# Presentation: 475259

## Maternal Asthma Medication Use and the Risk of Heart Defects and Gastroschisis

- Shao Lin, PhD                                   Erin M. Bell, PhD
- Jean Pierre Munsie, MS                    Marilyn Browne, PhD Charlotte M. Druschel, MD, MPH      Paul A. Romitti, PhD       Allen A. Mitchell, MD                         Angela E. Lin, MD         Richard S. Olney, MD, MPH
- The National Birth Defects Prevention Study

## Background

- The prevalence of asthma has been increasing.
- Between 1997 and 2001, 3.7%-8.4% pregnant women were affected by asthma (NHIS).
- Few studies have examined maternal asthma medication and congenital malformations.
- There has been also a secular increase in the prevalence of gastroschisis in the last 3 decades.
- A previous study in NYS found a positive association between mothers with asthma and use of asthma medication and CVM.

## Study Hypothesis 

- 	Does maternal use of asthma medication prior to and during the first trimester increase the risk of cardiovascular malformations and gastroschisis?

## Study Design

- Multi-center case-control study (NBDPS)
- Study Period:   Women who delivered between 1997 and 2002
- Controls: non-malformed, liveborn infants identified from birth certificates/birth hospitals
- Major CVM subtypes (specific CVM diagnoses designated as eligible defects in the NBDPS)
- Conotruncals (Fallot, dTGA)
- Septals (VSDpm, ASD2all)
- LVOTO (HLH, Coarctation)
- RVOTO (PSV)
- Gastroschisis (reviewed by physicians and classified as isolated cases)

## Exposure Definition

- Critical exposure period
- Asthma medication use at least once between one month prior to and end of the third pregnancy month
- Asthma medication use
- 		1. Anti-inflammatories (reduce airways inflammation /mucus production, e.g., corticosteroids, mast cell stabilizers, and leukotriene modifier drugs)
- 		2. Bronchodilators (dilate the airways, including beta 2-agonists, anticholinergics and theophilline)
- Daily use during the critical period
- Multiple asthma medications use

## Statistical Analysis

- Unconditional logistic regression was used to compute odds ratios (OR) and 95% Confidence Interval (CI)
- Potential confounders:  Maternal age, race/ethnicity, body Mass Index, parity, education, drinking habit, cigarette smoking, and cocaine or crack use

## Five most common bronchodilators and anti-inflammatories used during the critical period * 

|  |  |  |
| --- | --- | --- |
| Bronchodilators
Albuterol | Anti-Inflammatories
Fluticasone |  |
| Salmeterol | Prednisone |  |
| Pirbuterol | Beclomethasone |  |
| Ipratropium Bromide | Triamcinolone |  |
| Ephedrine | Cromolyn Sodium |  |
|  |  |  |
| *  Not mutually exclusive
 |  |  |

## Adjusted OR for Bronchodilator Use during the critical period

- 				Use		No Use	OR* (95% CI)
- Conotruncals		  21		  625		1.0 (0.6, 1.5)
- Controls		119		3846
- Septals		  40		1001		1.2 (0.8, 1.8)
- Controls		119		3846
- LVOTO		  21         	  483		1.3 (0.8, 2.1)
- Controls		119		3846
- RVOTO		  19	        	  392		1.6 (1.0, 2.5)
- Controls**		106		3270
- **Adjusted for BMI, income, maternal race, folic acid*
***** Control numbers differ due to change in case ascertainment*

## Adjusted OR for Anti-Inflammatory Use during the critical period

- 				Use		No Use	OR* (95% CI)
- Conotruncals		  15		  635		1.5 (0.8, 2.6)
- Controls		  65		3903
- Septals		  18		1024		1.1 (0.7, 1.9)
- Controls		  65		3903
- LVOTO		  12         	  493		1.5 (0.9, 2.8)
- Controls		  65		3903
- RVOTO		  10	        	  401		1.6 (0.8, 3.0)
- Controls**		  58		3320
- **Adjusted for BMI, income, maternal race, folic acid*
***** Control numbers differ due to change in case ascertainment*

## Adjusted OR for Bronchodilator and Anti-Inflammatory Use during the critical period

- 				Use		No Use	OR* (95% CI)
- Conotruncals		    6		  616		1.3 (0.5, 3.1)
- Controls		  25		3806
- Septals		  10		  993		1.5 (0.7, 3.0)
- Controls		  25		3806
- LVOTO		    9        	  480		2.5 (1.2, 5.3)
- Controls		  25		3806
- RVOTO		    8	        	  390		2.6 (1.1, 5.8)
- Controls**		  22		3234
- **Adjusted for BMI, income, maternal race, folic acid*
***** Control numbers differ due to change in case ascertainment*

## Adjusted OR for Daily and non-Daily use of Bronchodilators and Anti-inflammatories

- 				  Daily *   		  Not Daily*
- _Bronchodilators_
- Conotruncals		1.0 (0.6,1.8)		0.8 (0.4, 1.9)
- Septals		1.3 (0.8, 2.0)		1.1 (0.6, 2.0)
- LVOTO		1.7 (1.0, 2.8)		0.8 (0.3, 2.0)
- RVOTO		1.3 (0.7, 2.4)		2.0 (1.0, 4.0)
- _Anti-inflammatories_
- Conotruncals		0.8 (0.3, 2.2)		2.1 (1.1, 4.1)
- Septals		0.9 (0.4, 2.0)		1.4 (0.7, 2.7)
- LVOTO		2.3 (1.1, 4.7)		0.9 (0.3, 2.4)
- RVOTO		0.9 (0.3, 3.0)		2.1 (1.0, 4.7)
- * Reference: non-users; adjusted for BMI, income, maternal race and folic acid

## Maternal Asthma Medication Use and the Crude/ Adjusted OR of Gastroschisis

- 			Total	Case (%)	Crude OR	Adj.OR*						(95% CI)      (95% CI)
- Bronchodilators
- Yes	         147    19 (5.0)    1.63 (1.00-2.68)  1.69 (1.01-1.85)
- No 	      4,352  362(95.0)   1.0   (ref.)	          1.0   (ref.)
- Anti-Inflammatories
- Yes	          75       7 (1.8)    1.12 (0.51-2.45)  1.72 (0.75-3.91)
- No 	      4,425  374(98.2)   1.0   (ref.)	          1.0   (ref.)
- **Adjusted for BMI, income, maternal race, folic acid*

## Odds Ratios of Gastroschisis by Duration of Maternal Asthma Medication Use

- * **Reference group: Non users of medication.**
**** Reported use of asthma medications for 30 days in each of the following months: one month before pregnancy, and each of the first three months of pregnancy**.

## Odds Ratios of Gastroschisis by Number of Maternal Asthma Medication Use 

- * **Reference Group: Non users of medication.**
**** One Bronchodilator or one Anti-Inflammatory. **
** † ****More than one Bronchodilator and/or Anti-Inflammatory**.

## Summary

- Increased risk observed for RVOTO and LVOTO among those who reported using both medications.
- With the exception of LVOTO, non-daily users  of anti-inflammatories had larger risk of CVM than daily users but similar pattern not observed for bronchodilators.??
- A positive association was observed for maternal bronchodilators use and the risk of gastroschisis.
- Mothers who used asthma medication for entire critical period had higher risks of gastroschisis than those who used them for shorter period or non-users.
- The more types asthma medication mothers used, the higher risk of gastroschisis.
- All users of both medication classes during the critical period were also daily users of each class

## Discussion

- Strengths:
- 		Population-based study
- 		Systematic review and classification of cases
- 		Large sample size
- 		Extensive data on potential confounders
- Limitations:
- 		Unknown asthma status including severity
- 		Unable to separate effects of asthma medicine 			from asthma status
- 		Medications could be used for other conditions

## Conclusion and Recommendation

- Maternal asthma medication use or asthma status was found to be potentially associated with certain heart defects and gastroschisis
- Further study with detailed information on asthma severity is needed to distinguish the effect of medicine from disease status