this research. This study used the anonymized, singleton births with individual birth data from January 2016 to December 2022. A total of 25,417,949 births with 15,134 CCHD cases were analyzed. Details of the yearly number of total births and CCHD cases is listed in Appendix A.

Maternal Risk Factors

This study analyzed major identified risk factors available in the CDC dataset, including maternal age, prenatal care, trimester of prenatal care initiation, pre-pregnancy diabetes, BMI, smoking, and gestational diabetes on CCHD⁶.

The following variables were extracted and cleaned from the CDC dataset: maternal age, BMI, smoking, prenatal care, trimester of prenatal care initiation, pre-pregnancy diabetes, and gestational diabetes, and infant congenital anomalies and year of birth. BMI was categorized as underweight (< 18.5), normal (18.5–24.9), overweight (25–29.9), and obese (≥30). Age was categorized as under 20 years old, 20 to 34 years old, and 35 years or older. Although the average maternal age increased from 28.7 years in 2016 to 29.4 years in 2020¹¹, this shift had minimal impact on the distribution of mothers within the age categories and negligible effect on the analysis. The trimester of prenatal care initiation was categorized as 1st trimester, 2nd trimester, and 3rd trimester.

Statistical Analysis

Birth defect  rates were calculated annually from 2016 to 2022 as the number of cases per 100,000 live births to evaluate trends over this study period. Logistic regression was used to analyze the relationship between CCHD and maternal risk factors Initially, the independent variables were added into a univariate logistic model to provide the crude odds ratios, confidence intervals, and p-values. Next, those variables were analyzed in the adjusted multivariable logistic model, with maternal age, BMI, smoking, prenatal care, pre-pregnancy diabetes, and gestational diabetes as covariates. P-values were adjusted using the Benjamini-Hochberg procedure to control the false discovery rate¹². The model fit was assessed using the p-value of the Hosmer–Lemeshow (HL) test and sensitivity analyses were performed to assess the robustness of the results¹³. All statistical analyses were performed using IBM SPSS, p-value <0.05 was considered statistically significant.

Results

Figure 1(a) shows the trends and rates (per 100,000 live births) of twelve major birth defects from 2016 to 2022. CCHD has the highest birth defect rate among 12 major birth defects, followed by Hypospadias and Cleft lip with or without palate. In addition, CCHD shows a continuous increasing trend. The rest of the birth defect types show relatively low rates and stable trends compared to CCHD. Figure 1 (b) shows the rates of CCHD and total birth defects from 2016 to 2022. In those seven years, the CCHD rate increased from 55.6 to 66.0, accounting for 18% to 22% of total birth defects. The high and continuous increasing rate of CCHD trend indicates that CCHD is the dominant birth defect in the United States. 

Table 1 shows the associations between CCHD and maternal risk factors. In 2022, CCHD showed significant associations with maternal age ≥35 (OR: 1.13 95% CI: 1.02-1.25), smoking (: 1.26, 95% CI: 1.03-1.55), pre-pregnancy diabetes (OR: 4.31, 95% CI: 3.53-5.27), and gestational diabetes (OR: 1.32, 95% CI 1.14-1.52). These associations remained significant across all seven study years, except for smoking, which was significant in four of the seven years. The confidence intervals for these odds ratios are all greater than 1 with relatively narrow ranges, indicating that these odds ratios are relatively precise. In addition, the odds ratios of maternal age ≥35, smoking, pre-pregnancy diabetes, and gestational diabetes all show decreasing trends from 2016 to 2022, suggesting their influence on CCHD is decreasing. CCHD showed no significant associations with prenatal care, BMI, or maternal age <20.

Although prenatal care access shows no significant associations with CCHD, recent studies suggest that the timing of prenatal care initiation may influence CCHD risk^14,15. For example, periconceptional multivitamin use was associated with a reduced risk for CCHD, however, beginning multivitamin use after the first month of pregnancy showed no reduction in CCHD risk¹⁴. Thus, to further investigate the influence of prenatal care, this study examined prenatal care access and the trimester of prenatal care initiation.

Figure 2 (a) shows the percentage of mothers in relation to prenatal care. The percentage of mothers with and without prenatal care remained stable from 2016 to 2022, averaging 98% and 2%, respectively. Since CCHD develops in the first 10 weeks of pregnancy¹⁶, the timing of prenatal care initiation might be associated with CCHD. Figure 2(b) displays the percentage of mothers across four groups: mothers who began prenatal care in the first, second, or third trimester, and mothers who received no care. The percentages in these groups remained stable over time, with the majority of mothers (77%) initiating care in the first trimester, followed by 16% in the second trimester, 5% in the third trimester, and 2% receiving no prenatal care. Among mothers who received prenatal care, 79% of mothers-initiated care during the first trimester.

Table 2. Association between CCHD and the trimester of prenatal care initiation from 2016 to 2022

Table 2 shows the association between the trimester of prenatal care initiation and CCHD. CCHD shows significant associations with prenatal care initiated in the 2nd and 3rd trimesters, with odds ratios ranging from 1.33 to 1.57 for the 2nd trimester and from 2.65 to 3.63 for the 3rd trimester. The HL p-values calculated from 2016 to 2022 (excluding 2020) ranges from 0.169 to 0.698 indicating a good model fit. However, the HL p-value in 2020 shows a poor model fit with a value of 0.034, suggesting there might be major risk factors missing in the 2020 analysis.

Figure 3 shows the odds ratios for associations between the trimester of prenatal care initiation and CCHD. The odds ratios for initiating care in the 2nd and 3rd trimesters showed similar trends, increasing from 2016 to 2019, peaking in 2020 at 1.77 and 3.89, respectively, and then decreasing to 1.77 and 2.63, respectively, by 2022. In those years, all of the odds ratios are greater than 1, suggesting that delayed prenatal care is a risk factor for CCHD. In addition, odds ratios were consistently higher for prenatal care initiated in the 3rd trimester compared to the 2nd trimester, indicating that the later prenatal care begins, the greater the risk for CCHD.

Discussion

This study examined the association between maternal risk factors and CCHD in the United States from 2016 to 2022. In 2022, maternal age ≥35 (OR: 1.13 95% CI: 1.02-1.25), smoking (OR: 1.26, 95% CI: 1.03-1.55), pre-pregnancy diabetes (OR:4.31, 95% CI: 3.53-5.27), gestational diabetes (OR: 1.32, 95% CI 1.14-1.52), and prenatal care initiation in the 2nd trimester (OR: 1.33, 95% CI: 1.19-1.49) and 3rd trimester (OR: 2.63, 95% CI: 2.28-3.04) all show statistically significant associations with CCHD. These associations remained significant across all seven study years, except for smoking, which was significant in four of the seven years. BMI and Maternal age <20 show no statistical correlation with CCHD, which is consistent with previous studies^17,18.

Of the maternal risk factors studied, pre-pregnancy diabetes showed the strongest association with CCHD, with a large effect size of 5.55, suggesting pre-pregnancy diabetes is the major risk factor. Indeed, research has shown pre-pregnancy diabetes can interfere with fetal organ development, including the heart during the first 10 weeks of pregnancy, which may increase the risk of CCHD¹². Consequently, mothers with pre-pregnancy diabetes may be at a higher risk for having a child with CCHD. Research shows that pre-pregnancy and early pregnancy education for diabetes can decrease the risk of CCHD¹⁹. However, studies show 53% of pregnant women with preexisting diabetes received no pre-pregnancy education about how diabetes could affect pregnancy²⁰. Thus, providing pre-pregnancy education for all women with diabetes may improve diabetes management during early pregnancy and reduce the risk of CCHD.

The trimester of prenatal care initiation is significantly associated with CCHD, with good model fit in six of the seven years of analysis. The poor model fit in the 2020 analysis suggests there might be other risk factors impacting CCHD births in 2020. One major health related event in 2020 was the COVID-19 pandemic. Recent studies have reported maternal COVID-19 infection during pregnancy may impact fetal heart development²¹. In addition, studies have reported that COVID-19 is associated with the increasing trend in the heart defects rate²¹. Thus, COVID-19 might be one of the maternal risk factors influencing CCHD during the pandemic years. However, COVID-19 data is currently not complete and thus, the influence of COVID-19 on CCHD remains unclear and requires further research. Future studies may include parity, socioeconomic status, race, ethnicity, and COVID-19 as covariates to better understand the risk factors contributing to the CCHD increasing trend from 2016 to 2022.

Conclusion

This study conducted a systematic analysis of the association between six major maternal risk factors and the CCHD increasing trend from 2016 to 2022, and identified significant associations between CCHD and maternal age ≥35, smoking, pre-pregnancy diabetes, gestational diabetes, and prenatal care initiation in the 2nd trimester and 3rd trimester. Pre-pregnancy diabetes, with the highest odds ratios ranging from 4.31 to 5.62 for these seven study years, is one of the major risk factors for CCHD.

Acknowledgements

This research includes data collected from the CDC live birth dataset and EPA water quality dataset. I’d like to thank my mentor, Dr. Wan-Hsiang Hsu, and my teachers, Mr. Patrick Williams, Mrs. Deborah Boyce, and Mr. Jared Foro, for their support and guidance throughout my research.

Appendix A: Crude and adjusted odds ratios, 95% confidence intervals, p-values, adjusted p-values, and HL p-values for the association between maternal risk factors and CCHD.

Appendix B. The number of CCHD cases and state population-normalized rate of CCHD cases in all 50 states from 2016 to 2022. The rate listed in the table is multiplied by 100,000. Due to CDC confidentiality restrictions, exact birth counts could not be reported for states with fewer than 10 CCHD cases.

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