Journal of Asthma, 45:403–407, 2008Copyright C© 2008 Informa Healthcare USA, Inc.ISSN: 0277-0903 print / 1532-4303 onlineDOI: 10.1080/02770900801971826

ORIGINAL ARTICLE

Fetal Sex and Maternal Asthma Control in Pregnancy

LUDMILA N. BAKHIREVA, M.D., PH.D., M.P.H.,1,∗ MICHAEL SCHATZ, M.D., M.S.,2 KENNETH LYONS JONES, M.D.,3

CAREY M. TUCKER, M.P.H.,4 DONALD J. SLYMEN, PH.D.,5 HILLARY S. KLONOFF-COHEN, PH.D.,6

LOUISE GRESHAM, PH.D., M.P.H.,5 DIANA JOHNSON, M.S.,3 CHRISTINA D. CHAMBERS, PH.D., M.P.H.,3,6

AND THE OTIS COLLABORATIVE RESEARCH GROUP

1Division of Pharmacy Practice and Department of Family/Community Medicine, University of New Mexico, Albuquerque,New Mexico, USA

2Department of Allergy-Immunology, Kaiser-Permanente Medical Center, San Diego, California, USA3Department of Pediatrics, University of California, San Diego, La Jolla, California, USA

4Midwestern University, Glendale, Arizona, USA5Graduate School of Public Health, San Diego State University, San Diego, California, USA

6Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California, USA

Asthma is a prevalent chronic disorder that might substantially complicate pregnancy. Some recent reports suggest that the presence of a femalefetus might be associated with worse maternal asthma symptoms during pregnancy. We tested this hypothesis using the sample of 719 pregnant womenwith asthma prospectively enrolled in the OTIS study. The presence of a female fetus was associated with a higher incidence of hospitalizations forasthma during pregnancy (OR = 1.84; 95% CI: 1.05; 3.21) independent of maternal age, BMI, ethnicity, smoking, and socioeconomic status. Thecurrent study suggests that pregnant asthmatic women carrying a girl might be more susceptible to asthma exacerbations.

Keywords asthma, fetal sex, pregnancy, asthma control, asthma exacerbation

INTRODUCTION

Asthma is a prevalent chronic disorder which affects 3.7%to 8.4% of pregnant women in the United States (1). Mater-nal asthma, especially poorly controlled asthma, is associ-ated with an increased risk of both maternal and fetal adverseperinatal outcomes (2, 3). Thus careful monitoring and man-agement of asthma symptoms during pregnancy is of greatimportance.

Fetal sex has been implicated as one of the factors thatmight influence the course of asthma during the pregnancy.

The following members of the OTIS Collaborative Research Group con-tributed to this study: Arizona Teratogen Information Program, Universityof Arizona, Tucson: D. Quinn, D. Vogt; California Pregnancy Risk Informa-tion, University of California, San Diego: K. Kao; Connecticut PregnancyExposure Information Service, University of Connecticut Health Center,Farmington: S. Lavigne, J. Brochu; Nebraska Teratogen Project, Universityof Nebraska Medical Center, Omaha: Dr. B. Buehler, E. Conover; IllinoisTeratogen Information Service, Chicago: K. Ormond, C. Chou; MichiganTeratogen Information Servic, Children’s Hospital of Michigan, Detroit: Dr.Y. Johnson, S. Swerc; Missouri Teratogen Information Service, Universityof Missouri Hospital and Clinics, Columbia: Dr. S. Braddock, P. Slusher;Pregnancy Risk Network, University of Buffalo: Dr. L. Robinson, S. Gan-gell; Motherisk Program, Hospital for Sick Children, Toronto, Ontario: Dr.G. Koren, M. Morreti; Texas Teratogen Information Service, University ofNorth Texas, Denton: L. Wolfe; Pregnancy RiskLine Project, Utah Depart-ment of Health, Salt Lake City: Dr. J. Carey; J. Robertson; CARE Northwest,University of Washington, Seattle: Dr. J. Polifka, Dr. E. Rudy.

∗Corresponding author: Dr. Ludmila Bakhireva, Division of PharmacyPractice, College of Pharmacy, University of New Mexico, MSC09 5360,1 University of New Mexico, Albuquerque, NM 87131-0001; E-mail:lbakhireva@salud.unm.edu

A few recently published studies found female fetal sex tobe associated with an increase in asthma symptoms duringpregnancy (4), higher consumption of corticosteroids as aproxy measure of more severe asthma (5), and an increasedpeak expiratory flow lability indicating more severe asthma(6). However, other studies found no effect of fetal sex onmaternal asthma (7, 8).

The biological mechanisms which might explain such adifferential effect of fetal sex on maternal asthma remain un-certain. The presence of a female fetus was hypothesized toupregulate maternal inflammatory pathways, thus worseningasthma symptoms. It has been reported that the presence ofa female fetus is associated with increased maternal circulat-ing monocytes, which release numerous cytokines and couldcontribute to worsening of asthma symptoms (9). Addition-ally, a protective effect observed among women carrying amale fetus is thought to be due to surge of testosterone pro-duced by the male fetus during the second trimester (6, 10).Testosterone influences β-adrenergic-mediated relaxation ofbronchial tissue and inhibits response to histamine (6, 10),thus providing some amelioration of asthma symptoms. How-ever, the clinical significance of these findings is unclear.

The present study was conducted to test the following re-search questions: 1) whether pregnant asthmatic women car-rying a female fetus have poorer asthma symptom controlcompared to women carrying a male fetus; 2) weather the ef-fect of fetal sex on maternal asthma symptoms, if any, variesduring pregnancy 3) whether pregnant women with asthmacarrying a female fetus have a higher incidence of asthmaexacerbations during pregnancy compared to pregnant asth-matic women carrying a male fetus.

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404 L. N. BAKHIREVA ET AL.

METHODS

Study PopulationThis study used the data obtained through the multi-center

prospective study of Asthma Medication Use in Pregnancyconducted by the Organization of Teratology InformationSpecialists (OTIS). OTIS is a non-profit organization that pro-vides resources and counseling to individuals of reproductiveage and health care providers regarding known and potentialprenatal exposures. The detailed methodology of the OTISstudy has be previously described (11, 12). Briefly, the OTISAsthma Medication Use in Pregnancy study was conductedbetween 1998 and 2003 to gain additional information aboutthe safety of asthma medications in pregnancy and also theeffect of maternal asthma control on perinatal outcomes.

Subjects with physician-diagnosed asthma and non-asthmatic controls were recruited through the OTIS networkin the United States and Canada during the first part of preg-nancy (≤20 gestational weeks) and were followed-up with aseries of structured maternal interviews throughout the preg-nancy and in the postpartum period through a central coor-dinating center located at the University of California, SanDiego (UCSD). The UCSD Human Research Protection Pro-gram approved the study.

From the OTIS Asthma Medications in Pregnancy Studywomen with physician-diagnosed asthma (n = 819) wereinitially selected for purposes of this analysis. Among thosesubjects, 731 (89.3%) pregnancies results in live-born chil-dren, 3 (0.4%) in stillbirths, 45 (5.5%) in a pregnancy lossdue to ectopic pregnancy, spontaneous abortion or electivetermination, and 40 (4.9%) were lost to follow-up. For pur-poses of the present study, subjects who had a pregnancy loss(ectopic pregnancy, spontaneous abortion or a pregnancy ter-mination) or were lost to follow-up were excluded from theanalysis since fetal sex was unknown for the majority of them.Among 734 pregnancies that resulted in live-born or stillbornchildren, 721 (98.2%) involved singletons and 13 (1.8%) in-volved twins. Twin pregnancies were excluded from this anal-ysis since the effect of fetal sex in opposite- and same-sextwin pairs might have a different effect on maternal asthmacompared to the effect of singletons and therefore could in-troduce bias. Among 721 singleton pregnancies, 340 (47.3%)resulted in the birth of a girl, 379 (52.7%) in the birth of a boy,and two subjects had missing values for this variable. Thus,final sample size included 719 pregnant asthmatic women.

Data Collection and MeasurementsInformation about maternal demographic and lifestyle

characteristics (e.g., age, race/ethnicity, use of tobacco andalcohol during pregnancy, illicit drug use), medical and repro-ductive history (e.g., gravidity, parity, complications in previ-ous pregnancies), current pregnancy, asthma symptoms andexacerbations, use of prescribed and over-the-counter med-ications, and perinatal outcomes was obtained through ma-ternal structured interviews conducted at enrollment (meangestational age at enrollment was 13 weeks), 26, 32 gesta-tional weeks, and within 4–6 weeks after delivery. Familysocioeconomic status (SES) was assessed using a Holling-shead four-factor index, which incorporates both educationand occupation of the mother, father or other family supportperson (Hollingshead, Unpublished data, 1975). The sex of

the newborn was reported by mothers and verified by pedi-atric medical records.

Subjects were considered to be asthmatic based on a di-agnosis made by physicians, which has been shown to be avalid definition of asthma in epidemiological studies (13).The level of asthma control at each prenatal interview wasassessed using a 5-point scale, developed by one of the co-authors (MS) since at the time of study initiation in 1997no validated asthma control tools had been published. Thescale was based on asthma symptom presence and symptominterference with daily activities and sleep.

A score of 0 indicated no symptoms; a score of 1, somesymptoms that did not interfere with activity or sleep; a scoreof 2, occasional interference; a score of 3, frequent interfer-ence; and a score of 4, constant interference. Asthma controlwas categorized as “adequate” if women reported no symp-toms or some symptoms which did not interfere with sleepor activity (score 0–1), “fair” if symptoms occasionally in-terfered with sleep or activity (score 2), and “poor” if symp-toms frequently or constantly interfered with sleep or activity(score 3–4). Three subsequently published validated asthmacontrol tools used frequency of symptoms and their interfer-ence with sleep and activity as key components of their scales(14–16).

In addition, information on hospitalization and unsched-uled clinic visits for asthma since the last menstrual periodwas collected through maternal structured interviews and val-idated by medical records. Although this study was com-pleted before the 2007 National Asthma Education and Pre-vention Program guidelines defined an impairment domainand a risk domain to asthma control (17), the control scaledetermined by patient interview in the current study corre-sponds to the impairment domain of asthma control, and theexacerbations requiring unscheduled care are related to therisk domain.

Statistical AnalysisDistribution of demographic, lifestyle, and reproductive

health variables were compared among asthmatic womenwho gave birth to male children versus women who gavebirth to female children. ANOVA was used for comparisonof continuous variables and χ2 tests for categorical variables.The proportion of subjects at each level of asthma symptomcontrol (adequate, fair, poor) was compared among womenwho gave birth to male children versus women who gavebirth to female children using χ2 tests. This analysis wasconducted for each time point when asthma control was as-sessed (enrollment, 26, and 32 gestational weeks). In additionto asthma symptom control, exacerbation measures (i.e., hos-pitalizations for asthma during pregnancy and unscheduledasthma visits) were compared between women carrying agirl versus women carrying a boy using χ2 tests. The riskof exacerbations by fetal sex was determined in multivariateanalysis by logistic regression after adjustment for maternalage, BMI, ethnicity, smoking, and socioeconomic status.

Longitudinal analysis of the effect of fetal sex on maternalasthma control over the course of pregnancy was conductedusing the generalized estimating equations (GEE) approachfor repeated measures. A GEE model was fit using theGENMOD procedure of SAS to account for repeated

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FETAL SEX AND MATERNAL ASTHMA CONTROL 405

TABLE 1.—Distribution of asthma symptom control and exacerbation measuresin the study population (N = 719).

Measures of Asthma Control N∗ (%)

Asthma symptom control at ≤20 gestational weeks:Adequate 396 (56.3)Fair 227 (32.2)Poor 81 (11.5)

Asthma symptom control at 26 gestational weeks:Adequate 411 (64.7)Fair 178 (28.0)Poor 46 (7.2)

Asthma symptom control at 32 gestational weeks:Adequate 445 (69.6)Fair 137 (21.4)Poor 57 (8.9)

Hospitalization(s) for asthma during pregnancy 61 (8.5)Unscheduled asthma visits during pregnancy 153 (21.3)

∗Sample size varies due to pairwise deletion of missing data.

measures of asthma symptom control during the course ofpregnancy. Since the outcome variable (asthma control)is ordinal (adequate/fair/poor), a cumulative logit linkfunction was used. A fetal sex by time interaction term wastested in the GEE model in addition to the main effects.Since subjects were eligible to enroll up to 20 gestationalweeks of pregnancy, some enrolled at the beginning of thesecond trimester of pregnancy. A longitudinal analysis wasrepeated on the subset of subjects who enrolled during theirfirst trimester (≤13 gestational weeks) in order to capturepotential changes in asthma severity between first andsubsequent trimesters in relation to fetal sex.

RESULTS

The majority of subjects in our study reported adequatecontrol of their asthma symptoms at enrollment (56.3%),while 32.2% reported fair and 11.5% poor control of theirasthma (Table 1). During pregnancy 8.5% of subjects werehospitalized for asthma, 21.3% had unscheduled asthmavisits.

The distribution of selected maternal demographic,lifestyle, and reproductive health characteristics by fetal sexis presented in Table 2. No differences in maternal age, BMI,gravidity, parity, ethnicity, socioeconomic status, use of to-

TABLE 2.—Maternal characteristics by fetal sex (N = 719).

Pregnancy Pregnancywith a with a Overall

Maternal Characteristics girl (N = 340) boy (N = 379) p-value

N (%) N (%)Maternal Age: 0.539

<25 years 31 (9.1) 41 (10.8)25–34 years 200 (58.8) 229 (60.4)35+ years 109 (32.1) 109 (28.8)

BMI (kg/m2): 0.416<24 166 (48.8) 191 (50.4)24–28 92 (27.1) 87 (22.9)>28 82 (24.1) 101 (26.7)

Gravidity >1 216 (63.5) 230 (60.7) 0.433Parity >0 156 (45.9) 173 (45.7) 0.950White non-hispanic 306 (90.5) 334 (88.1) 0.299Any tobacco use 32 (9.5) 43 (11.4) 0.414Any alcohol use 164 (50.8) 164 (46.1) 0.220SES status above average∗ 243 (72.8) 261 (69.8) 0.384

∗Hollingshead 4-factor socioeconomic status category 1 or 2 on a scale of 1–5 with 1being the highest.

TABLE 3.—Effect of fetal sex on maternal asthma symptom control and exacer-bations during pregnancy.

Pregnancy Pregnancywith a with a

Asthma Control girl (N = 340) boy (N = 379) p-value

N (%)* N (%)*Asthma control: 1st interview∗∗ 0.037

Adequate 196 (58.7) 200 (54.1)Fair 93 (27.8) 134 (36.2)Poor 45 (13.5) 36 (9.7)

Asthma control: 26 gestational weeks 0.415Adequate 190 (63.3) 221 (66.0)Fair 84 (28.0) 94 (28.1)Poor 26 (8.7) 20 (6.0)

Asthma control: 32 gestational weeks 0.405Adequate 202 (67.1) 243 (71.9)Fair 69 (22.9) 68 (20.1)Poor 30 (10.0) 27 (8.0)

Hospitalization(s) for asthma 38 (11.2) 23 (6.1) 0.014Unscheduled asthma visits – anytime

in pregnancy75 (22.1) 78 (20.6) 0.629

Unscheduled visits: 1st interview 38 (12.8) 27 (8.2) 0.060Unscheduled visits: 26 gestational

weeks28 (8.5) 35 (9.7) 0.580

Unscheduled visits: 32 gestationalweeks

19 (5.8) 29 (8.0) 0.252

∗Sample size varies due to missing data.∗∗First maternal interview at enrollment (on average at 13 gestational weeks).

bacco or alcohol anytime in pregnancy were observed amongasthmatic women carrying a boy compared with asthmaticwomen carrying a girl (all p-values > 0.1).

No difference in the asthma symptom control during thesecond or third trimesters was observed between women car-rying a girl versus women carrying a boy (Table 3). How-ever, a higher proportion of women carrying a girl had poorasthma symptom control during the first part of pregnancy(13.5%) compared with asthmatic women carrying a boy(9.7%; p = 0.037). The GEE analysis, conducted to evaluatethe effect of fetal sex on change in asthma symptom controlover the course of pregnancy, yielded non-significant results(p = 0.206). This suggests that even though some differencesin asthma control by fetal sex were observed early in preg-nancy, fetal sex did not significantly influence the course ofmaternal asthma later in pregnancy. When the analysis was re-peated for a subset of 352 asthmatic subjects who enrolled inthe study prior to or at 13 gestational weeks, results remainednon-significant (p = 0.102; data not shown). Additionally,use of systemic corticosteroids (chronic use or courses) didnot vary among study groups (p > 0.1; data not shown).

As shown in Table 3, female-bearing pregnancy was as-sociated with a significant increase in hospitalizations forasthma exacerbations (11.2%) compared with male-bearingpregnancy (6.1%; p = 0.014). In multivariate analysis, thepresence of a female fetus was associated with a higher inci-dence of hospitalizations for asthma during pregnancy (OR =1.84; 95% CI: 1.05; 3.21) independent of maternal age, BMI,ethnicity, smoking, and socioeconomic status. While no dif-ference in unscheduled asthma visits anytime during preg-nancy was observed between the two groups (p = 0.629), atendency of borderline statistical significance was observedfor unscheduled asthma visits during the first half of preg-nancy (Table 3). Specifically, 12.8% of asthmatic pregnantwomen carrying a girl had unscheduled asthma visits dur-ing the first part of pregnancy compared with only 8.2% ofwomen carrying a boy (p = 0.060).

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406 L. N. BAKHIREVA ET AL.

DISCUSSION

Even though no overall effect of fetal sex on change inmaternal asthma symptom control during pregnancy was ob-served in the longitudinal analysis, the presence of a femalefetus was associated with a significantly higher rate of hospi-talizations for asthma and a tendency for an increased numberof unscheduled clinic visits for asthma exacerbations dur-ing pregnancy. Self-reported measures of asthma symptomcontrol utilized in this study might not be adequately sen-sitive or specific enough to capture the effect of fetal sex,while health care utilization measures (i.e., hospitalizationsand clinic visits) might be more objective means to evaluatematernal asthma control.

While we are not aware of any previous studies that eval-uated the effect of fetal sex on hospitalizations for asthma,a few reports have found more severe maternal asthma infemale-bearing pregnancies. Beecroft et al. reported that agreater proportion of pregnant women carrying a girl tendedto report an increase in asthma symptoms during pregnancy(i.e., cough, shortness of breath, nocturnal waking, generalstate of asthma, and visits to doctors) compared to womencarrying a boy (4). In a recent cohort study, pregnant asth-matic women carrying a female fetus had increased peakexpiratory flow lability indicating increased asthma severity,while women carrying a male fetus had an improvement inairway lability by almost 10% throughout the pregnancy (6).

Similar to some previous reports, this study suggests thatan effect of fetal sex on maternal asthma might be more evi-dent during the first part of pregnancy and then appears to belost as pregnancy progresses. Such an early effect might bedue to some physiological factors, e.g., a surge of testosteronein male fetuses between 12 and 16 weeks. In fact, the pro-tective effect of the male fetus on maternal asthma severityobserved in the study by Beecroft et al. was noted in the sec-ond trimester of pregnancy. However, Kwon et al. were notable to support their hypothesis that the fetal effect on PEFlability would peak in the second trimester (6). In additionto a possible physiologic effect, lack of a fetal sex-specificeffect later in pregnancy in our study could occur if asthmatherapy was increased in women carrying a female fetus asthe pregnancy progressed to mitigate poor asthma control andprevent severe exacerbations.

Several earlier reports presented convincing evidence thattestosterone levels are higher in amniotic fluid (18, 19) andumbilical cord blood (20) in the presence of a male fetus com-pared with a female fetus. However, there is no agreement inthe literature on whether sex of the fetus can significantlyinfluence hormonal level in maternal serum. In singletonpregnancies, some studies found higher androgen levels inmaternal blood in male-bearing pregnancies (21), while oth-ers failed to detect any difference by fetal sex (18, 22–24).Studies conducted in opposite-sex twin pregnancies foundsome evidence of masculinization in female fetuses (25, 26)presumably due to increased prenatal testosterone exposurethrough direct or indirect hormone transfer from their twinbrothers.

Even though this report and all previous studies on thistopic evaluated maternal asthma control as an outcome mea-sure, one might hypothesize that poor control of maternalasthma in periconceptional period might influence fetal sex

determination and/or lead to increased risk of selective earlypregnancy loss of male embryos. However, the study designdid not allow collecting information on pre- and periconcep-tional maternal asthma control or to assess clinically unrec-ognized early pregnancy loss.

Several limitations of this study should be discussed. Eventhough this study was able to capture the change in asthmacontrol from the first trimester onwards, change very early inpregnancy could not be evaluated since no information aboutasthma severity and control prior to pregnancy was available.Another limitation of this study is the lack of data on mater-nal pulmonary function. Contradictory findings of previousreports might be at least partially attributed to the hetero-geneity of asthma control and severity measures utilized inthese studies. While some studies utilized specific asthmasymptoms (4) or pulmonary function tests (6), others usedself-reported change in asthma course during pregnancy (8)or use of corticosteroids as a surrogate measures of asthmacontrol (5).

Even though pulmonary function data were not available inthe present study, multiple measures of both asthma controland asthma exacerbations assessed repeatedly during preg-nancy were utilized. Although increased symptoms requiringsystemic corticosteroids could be included in the definition ofexacerbation, we did not use it due to our inability to capturethis occurrence in steroid-dependent patients due to the studydesign. Thus, exacerbations requiring unscheduled medicalcare were chosen as an outcome. While hospitalizations andunscheduled clinic visits can be influenced by management,compliance to therapy, and access to health care, all subjectsin this study population received prenatal care since the firsthalf of pregnancy and majority had an access to allergists.

In summary, this study demonstrated that the risk of hospi-talization for severe asthma exacerbations during pregnancywas almost doubled in pregnant women carrying a femalefetus compared to women carrying a male fetus. Moreover,women carrying a female fetus tended to have a higher num-ber of unscheduled clinic visits for asthma exacerbationsearly in pregnancy. Compared with the previous reports eval-uating the role of fetal sex in maternal asthma, this study hadthe largest sample size and utilized multiple and repeatedmeasures of asthma control in pregnancy. This study com-bined with prior data suggests that asthmatic women car-rying a girl might be more susceptible to asthma exacerba-tions during pregnancy. Given that fetal sex is not usuallyknown early in pregnancy and other risk factors that affectthe course of asthma during pregnancy, all pregnant womenwith asthma should be carefully monitored for pregnancy-associated changes in asthma symptoms so that their ther-apy can be appropriately adjusted. Findings of this studyprovide some insights on changes in the course of mater-nal chronic disorders during pregnancy and the role of thefetus.

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