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DSHS Authors: 2021 Research Articles by DSHS Staff

The following list includes peer-reviewed research articles that have been written by staff of the Texas Department of State Health Services. For more information about these articles or for a full-text copy, please contact the Medical and Research Library by email at library@dshs.texas.gov by calling 512-776-7559.

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2021 Articles (in date order with most recent first)

Garcia F, et al. Efficacy, pharmacokinetics, and safety over 48 weeks with ibalizumab-based therapy in treatment-experienced adults infected with HIV-1: A Phase 2a study. J Acquir Immune Defic Syndr. 2021 Apr 1;86(4):482-489. doi: 10.1097/QAI.0000000000002591.
Ibalizumab, a humanized monoclonal antibody targeting CD4, blocks HIV-1 entry into cells and is the first Food and Drug Administration-approved long-acting agent for HIV-1 treatment. In this phase 2a study, 82 HIV-infected adults failing antiretroviral therapy were assigned an individually optimized background regimen (OBR) and randomized 1:1:1 to arm A (15 mg/kg ibalizumab q2wk), arm B (10 mg/kg weekly for 9 weeks, then q2wk), or placebo. Subjects with an inadequate response at week 16 were permitted to cross over to a new OBR plus 15 mg/kg ibalizumab q2wk. At week 16, viral load (VL) reduction was significantly greater than placebo (0.26 log10) in arms A (1.07 log10; P = 0.002) and B (1.33 log10; P < 0.001); CD4+ T cell counts increased significantly in arm A. After week 16, 11/27 (arm B) and 19/27 (placebo) subjects crossed over to OBR plus 15 mg/kg ibalizumab; 8/28 in arm A initiated a new OBR. Ibalizumab treatment resulted in VL reduction at week 24 (-0.77 and -1.19 log10 for arms A and B, respectively, versus -0.32 log10 for placebo) and 48 weeks (-0.54 and -0.77 versus -0.22 log10). Compared with placebo, VL differences were statistically significant for arm B at week 24 (P = 0.001) and week 48 (P = 0.027). CD4+ T cell counts increased significantly by week 48 in both arm A and arm B, relative to placebo. No ibalizumab-related serious adverse events were reported. The durable antiviral activity and tolerability of ibalizumab support its use in treating individuals harboring multidrug-resistant HIV-1.

Canfield MA, et al. Survival of infants born with esophageal atresia among 24 international birth defects surveillance programs. Birth Defects Res. 2021 Mar 18. doi: 10.1002/bdr2.1891. [Epub ahead of print]
 Esophageal atresia (EA) affects around 2.3-2.6 per 10,000 births world-wide. Infants born with this condition require surgical correction soon after birth. Most survival studies of infants with EA are locally or regionally based. We aimed to describe survival across multiple world regions.
METHODS: We included infants diagnosed with EA between 1980 and 2015 from 24 birth defects surveillance programs that are members of the International Clearinghouse for Birth Defects Surveillance and Research. We calculated survival as the proportion of liveborn infants alive at 1 month, 1- and 5-years, among all infants with EA, those with isolated EA, those with EA and additional anomalies or EA and a chromosomal anomaly or genetic syndrome. We also investigated trends in survival over the decades, 1980s-2010s.
RESULTS: We included 6,466 liveborn infants with EA. Survival was 89.4% (95% CI 88.1-90.5) at 1-month, 84.5% (95% CI 83.0-85.9) at 1-year and 82.7% (95% CI 81.2-84.2) at 5-years. One-month survival for infants with isolated EA (97.1%) was higher than for infants with additional anomalies (89.7%) or infants with chromosomal or genetic syndrome diagnoses (57.3%) with little change at 1- and 5-years. Survival at 1 month improved from the 1980s to the 2010s, by 6.5% for infants with isolated EA and by 21.5% for infants with EA and additional anomalies.
CONCLUSIONS: Almost all infants with isolated EA survived to 5 years. Mortality was higher for infants with EA and an additional anomaly, including chromosomal or genetic syndromes. Survival improved from the 1980s, particularly for those with additional anomalies.

Garza E, et al. Epidemiology surveillance and capacity improvement: A characterization of Texas, 2017. Disaster Med Public Health Prep. 2021 Mar 17:1-8. doi :10.1017/dmp.2020.471. [Epub ahead of print]
OBJECTIVES: In response to increasing caseloads of foodborne illnesses and high consequence infectious disease investigations, the Texas Department of State Health Services (DSHS) requested funding from the Texas Legislature in 2013 and 2015 for a new state-funded epidemiologist (SFE) program.
METHODS: Primary cross-sectional survey data were collected from 32 of 40 local health departments (LHDs) via an online instrument and analyzed to quantify roles, responsibilities, and training of epidemiologists in Texas in 2017 and compared to similar state health department assessments.
RESULTS: Sixty-six percent of SFEs had epidemiology-specific training (eg, master's in public health) compared to 45% in state health department estimates. For LHDs included in this study, the mean number of epidemiologists per 100,000 was 0.73 in medium LHDs and 0.46 in large LHDs. SFE positions make up approximately 40% of the LHD epidemiology workforce of all sizes and 56% of medium-sized LHD epidemiology staff in Texas specifically.
CONCLUSIONS: Through this program, DSHS increased epidemiology capacity almost twofold from 0.28 to 0.47 epidemiologists per 100,000 people. These findings suggest that capacity funding programs like this improve epidemiology capacity in local jurisdictions and should be considered in other regions to improve general public health preparedness and epidemiology capacity.

Hall N, et al. Myopericarditis associated With smallpox vaccination among US Army personnel - Fort Hood, Texas, 2018. Disaster Med Public Health Prep. 2021 Mar 15:1-7. doi: 10.1017/dmp.2020.478. [Epub ahead of print]
In March 2018, the US Department of Defense (DOD) added the smallpox vaccination, using ACAM2000, to its routine immunizations, increasing the number of persons receiving the vaccine. The following month, Fort Hood reported a cluster of 5 myopericarditis cases. The Centers for Disease Control and Prevention and the DOD launched an investigation.
METHODS: The investigation consisted of a review of medical records, establishment of case definitions, causality assessment, patient interviews, and active surveillance. A 2-sided exact rate ratio test was used to compare myopericarditis incidence rates.
RESULTS: This investigation identified 4 cases of probable myopericarditis and 1 case of suspected myopericarditis. No alternative etiology was identified as a cause. No additional cases were identified. There was no statistically significant difference in incidence rates between the observed cluster (5.23 per 1000 vaccinated individuals, 95% CI: 1.7-12.2) and the ACAM2000 clinical trial outcomes for symptomatic persons, which was 2.29 per 1000 vaccinated individuals (95% CI: 0.3-8.3).
CONCLUSIONS: Vaccination with ACAM2000 is the presumptive cause of this cluster. Caution should be exercised before considering vaccination campaigns for smallpox given the clinical morbidity and costs incurred by a case of myopericarditis. Risk of myopericarditis should be carefully weighed with risk of exposure to smallpox.

Shuford JA, Prot E, Cuevas E, Moon K, Tyler CG, Freeland M, et al. Travel from the United Kingdom to the United States by a symptomatic patient infected with the SARS-CoV-2 B.1.1.7 variant - Texas, January 2021. MMWR Morb Mortal Wkly Rep. 2021 Mar 12;70(10):348-349. doi: 10.15585/mmwr.mm7010e2. 
In December 2020, the B.1.1.7 genetic variant of SARS-CoV-2, the virus that causes COVID-19, was first reported after emergence and rapid circulation in the United Kingdom (1). Evidence suggests that the B.1.1.7 variant is more efficiently transmitted than are other SARS-CoV-2 variants, and widespread circulation could thereby increase SARS-CoV-2 infection and hospitalization rates (1,2). The first reported SARS-CoV-2 B.1.1.7 variant case in the United States was confirmed by sequencing in Colorado on December 29, 2020.* This report describes a person who traveled from the United Kingdom to the United States after experiencing COVID-19-compatible symptoms† and was eventually confirmed to be infected with the B.1.1.7 variant.

Stoner D, et al. Cost-Effectiveness of the Wellness Incentives and Navigation (WIN) Program. Value Health. 2021 Mar;24(3):361-368. doi: 10.1016/j.jval.2020.06.019.
OBJECTIVES: Promoting patient involvement in managing co-occurring physical and mental health conditions is increasingly recognized as critical to improving outcomes and controlling costs in this growing chronically ill population. The main objective of this study was to conduct an economic evaluation of the Wellness Incentives and Navigation (WIN) intervention as part of a longitudinal randomized pragmatic clinical trial for chronically ill Texas Medicaid enrollees with co-occurring physical and mental health conditions.
METHODS: The WIN intervention used a personal navigator, motivational interviewing, and a flexible wellness expense account to increase patient activation, that is, the patient's knowledge, skills, and confidence in managing their self-care and co-occurring physical and mental health conditions. Regression models were fit to both participant-level quality-adjusted life years (QALYs) and total costs of care (including the intervention) controlling for demographics, health status, poverty, Medicaid managed care plan, intervention group, and baseline health utility and costs. Incremental costs and QALYs were calculated based on the difference in predicted costs and QALYs under intervention versus usual care and were used to calculate the incremental cost-effectiveness ratios (ICERs). Confidence intervals were calculated using Fieller's method, and sensitivity analyses were performed.
RESULTS: The mean ICER for the intervention compared with usual care was $12,511 (95% CI $8,971-$16,842), with a sizable majority of participants (70%) having ICERs below $40,000. The WIN intervention also produced higher QALY increases for participants who were sicker at baseline compared to those who were healthier at baseline.
CONCLUSION: The WIN intervention shows considerable promise as a cost-effective intervention in this challenging chronically ill population.

Sardell R, Miller P, et al. Texas has the highest hepatocellular carcinoma incidence rates in the USA. Dig Dis Sci. 2021 Mar;66(3):912-916. doi: 10.1007/s10620-020-06231-4.
BACKGROUND: Texas is the second largest state by area and population in the USA and is reported to have high incidence and mortality rates for hepatocellular carcinoma (HCC). The reasons for the increasingly high burden of HCC in Texas are not clear.
AIMS: We explored trends and demographic and regional variations in HCC incidence to better understand reasons for the high burden in Texas.
METHODS: We analyzed Texas Cancer Registry incidence data from 2001 to 2015 and compared results to the U.S. National Program of Cancer Registries and SEER for the same period. Rates were stratified by sex, race/ethnicity, and age at diagnosis. Rates were also compared between the US/Mexico border region of Texas and the rest of Texas.
RESULTS: Texas had the highest HCC age-adjusted incidence rate of all states, 13.2/100,000, which was 45% higher than the national average. In Texas and nationally, rates increased by 4% per year between 2001 and 2015. Rates in Texas were 26-37% greater than national rates for Hispanics, African-Americans, and non-Hispanic whites. Among Hispanics in states with the largest percentage of Hispanics, Texas-based Hispanics had the highest HCC incidence rate in 2015 (21.2/100,000) compared with Hispanics in New Mexico, California, Arizona, Nevada, and Florida. Incidence rates were highest in South Texas and US/Mexico border regions.
CONCLUSIONS: Increasing rates in the large Hispanic population may explain why Texas now has the highest HCC incidence rate in the USA.

Norkin SK, et al. Inadequate engagement in HIV care among people with HIV newly diagnosed with an STD: A multi-jurisdictional analysis. Sex Transm Dis. 2021 Feb 23. doi: 10.1097/OLQ.0000000000001381. [Epub ahead of print]
BACKGROUND: A key challenge of HIV surveillance-based HIV care re-engagement is locating people living with HIV (PLWH) who appear to be out of care in order to re-engage them in care. Providing re-engagement services to PLWH diagnosed with an STD - individuals who are in jurisdiction and connected to the health care system - could be an efficient means of promoting HIV treatment and reducing HIV transmission.
METHODS: Early and late syphilis (ES/LS) and gonorrhea (GC) cases diagnosed in 2016 and 2017 in Louisiana, Michigan, Mississippi, Oregon, Rhode Island, and Texas were matched to each state's HIV surveillance data to determine the proportion of PLWH with these infections who (1) did not have evidence of a CD4 count or viral load in the prior >13 months (out-of-care) or, (2) had a viral load ≥1500 copies/mL on their most recent HIV RNA test prior to STD diagnosis (viremic).
RESULTS: Previously diagnosed HIV infection was common among persons diagnosed with ES (n=6942, 39%), LS (n=4329, 27%) and GC (n=9509, 6%). Among these ES, LS, and GC cases 26% (n=1543), 33% (n=1113), and 29% (n=2391) were out of HIV medical care or viremic at the time of STD diagnosis.
CONCLUSIONS: A large proportion of STD cases with prior HIV diagnosis are out of care or viremic. Integrating relinkage to care activities into STD partner services and/or the use of matching STD and HIV data systems to prioritize data to care (D2C) activities could be an efficient means for relinking patients to care and promoting viral suppression.

Canfield MA, et al. Maternal hypertension-related genotypes and congenital heart defects. Am J Hypertens. 2021 Feb 18;34(1):82-91. doi: 10.1093/ajh/hpaa116.
BACKGROUND: Maternal hypertension has been associated with congenital heart defect occurrence in several studies. We assessed whether maternal genotypes associated with this condition were also associated with congenital heart defect occurrence.
METHODS: We used data from the National Birth Defects Prevention Study to identify non-Hispanic white (NHW) and Hispanic women with (cases) and without (controls) a pregnancy in which a select simple, isolated heart defect was present between 1999 and 2011. We genotyped 29 hypertension-related single nucleotide polymorphisms (SNPs). We conducted logistic regression analyses separately by race/ethnicity to assess the relationship between the presence of any congenital heart defect and each SNP and an overall blood pressure genetic risk score (GRS). All analyses were then repeated to assess 4 separate congenital heart defect subtypes.
RESULTS: Four hypertension-related variants were associated with congenital heart defects among NHW women (N = 1,568 with affected pregnancies). For example, 1 intronic variant in ARHGAP2, rs633185, was associated with conotruncal defects (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1-1.6). Additionally, 2 variants were associated with congenital heart defects among Hispanic women (N = 489 with affected pregnancies). The GRS had a significant association with septal defects (OR: 2.1, 95% CI: 1.2-3.5) among NHW women.
CONCLUSIONS: We replicated a previously reported association between rs633185 and conotruncal defects. Although additional hypertension-related SNPs were also associated with congenital heart defects, more work is needed to better understand the relationship between genetic risk for maternal hypertension and congenital heart defects occurrence.

Waldrup K, et al. Surveillance of Trypanosoma cruzi infection in triatomine vectors, feral dogs and cats, and wild animals in and around El Paso county, Texas, and New Mexico. PLoS Negl Trop Dis. 2021 Feb 18;15(2):e0009147. doi: 10.1371/journal.pntd.0009147.
The causative agent of Chagas disease, Trypanosoma cruzi, is transmitted by triatomine vectors. The insect is endemic in the Americas, including the United States, where epidemiological studies are limited, particularly in the Southwestern region. Here, we have determined the prevalence of T. cruzi in triatomines, feral cats and dogs, and wild animals, the infecting parasite genotypes and the mammalian host bloodmeal sources of the triatomines at four different geographical sites in the U.S.-Mexico border, including El Paso County, Texas, and nearby cities in New Mexico. Using qualitative polymerase chain reaction to detect T. cruzi infections, we found 66.4% (n = 225) of triatomines, 45.3% (n = 95) of feral dogs, 39.2% (n = 24) of feral cats, and 71.4% (n = 7) of wild animals positive for T. cruzi. Over 95% of T. cruzi genotypes or discrete typing units (DTUs) identified were TcI and some TcIV. Furthermore, Triatoma rubida was the triatomine species most frequently (98.2%) collected in all samples analyzed. These findings suggest a high prevalence of T. cruzi infections among triatomines, and feral and wild animals in the studied sites. Therefore, our results underscore the urgent need for implementation of a systematic epidemiological surveillance program for T. cruzi infections in insect vectors, and feral and wild animals, and Chagas disease in the human population in the southwestern region of the United States.

Canfield MA, et al. Causes of neonatal and postneonatal death among infants with birth defects in Texas. Birth Defects Res. 2021 Feb 15. doi: 10.1002/bdr2.1879. [Epub ahead of print]
The proportion of deaths attributed to various causes has not been quantified among infants with birth defects. We sought to describe the causes of neonatal and postneonatal death among infants in the Texas Birth Defects Registry.
METHODS: We calculated frequencies and percentages for both underlying causes and all causes (underlying or contributing) of neonatal (0-27 days) and postneonatal (28-364 days) death listed on death certificates among infants born alive with birth defects and delivered in Texas during 1999-2013 (n = 8,389 deaths). Analyses were repeated separately for infants with isolated, multiple, and syndromic defects.
RESULTS: After birth defects, the most frequently listed causes of neonatal death were preterm/low birth weight (10%), circulatory system diseases (8%), and sepsis (5%). The leading postneonatal causes of death beyond birth defects were circulatory system diseases (32%), sepsis (11%), and renal failure (7%).
CONCLUSIONS: Improved understanding of the causes of mortality among infants with birth defects may help identify priorities for postnatal care. Our results suggest that potentially modifiable causes of death (e.g., circulatory system diseases, sepsis) contribute substantially to mortality in this population. Prioritizing continued improvements in prevention, diagnosis, and management of preventable conditions may reduce mortality among infants born with birth defects.

Canfield MA, et al. 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. J Assist Reprod Genet. 2021 Feb 5. doi: 10.1007/s10815-021-02095-3. [Epub ahead of print]
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.

Johnson EP, et al. ChicagO Multiethnic Prevention and Surveillance Study (COMPASS): Increased response rates among African American residents in low socioeconomic status neighborhoods. Racial Ethn Health Disparities. 2021 Feb;8(1):186-198. doi: 10.1007/s40615-020-00770-2.
African American (AA) populations experience persistent health disparities in the USA. Low representation in bio-specimen research precludes stratified analyses and creates challenges in studying health outcomes among AA populations. Previous studies examining determinants of bio-specimen research participation among minority participants have focused on individual-level barriers and facilitators. Neighborhood-level contextual factors may also inform bio-specimen research participation, possibly through social norms and the influence of social views and behaviors on neighbor's perspectives. We conducted an epidemiological study of residents in 5108 Chicago addresses to examine determinants of bio-specimen research participation among predominantly AA participants solicited for participation in the first 6 years of ChicagO Multiethnic Prevention and Surveillance Study (COMPASS). We used a door-to-door recruitment strategy by interviewers of predominantly minority race and ethnicity. Participants were compensated with a $50 gift card. We achieved response rates of 30.4% for non-AA addresses and 58.0% for AA addresses, with as high as 80.3% response among AA addresses in low socioeconomic status (SES) neighborhoods. After multivariable adjustment, we found approximately 3 times the odds of study participation among predominantly AA addresses in low vs. average SES neighborhoods (odds ratio (OR) = 3.06; 95% confidence interval (CI) = 2.20-4.24). Conversely, for non-AA addresses, we observed no difference in the odds of study participation in low vs. average SES neighborhoods (OR = 0.89; 95% CI = 0.69-1.14) after multivariable adjustment. Our findings suggest that AA participants in low SES neighborhoods may be recruited for bio-specimen research through door-to-door approaches with compensation. Future studies may elucidate best practices to improve bio-specimen research participation among minority populations.

Langlois PH, Canfield MA, et al. Patterns of co-occurring birth defects among infants with hypospadias. J Pediatr Urol. 2021 Feb;17(1):64.e1-64.e8. doi: 10.1016/j.jpurol.2020.11.015.
Introduction: Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally.
Objective: This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects.
Study design: We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA).
Results: Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias.
Discussion: Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified.
Conclusion: In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices.

Langlois PH, et al. Associations between cumulative environmental quality and ten selected birth defects in Texas. Birth Defects Res. 2021 Jan 15;113(2):161-172. doi: 10.1002/bdr2.1788.
Causes of most birth defects are largely unknown. Genetics, maternal factors (e.g., age, smoking) and environmental exposures have all been linked to some birth defects, including neural tube, oral cleft, limb reduction, and gastroschisis; however, the contribution of cumulative exposures across several environmental domains in association with these defects is not well understood.
The Environmental Quality Index (EQI) and its domains (air, water, land, sociodemographic, built) were used to estimate county-level cumulative environmental exposures from 2006-2010 and matched to birth defects identified from Texas Birth Defects Registry and live birth records from births in years 2007-2010 (N = 1,610,709). Poisson regression models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for associations between 10 birth defects and the EQI.
We observed some positive associations between worst environmental quality and neural tube, anencephaly, spina bifida, oral cleft, cleft palate, cleft lip with and without cleft palate, and gastroschisis [PR range: 1.12-1.55], but near null associations with limb reduction defects. Among domain specific results, we observed the strongest positive associations with the sociodemographic domain across birth defects but varied positive associations among the air and water domains, and negative or null associations with the land and built domains. Overall, few exposure-response patterns were evident.
CONCLUSIONS: Our results highlight the complexities of cumulative, simultaneous environmental exposures in the prevalence rates of 10 selected birth defects. We were able to explore the impact of overall and domain specific environmental quality on birth defects and identify potential domain specific drivers of these associations.

Le M, et al. Prevalence of structural birth defects among infants with Down syndrome, 2013-2017: A US population-based study. Birth Defects Res. 2021 Jan 15;113(2):189-202. doi: 10.1002/bdr2.1854. 
Down syndrome is the most common chromosomal disorder at birth and is often accompanied by structural birth defects. Current data on major structural defects in this population are limited.
States and territorial population-based surveillance programs submitted data on identified cases of Down syndrome and identified structural birth defects during 2013-2017. We estimated prevalence by program type and maternal and infant characteristics. Among programs with active case ascertainment, we estimated the prevalence of birth defects by organ system and for specific defects by maternal age (<35, ≥35) and infant sex.
We identified 13,376 cases of Down syndrome. Prevalence among all programs was 12.7 per 10,000 live births. Among these children, 75% had at least one reported co-occurring birth defect diagnosis code. Among 6,210 cases identified by active programs, 66% had a cardiovascular defect with septal defects being the most common: atrial (32.5%), ventricular (20.6%), and atrioventricular (17.4%). Defect prevalence differed by infant sex more frequently than by maternal age. For example, atrioventricular septal defects were more common in female children (20.1% vs. 15.1%) while limb deficiencies were more prevalent in male children (0.4% vs. 0.1%).
Our study provides updated prevalence estimates for structural defects, including rare defects, among children with Down syndrome using one of the largest and most recent cohorts to date. These data may aid clinical care and surveillance.

Langlois PH, Canfield MA, et al. Risk factors and time trends for isolated craniosynostosis. Birth Defects Res. 2021 Jan 1;113(1):43-54. doi: 10.1002/bdr2.1824.
BACKGROUND: We sought to investigate associations between maternal/infant characteristics and isolated craniosynostosis as well as its subtypes sagittal, metopic, and coronal synostosis, and assess trends in the prevalence of these conditions.
METHODS: We identified cases in the Texas Birth Defects Registry from 1999 to 2014. We used Poisson regression to identify associations between maternal/infant characteristics and craniosynostosis. We used joinpoint regression and unadjusted Poisson regression to evaluate temporal trends. Finally, we computed adjusted Poisson models to evaluate whether temporal trends were evident after accounting for changes in the population distributions of maternal/infant characteristics over time.
RESULTS: Relative to all live births in the general population, cases were more frequently male or preterm. Mothers of cases were more frequently non-Hispanic white and more frequently obese. Non-Hispanic black or Hispanic maternal race/ethnicity was associated with a lower prevalence of all craniosynostosis subtypes. Previous live births were associated with sagittal synostosis; residence on the U.S.-Mexico border was associated with sagittal and coronal synostosis. The prevalence of any isolated craniosynostosis increased (average annual percent change estimated from joinpoint regression [AAPC]: 2.9%), as did the prevalences of sagittal (AAPC: 3.3%) and metopic synostosis (AAPC: 5.4%). In crude Poisson models, the same temporal trends were observed, however these were attenuated after adjusting for maternal/infant characteristics.
CONCLUSIONS: Prevalence of isolated craniosynostosis increased from 1999 to 2014. The largest AAPC was observed for metopic synostosis. Changes in the population distribution of associated maternal/infant characteristics may explain these trends.

Ethen MK, Canfield MA, et al. The risk of birth defects with conception by ART. Hum Reprod. 2021 Jan 1;36(1):116-129. doi: 10.1093/humrep/deaa272. 
STUDY QUESTION: What is the association between ART conception and treatment parameters and the risk of birth defects?
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.

Langlois PH, et al. Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: A phenome-wide association study. Ann Epidemiol. 2021 Jan;53:14-20.e8. doi: 10.1016/j.annepidem.2020.08.006.
Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, using the phenome-wide association (PheWAS) methodology.
We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999-2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130).
Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval [CI] 1.38-1.42), multiple defects (PRR 1.86, 95% CI 1.81-1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93-2.07), multiple defects (PRR 3.27, 95% CI 3.11-3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19-1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes.
The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%-9% during pregnancy, our results highlight a significant public health concern.

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Last updated April 16, 2021