BIRTH DEFECTS IN TEXAS AND BEYOND: UPDATE - PowerPoint Presentation

BIRTH DEFECTS IN TEXAS AND BEYOND: UPDATE Mark Canfield, Ph.D., ManagerBirth Defects Epidemiology and Surveillance Branch,Texas Department of State Health Services 1

The authors of this research have no financial or other interests which pose a conflict of interest. This research was funded by general revenue from the State of Texas, the Maternal and Child Health Title V block grant, and 2 cooperative agreements from CDC: data utilization (DD16-1601) and Zika-related birth defects surveillance (DD16-1605).Disclosure 2

Topics Program history and overviewPatterns in occurrence and survival of birth defectsRisk factors for birth defects Border study of neural tube defects: summary of findings Zika in Texas: current status Birth defects consistent with Zika: definition, surveillance Surveillance approaches and information flow Historical data on Zika-type birth defects, Texas, pre-Zika Zika project on neonatal ascertainment Related initiatives Discussion

Program History and Overview 4

History 1991 Headlines “Baby tragedy has no bounds/Woodlands, like the Valley, sees infants missing brains.”

Early Program Milestones 1993: Legislation enacted1994: Registry established1996: Center established1999: Registry became statewide

Features of the Texas Birth Defects Registry Computerized database of infants and pregnancies affected by birth defectsActive surveillance--trained staff visit facilities to identify cases and collect info Structural/chromosomal malformations Emphasis on diagnostic accuracy Emphasis on hospitals/related clinics Includes all pregnancy outcomes

Patterns in Birth Defects Prevalence and Survival

Prevalence of Any Monitored Birth Defect Over Time, Texas, 1999-2013

Prevalence of Two Selected Birth Defects Over Time, Texas, 1999-2013

Prevalence of Pyloric Stenosis Over Time, Texas, 1999-2013

Any Monitored Defect Texas, 1999-2013 Mother’s Age Sex of Infant/Fetus

Selected Birth Defects with Statistically Significant Differences in Prevalence among Three Racial/Ethnic Groups, Texas, 1999-2013

Birth Defects that are Higher in Males, Higher in Females, Similar in Both

15 Prevalence of Selected Birth Defects, by Mother's Education, Texas, 1999-2013

Spina Bifida Prevalence, Texas, 1999-2013 Arrows indicate statistically significant higher (  ) or lower (  ) prevalence, compared to Texas statewide prevalence.                                                                                                     3.4 3.8 4.3 4.4 3.3  4.9 Harlingen 4.0 3.2 4.0  3.1 Houston 3.4 Texas statewide prevalence = 3.8 cases per 10,000 live births 16

Spina Bifida Prevalence, by Border Status, Texas, 1999-2014 ~ Cases are definite, vital record status live born or fetal demise + Birth to non-Texas residents were excluded from the denominator for all calculations

1 Definite Cases, liveborn and fetal deaths 2 per 10,000 births to Texas residents Prevalence of Neural Tube Defects, Cameron County, Texas, 1999-2014

1 Definite Cases, liveborn and fetal deaths 2 per 10,000 births to Texas residents Prevalence of Neural Tube Defects, Hidalgo County, Texas, 1999-2014

Birth Defects Survival

Adjusted Hazard Ratios* for Selected Birth Defects, by Maternal Race/Ethnicity: 12 State Birth Defects Surveillance Programs, NBDPN, 1999-2007 21 Wang Y et al , Journal of Pediatrics  2015. *Non-Hispanic White was the referent group Birth Defects Non-Hispanic Black Hispanic Neonatal (<28 days) Postneonatal (28-364 days) Neonatal (<28 days) Postneonatal (28-364 days) Congenital heart defects         Common Truncus 1.5 1.4 1.7* 1.2 Transposition of great arteries 1.0 2.1* 0.9 1.5* Tetralogy of Fallot 1.0 1.8*1.11.7*Atrioventricular septal defects (AVSD)1.21.6*1.21.7*AVSD (without Down Syndrome)1.01.3*1.01.6*Hypoplastic left heart syndrome0.91.3*1.01.3*Coarctation of aorta 1.31.8*0.91.2Oral Clefts     Cleft Palate w/o cleft lip 1.21.9*1.4*1.7*Cleft lip w/ or w/o cleft palate1.22.4*1.2*1.5*

Adjusted Hazard Ratios* for Selected Birth Defects, by Maternal Race/Ethnicity: 12 State Birth Defects Surveillance Programs, NBDPN, 1999-2007 (Continued) 22 Wang Y et al , Journal of Pediatrics  2015. *Non-Hispanic White was the referent group Birth Defects Non-Hispanic Black Hispanic Neonatal (<28 days) Postneonatal (28-364 days) Neonatal (<28 days) Postneonatal (28-364 days) Gastrointestinal defects Esophageal atresia/ tracheoosophageal fistula 1.9* 2.8* 1.6* 1.5 Rectal and large intestinal atresia/stenosis 1.1 1.6* 1.3* 1.5* Musculoskeletal defects         Upper limb deficiencies 1.02.1*1.11.7*Diaphragmatic hernia1.21.7*0.8*1.4*Chromosomal defects    Trisomy 21 (Down syndrome)1.01.9*0.81.2

23 Infant Case Fatality Rate (%) of Critical Congenital Heart Defects Targeted for Pulse Oximetry Screening, Texas, 2005-2013

1 Live born cases only 2 Case Fatality Rate = (cases with defect who died / all cases with same defect) x 100. Note: uses indicaton of death from both medical and vital records by 1 year of age. Hypoplastic Left Heart Syndrome 1 Case-Fatality Rate (%) 2 , Texas, 1999-2013

Risk Factors from the National Birth Defects Prevention Study

States that Participated in the National Birth Defects Prevention Study *From http://www.nbdps.org/

Texas Center for Birth Defects Research and Prevention, 1996-2013 Cooperative agreement grant with CDC One of 10 centers in the nation National Birth Defects Prevention Study Largest population-based case-control study on birth defects Study includes 30 specific birth defects Additional clinical review and classification of cases Computer-assisted maternal phone interview Cheek cell samples (DNA): mom, dad, infant

Adjusted Odds Ratios for Pre-pregnancy Obesity and Selected Isolated Birth Defects, 1997–2002 Waller DK et al. Archives Pediatr & Adolesc Med 2007. aOR 28

Fever, Antipyretics, and Oral Clefts, 1997-2004: Adjusted Odds Ratios _I: Isolated defects; _M: Multiple defects Hashmi S et al . Birth Defects Res A Clin Mol Teratol 2008. 29

Periconceptional * Fever and Major Birth Defects, 1997-2011 30 Waller DK et al. Provisional Unpublished Data, 2016. * 1 month before to 2 months after conception.

ᵠ Adjusted for: Maternal age, race, BMI, nativity, folic acid intake in multivitamins or alone, dietary folate equivalent, parity, pregnancy intention, household income, study center, and time to interview. Mothers Exposed to Secondhand Smoke Exposure (B1P3) & Selected Isolated Defects Birth Defect n No Exposure (Referent) n Any Exposure in the Workplace/School or Household Controls 5468 1012   Controls (clefts) 5363 1005     Amniotic band syndrome-limb body wall complex (ABS-LBWC) 104 1.00 40 1.66 (1.10-2.51) Neural tube defects 823 1.00 219 1.55 (1.29-1.85) Anencephaly and craniorachischisis 247 1.00 66 1.66 (1.22-2.25) Cleft palate 570 1.00 125 1.31 (1.06-1.63) Cleft lip +/- cleft palate 1147 1.00 245 1.24 (1.05-1.46) Cleft lip without cleft palate4401.00941.41 (1.10-1.81)Bilateral renal agenesis or hypoplasia45 1.00151.99 (1.05-3.75)Adjusted OR (95%CI)ᵠSecondhand Smoke Exposure (B1P3)31Hoyt AT et al. Am J Obstet Gynecol, 2016.

Neural Tube Defect Study in the 14 Texas Counties Bordering Mexico, 1992-2000:Summary of Findings 32

Texas Neural Tube Defect (NTD) Project Summary of Important Findings Maternal Environmental Exposures Associated w/ NTDs: TX-Mexico Border: Pesticides In/around home or yard Living near cultivated fields Solvents (hobbies, work) Other work exposures Glycol ethers Cleaning and health care professions Mercury (but only among highest-income subjects) *Burned treated wood * Nitrosatable drugs (esp. w/ higher levels of nitrite/nitrate intake)Cigarette smoke (active smoking and second-hand)*Fumonisins Maternal Environmental Exposures NOT Associated w/ NTDs:PCBsLead, Arsenic, CadmiumAflatoxins*Novel findings33

Texas Neural Tube Defect (NTD) Project Summary of Important Findings Other Factors Associated w/ NTDs:Low serum B12 post partumIndependent of vitamin use, dietary B12/folate, RBC folate Decreasing risk with increasing B12 levels *High blood insulin levels post partum Independent of hyperglycemia, obesity High serum homocysteine levels post partum Independent of RBC folate, serum B12 *Low serum ferritin post partum *Stress in the periconceptional period *Diarrhea in the periconceptional period Dieting in the periconceptional periodPericonceptional fever/hyperthermiaGenetic polymorphisms, including for enzymes in FA pathway34*Novel findings

Zika Virus in Texas Current Status

CURRENT ZIKA VIRUS OUTBREAK Fall 2015 : NE Brazil reported a twenty-fold microcephaly increase that coincided with local transmission of Zika virus February 2016 : World Health Organization declares Zika to be a global public health emergency August 2016 : First cases of Zika virus infection locally spread by mosquitos in continental US (Florida) November 2016 : First apparently locally-transmitted cases in Texas

Zika in Texas Brownsville

334 cases of Zika virus disease reported as of May 12, 2017 Cases of Zika Virus Disease by County, Texas San Antonio Austin Brownsville Dallas/ Ft. Worth Houston

Zika Virus and Birth Defects 39

Birth Defects Consistent with Prenatal Zika Exposure

Microcephaly: Definition Clinical finding of a small head Congenital Microcephaly: present prenatally or at birth/delivery.

Microcephaly and Head Circumference Used to measure “severity” Severe: < 3 rd percentile for age and sex Also called occipital-frontal circumference (OFC)

Other Birth Defects Consistent with Prenatal Zika Exposure Other brain reduction defects NTDs and other early brain abnormalities Eye abnormalities Consequences of CNS dysfunction

Birth Defects Consistent with Prenatal Exposure to Zika Virus: Surveillance Approaches and Information Flow

USUAL ASCERTAINMENT: Usual way of getting records into the TBDR (2 years) 1. RAPID ASCERTAINMENT: Speed up getting kids with any birth defects consistent with prenatal Zika virus exposure into the Texas Birth Defects Registry (3 months) 2. REAL-TIME OR NEONATAL ASCERTAINMENT : Find out about birth defects in children born to women with evidence of Zika virus infection while pregnant (ASAP) Collecting Data More Rapidly (Enhanced Surveillance) 45

Routine Birth Defects Surveillance Discharge data and medical records from hospitals and associated clinicsFacilities with deliveries and pediatric admissions Selected International Classification of Diseases , 9 th and 10 th Revision codes 9 th Revision codes: 740-760 10 th Revision codes: Q00-Q9 Diagnoses collected through the first birthdayDelivery year 95% completed within 23 months

Enhanced Surveillance: Rapid Ascertainment for Birth Defects Consistent with Congenital Zika, Texas Birth Defects Epidemiology and Surveillance Branch Providers/ Facilities Rapid ascertainment for birth defects consistent with prenatal Zika exposure, retrospectively Goal: most registry records completed within 3 months

Enhanced Surveillance: Neonatal Ascertainment Determine pregnancy outcomes of women with evidence of Zika virus infection during pregnancy

CDC Birth Defects Surveillance Enhanced Surveillance for Congenital Zika and Birth Defects Consistent with Congenital Zika Vital Records Data Zoonosis Control Branch Local Health Departments Birth Defects Epidemiology and Surveillance Branch Providers/ Facilities CDC US Zika Pregnancy Registry Laboratory Testing Reports Arboviral Case Investigation Forms Regional Social Workers, DSHS

Historical Epidemiologic Data on Birth Defects Consistent with Prenatal Exposure to Zika Virus, 2009-2013 (pre-Zika Era)

Birth prevalence of 1 or more birth defects consistent with Zika in TX, 2009-2013 = 43.9 cases / 10,000 live births (0.4%)95% CI = 42.9 – 44.8 Comparison with 3 states in 2013-2014* = 28.6 cases / 10,000 live births (0.3%) 95% CI = 26.5 – 30.7 * Cragan JD, et al. 2017. MMWR 66(8): 219-222 Analyzing Data on Birth Defects in Texas Consistent with Congenital Zika Infection:Results From Routine Ascertainment51

MEASURE CASES BIRTH PREV (cases per 10,000 LBs) 95 % CI FOR PREV Severe Microcephaly 753 3.9 3.6-7.2 Other Brain Abnormalities 4282 22.1 21.5-22.8 NTDs and Early Brain Abnormalities 1874 9.7 9.3-10.1 Eye Abnormalities 1408 7.3 6.9-7.7 Consequences of CNS Dysfunction 1858 9.6 9.2-10.0Birth Prevalence by Category, Texas,2009-2013 (Routine Ascertainment) 52

Birth Defects Consistent with Zika, by Maternal Age, Texas, 2009-2013 Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction

Birth Defects Consistent with Zika, by Maternal Education, Texas, 2009-2013 Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction

Birth Defects Consistent with Zika, by Mother’s Pre-pregnancy Body Mass Index Group, Texas, 2009-2013 Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction

Birth Defects Consistent with Zika, by Maternal Diabetes Status, Texas, 2009-2013 Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction

Birth Defects Consistent with Zika, by Maternal Race/Ethnicity, Texas, 2009-2013 Severe Other Brain NTDs and Early Eye Abnormalities Consequences of Microcephaly Abnormalities Brain Abnormalities CNS Dysfunction

CHARACTERISTIC PATTERNS / HIGHEST RATES Mother’s age U- or J-shaped Mother’s education Lower education Mother’s BMI Microcephaly lower BMI, Other Brain U-shaped, NTDs J-shaped, Others no pattern Mother diabetes Mother diabetic Mother’s race/ethnicity Microcephaly and Other Brain NH Black, NTDs and Eyes Hispanic, CNS Black and Hispanic Summary of Descriptive Epidemiologic Findings in Texas (Person) 58

59 Birth Defects Consistent with Zika , by Year, Texas, 1999-2013 Other Brain Abnormalities NTDs and Early Brain Abnormalities Eye Abnormalities Consequences of CNS Dysfunction Severe Microcephaly 30  20  10  0  Year Prevalence 1999 2006 2013

Birth Prevalence of Severe Microcephaly, Texas, 2009-2013                                                                                                     2.3 3.2 1.7 3.7 2.7 4.8 3.2  4.8 3 .4 3.2 Texas statewide prevalence = 3.9 cases per 10,000 live births 5. 4

Neonatal Ascertainment Project, Texas Results

Zika Pregnancy Outcomes in Texas (5/3/2017) 192 137 Pregnant women with evidence of Zika virus infection Completed pregnancies 115 Pregnancy outcomes with known birth defects status and Zika testing status 41 Pregnancy outcomes with completed testing Infant serum tested 74 Pregnancy outcomes without completed testing

Country of Travel for Pregnant Women with Evidence of Zika Virus Infection with Known Pregnancy Outcomes, Texas, 2015 – 2017*, N = 115 Country of Travel Number *As of May 3, 2017

(64%) Zika Testing Not Completed on Pregnancy Outcomes of Mothers with Evidence of Zika Virus Infection, TX, N = 74

Zika Pregnancy Registry (ZPR) Case Breakdown, Texas (5/3/17) FETUS/INFANT LAB TESTING COMPLETED INCOMPLETE LAB TESTING BIRTH DEFECT STATUS Lab Evidence of Zika Inf. No Lab Evidence of Zika Inf. Lab Testing Pending/ Not Complete Total Birth Defects Consistent w/ Zika 3 5 2 10 Other Birth Defects 0 1 5 6 No Apparent Birth Defects 7 25 67 99 Total 10 31 74 115 Among the known pregnancy outcomes:

% with Birth Defects Among Known Pregnancy Outcomes from Mothers with Suspected Zika Percentage of known pregnancy outcomes with Zika-related Birth Defects in Texas as of April 7, 2017: 9% (95% CI: 2%-11%) Percentage of known pregnancy outcomes with Zika-related Birth Defects reported to the USZPR from all participating states, January – September 2016: 5% (95% CI: 4%-7%) Reynolds MR et al. MMWR 66(13):366-373, Apr. 7, 2017

Percentage of Infants/Fetuses with Zika-related Birth Defects, among 972 Completed Deliveries by Mothers with Evidence of Possible Recent Zika Infection, U.S. Zika Pregnancy Registry, 2016 5% overall (51/972): Any trimester of exposure Regardless of lab confirmed-maternal infection (e.g. other flaviviruses ?) Mostly brain abnormalities or microcephaly (43/51) (84% of total) Similar % for symptomatic (6%) and asymptomatic (5%) mothers 10% (24/250): among pregnancies with laboratory-confirmed infection 15% (9/60) among pregnancies with laboratory-confirmed infection and only first trimester/periconceptional exposure Only 25% of all infants had the recommended head ultrasounds * Reynolds MR et al. MMWR 2017; 66(13): 366-373 (April 7, 2017)

Summary 9% of known pregnancy outcomes have birth defects consistent with ZikaEnhanced surveillance allows more timely collection of data74/115 (64%) of known pregnancy outcomes did not receive complete testing 2 had birth defects consistent with Zika

Recommendations Increase testing of infantsEducate physiciansRemove financial barriers to testingEnsure that neonatal neuroimaging is completed Ensure that infants with severe birth defects are referred to services

Other Activities Related to Surveillance of Birth Defects Consistent with ZikaReferral Outcomes developmental milestones survival Interviews

Acknowledgments Texas Department of State Health ServicesBirth Defects Epidemiology and Surveillance Branch Noemi Hall, PhD Peter Langlois , PhD Erin Thompson, MEd Rebecca Breidenbach , MPA Adrienne Hoyt, MS Shady Al-Sayyad, MPH Regional Staff Zoonosis Control BranchNicole Evert, MSKelly Broussard, MPH Local Health Departments Epidemic Intelligence Service Program, Centers for Disease Control and Prevention

Thanks Mark A. Canfield, PhD mark.canfield@dshs.texas.gov Phone: 512-776-7232 72