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Obstetric complications among US women with asthma

Published:November 19, 2012DOI:https://doi.org/10.1016/j.ajog.2012.11.007

      Objective

      We sought to characterize complications of pregnancy, labor, and delivery associated with maternal asthma in a contemporary US cohort.

      Study Design

      We studied a retrospective cohort based on electronic medical record data from 223,512 singleton deliveries from 12 clinical centers across the United States from 2002 through 2008.

      Results

      Women with asthma had higher odds of preeclampsia (adjusted odds ratio [aOR], 1.14; 95% confidence interval [CI], 1.06−1.22), superimposed preeclampsia (aOR, 1.34; 95% CI, 1.15−1.56), gestational diabetes (aOR, 1.11; 95% CI, 1.03−1.19), placental abruption (aOR, 1.22; 95% CI, 1.09−1.36), and placenta previa (aOR, 1.30; 95% CI, 1.08−1.56). Asthmatic women had a higher odds of preterm birth overall (aOR, 1.17; 95% CI, 1.12−1.23) and of medically indicated preterm delivery (aOR, 1.14; 95% CI, 1.01−1.29). Asthmatics were less likely to have spontaneous labor (aOR, 0.87; 95% CI, 0.84−0.90) and vaginal delivery (aOR, 0.84; 95% CI, 0.80−0.87). Risks were higher for breech presentation (aOR, 1.13; 95% CI, 1.05−1.22), hemorrhage (aOR, 1.09; 95% CI, 1.03−1.16), pulmonary embolism (aOR, 1.71; 95% CI, 1.05−2.79), and maternal intensive care unit admission (aOR, 1.34; 95% CI, 1.04−1.72).

      Conclusion

      Maternal asthma increased risk for nearly all outcomes studied in a general obstetric population.

      Key words

      Asthma is the most common chronic disease in pregnancy, complicating 4-8% of pregnancies nearly 10 years ago
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      The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms.
      and the rate of asthma continues to increase. Approximately 10% of US women of reproductive age had active asthma in 2008 through 2010
      Centers for Disease Control and Prevention, National Center for Health Statistics
      Health data interactive.
      and 4.2% used a bronchodilator medication at least once during the past month during 2005 through 2008.
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      In the National Hospital Discharge Survey, the rate of asthma reported during labor and delivery nearly doubled from 1993 through 1997 and from 2001 through 2005.
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      A recent metaanalysis
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      • et al.
      A meta-analysis of adverse perinatal outcomes in women with asthma.
      concluded that maternal asthma increased the risk of low-birthweight and small-for-gestational-age infants, preterm delivery, and preeclampsia. Other conditions, such as gestational diabetes and serious obstetric complications (eg, hemorrhage, placental abruption, and placenta previa), are not consistently associated with maternal asthma, possibly due to underlying differences in patient populations, methodologic inadequacies (particularly for early studies), and relatively small numbers of women with asthma studied.
      • Dombrowski M.P.
      Outcomes of pregnancy in asthmatic women.
      Studies generally find that outcomes are more adverse when asthma is poorly controlled
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      Effect of maternal asthma and asthma control on pregnancy and perinatal outcomes.
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      but few studies are large enough to examine specific risks for less common complications of pregnancy, labor, and delivery. The objectives of this study were to use a large, recent cohort of women in the United States to examine specific risks for complications of pregnancy, labor, and delivery including less frequent adverse outcomes and to explore the reasons for the increased risk of preterm delivery in women with asthma.

      Materials and Methods

      The Consortium on Safe Labor included 12 clinical centers (with 19 hospitals) across 9 American Congress of Obstetricians and Gynecologists (ACOG) US districts. Details of the study and data collection procedures are described elsewhere.
      • Zhang J.
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      Contemporary cesarean delivery practice in the United States.
      Briefly, centers provided electronic medical records and International Classification of Diseases, Ninth Revision (ICD-9) discharge codes from the intrapartum admission for 228,562 pregnancies among 208,695 women from 2002 through 2008. The majority of the cohort (87%) delivered from 2005 through 2007. This analysis is restricted to singleton pregnancies (n = 223,512) among 204,180 women. Most women (n = 185,785; 83.1%) contributed only 1 pregnancy. Institutional review board approval was obtained by all participating institutions.
      Most complications of pregnancy, labor, and delivery as well as the diagnosis of asthma were derived from medical record data supplemented with ICD-9 codes where available (Table 1). The source of case ascertainment (medical record or ICD-9 codes) varied by site. Overall, only 10.7% of asthma cases were reported in ICD-9 discharge codes alone while the remaining cases were noted in the medical record or both sources. We examined various obstetric outcomes including gestational hypertension, preeclampsia, superimposed preeclampsia, maternal seizure (with or without mention of hypertension), gestational diabetes, chorioamnionitis, placenta previa, placental abruption, hemorrhage, pulmonary embolism, postpartum fever, premature rupture of membranes (PROM), preterm PROM (PPROM) (defined as PROM <37 gestational weeks), and breech presentation.
      TABLE 1ICD-9 diagnoses used to define asthma, chronic disease, and outcomes in Consortium on Safe Labor
      Definition in current studyCollected ICD-9 codesDefinition
      Asthma493-493.9Asthma
      Other chronic diseases
       Diabetes250-250.9Diabetes mellitus
      648.0Other current conditions in mothers classifiable elsewhere but complicating pregnancy, childbirth, or puerperium–diabetes mellitus
       Hypertension401Essential hypertension
      402Hypertensive heart disease
      403Hypertensive renal disease
      404Hypertensive heart and renal disease
      405Secondary hypertension
      642.0Benign essential hypertension complicating pregnancy, childbirth, and puerperium
      642.1Hypertension secondary to renal disease complicating pregnancy childbirth and puerperium
      642.2Other preexisting hypertension complicating pregnancy, childbirth, and puerperium
       Thyroid diseases193Malignant neoplasm of thyroid gland
      226Benign neoplasm of thyroid glands
      240-240.9Simple and unspecified goiter
      241-241.9Nontoxic nodular goiter
      242-242.9Thyrotoxicosis with or without goiter
      243Congenital hypothyroidism
      244.0-244.9Acquired hypothyroidism
      245-245.9Thyroiditis
      246-246.9Other disorders of thyroid
      648.1Other current conditions in mothers classifiable elsewhere but complicating pregnancy, childbirth, or puerperium–thyroid dysfunction
       HIV42HIV disease
      Outcomes
       Gestational diabetes648.8Other current conditions in mothers classifiable elsewhere but complicating pregnancy, childbirth, or puerperium–abnormal glucose tolerance
      Gestational hypertension642.3Transient hypertension of pregnancy
      Preeclampsia642.4Mild or unspecified preeclampsia
      642.5Severe preeclampsia
      Superimposed preeclampsia642.7Preeclampsia or eclampsia superimposed on preexisting hypertension
      Placental abruption641.2Premature separation of placenta
       Placenta previa641.0Placenta previa without hemorrhage
      641.1Hemorrhage from placenta previa
       Pulmonary embolism415.1Pulmonary embolism and infarction
      673Obstetrical pulmonary embolism
       Hemorrhage666-666.3Postpartum hemorrhage
       Chorioamnionitis658.4Infection of amniotic cavity
      762.7Chorioamnionitis
       Preterm rupture of membranes658.1Premature rupture of membranes
       Breech presentation652.2Breech presentation without mention of version
       Fever672Pyrexia of unknown origin during puerperium
      HIV, human immunodeficiency virus; ICD-9, International Classification of Diseases, Ninth Revision.
      Mendola. Obstetric complications among US women with asthma. Am J Obstet Gynecol 2013.
      Outcomes derived solely from medical records include prelabor cesarean delivery (defined as a cesarean delivery without any indication of labor and <2 vaginal examinations after admission to hospital), induction, spontaneous labor, route of delivery (vaginal or cesarean), preterm birth (<37 gestational weeks), low birthweight (<2500 g), intrauterine fetal death, maternal intensive care unit (ICU) admission, and maternal death.
      Pregnancy was the unit of analysis for all statistical testing. Descriptive statistics were calculated for all study variables and significance testing was based on either linear or logistic regression using generalized estimating equations (GEE) to account for correlations between pregnancies contributed by the same woman. Odds ratios (ORs) and 95% confidence limits were calculated using logistic regression with GEE using a first-order autoregressive covariance structure. Pregnancies among women without asthma were the reference group in all analyses. All reported odds are adjusted for site and fully adjusted models included site, maternal age, race/ethnicity, marital status, prepregnancy body mass index (weight in kg/height in m2), insurance status, smoking and alcohol use during pregnancy, presence of chronic disease (preexisting diabetes, chronic hypertension, thyroid disease, or human immunodeficiency virus), and parity. Women with chronic hypertension were excluded from the analyses of gestational hypertension and preeclampsia. Women with preexisting diabetes were excluded from the analyses of gestational diabetes. In the analyses of superimposed preeclampsia, women with chronic hypertension were not categorized as having a chronic disease unless they had another chronic condition. Analyses regarding labor and route of delivery were also adjusted for prior cesarean delivery.
      Multiple sensitivity analyses were conducted, first to test the robustness of our findings given potential bias or error in medical record ascertainment, including restriction to women with ICD-9-coded asthma as these women may be more likely to have active asthma (as opposed to a history); removing sites with asthma rates at the tails of the distribution (2 sites each at the high and the low end); restriction to sites with complete data; and finally, restriction to patients with no missing data. Results from these logistic regression with GEE analyses yielded similar findings, so only the full sample analysis is presented. We also ran 2 subgroup analyses: (1) restricted to nulliparas to explore the potential for residual confounding by history of preterm delivery, cesarean delivery, or other prior complications in multiparas, and (2) restricted to preterm deliveries to determine if the precursors of preterm delivery were different for women with asthma.
      All statistical analyses were performed using PROC GENMOD in SAS software (version 9.2; SAS Institute Inc, Cary, NC).

      Results

      Maternal asthma complicated 7.6% of singleton pregnancies. Mothers with asthma were younger (26.2 vs 27.5 years, P < .0001) and more likely to be non-Hispanic black, be unmarried, and have public insurance than their counterparts without asthma (Table 2). Women with asthma were more likely to be obese prior to pregnancy and more likely to have smoking (12.2% vs 6.2%, P < .0001) or alcohol use (3.1% vs 1.7%, P < .0001) during pregnancy recorded in their medical records. Pregnancies complicated by asthma had a significantly greater burden of other chronic diseases as well (8.2% vs 6.2%, P < .0001). Parity was similar among pregnancies with and without asthma but among multiparas, women with asthma had more prior cesarean deliveries (15.3% vs 14.0%, P < .0001).
      TABLE 2Characteristics of mothers with and without asthma
      Maternal characteristicsNo asthma n = 206,468Asthma n = 17,044Site-adjusted P value
      P values are based on generalized estimating equations that account for multiple pregnancies to same woman.
      Demographic factors
       Maternal age, y mean (SD)27.5 (6.2)26.6 (6.2)< .0001
       Race, n (%)
        Non-Hispanic white102,447 (49.6)8156 (47.9)< .0001
        Non-Hispanic black44,840 (21.7)5444 (31.9)
        Hispanic36,543 (17.7)2288 (13.4)
        Asian8970 (4.3)211 (1.2)
        Other4966 (2.4)265 (1.6)
        Missing8702 (4.2)680 (4.0)
      Marital status, n (%)
        Not married76,248 (36.9)8765 (51.4)< .0001
        Married123,800 (60.0)7461 (43.8)
        Missing6420 (3.1)818 (4.8)
       Insurance, n (%)
        Private116,084 (56.2)8883 (52.1)< .0001
        Public65,097 (31.5)7105 (41.7)
        Other2774 (1.3)208 (1.2)
        Missing22,513 (10.9)848 (5.0)
       Pregnancies per woman, n (%)
        1172,355 (91.2)14,074 (90.7)
        215,878 (8.4)1355 (8.7)
        3724 (0.4)80 (0.5)
        445 (0.02)5 (0.03)
        51 (< .01)0 (0.0)
      Clinical factors
       Prepregnancy BMI, kg/m2, n (%)
        Underweight, <18.57517 (3.6)463 (2.7)< .0001
        Normal weight, 18.5–<2574,442 (36.1)4641 (27.2)
        Overweight, 25–<3030,909 (15.0)2614 (15.3)
        Obese, 30–<3514,212 (6.9)1530 (9.0)
        Severely obese, ≥3510,553 (5.1)1605 (9.4)
        Unknown68,835 (33.3)6191 (36.3)
       Smoking during pregnancy, n (%)12,858 (6.2)2075 (12.2)< .0001
       Alcohol during pregnancy, n (%)3559 (1.7)532 (3.1)< .0001
       Preexisting diabetes, n (%)2931 (1.4)381 (2.2)< .0001
       Chronic hypertension, n (%)3733 (1.8)480 (2.8)< .0001
      Thyroid disease, n (%)6043 (2.9)568 (3.3).003
      HIV/AIDS, n (%)778 (0.4)107 (0.6)< .0001
      Any chronic disease (diabetes, hypertension, thyroid, HIV), n (%)12,722 (6.2)1404 (8.2)< .0001
      Parity, n (%)
       Nulliparous82,417 (39.9)6824 (40.0).84
       Multiparous124,051 (60.1)10,220 (60.0)
      Prior cesarean section, n (%)
       Nullipara82,417 (39.9)6824 (40.0)< .0001
       Multipara–no95,123 (46.1)7608 (44.6)
       Multipara–yes28,928 (14.0)2612 (15.3)
      Analyses are based on singleton pregnancies from the Consortium on Safe Labor, 2002-2008.
      AIDS, acquired immunodeficiency syndrome; BMI, body mass index; HIV, human immunodeficiency virus.
      Mendola. Obstetric complications among US women with asthma. Am J Obstet Gynecol 2013.
      a P values are based on generalized estimating equations that account for multiple pregnancies to same woman.
      Analyses of the complications of pregnancy, labor, and delivery encountered by women with and without asthma (Table 3) demonstrate a general pattern of increased risk for asthmatic pregnancies.
      TABLE 3Singleton pregnancy complications among US women with asthma
      OutcomesNo asthma n = 206,468 n (%)Asthma n = 17,044 n (%)Site-adjusted P value
      All P values are based on generalized estimating equations that account for multiple pregnancies to the same woman. All P values are adjusted for site
      Site-adjusted odds ratio (95% CI)
      All P values are based on generalized estimating equations that account for multiple pregnancies to the same woman. All P values are adjusted for site
      Fully adjusted odds ratio (95% CI)
      All P values are based on generalized estimating equations that account for multiple pregnancies to the same woman. All P values are adjusted for site
      ,
      Adjusted for site; maternal age; maternal race; marital status; insurance; prepregnancy body mass index; smoking during pregnancy; alcohol use during pregnancy; history of diabetes (except for gestational diabetes), human immunodeficiency virus, chronic hypertension (except for gestational hypertension, preeclampsia, eclampsia, or maternal seizure with hypertension), or thyroid disease; and parity (spontaneous labor, induction, cesarean delivery, and vaginal delivery adjusted for prior cesarean delivery instead of parity alone).
      Hypertensive disorders of pregnancy
       Superimposed preeclampsia1680 (0.8)213 (1.3)< .00011.54 (1.33–1.79)1.34 (1.15–1.56)
       Eclampsia207 (0.1)33 (0.2).011.61 (1.10–2.36)1.41 (0.96–2.07)
       Preeclampsia9628 (4.7)924 (5.4)< .00011.24 (1.16–1.33)1.14 (1.06–1.22)
       Gestational hypertension5523 (2.7)557 (3.3).00031.18 (1.08–1.30)1.08 (0.98–1.19)
      Maternal seizure
       All maternal seizures176 (0.1)33 (0.2).00081.93 (1.32–2.83)1.79 (1.21–2.63)
        Maternal seizure without hypertension noted93 (0.05)14 (0.09).191.45 (0.83–2.55)1.35 (0.77–2.37)
        Maternal seizure with hypertension noted83 (0.05)19 (0.12).00062.51 (1.48–4.25)2.37 (1.40–4.02)
      Other pregnancy complications
       Gestational diabetes10,420 (5.1)927 (5.4).061.07 (1.00–1.15)1.11 (1.03–1.19)
       Chorioamnionitis6415 (3.1)504 (3.0).321.05 (0.95–1.16)1.06 (0.96–1.17)
       Placenta previa1444 (0.7)141 (0.8).061.19 (0.99–1.42)1.30 (1.08–1.56)
      Complications of labor and delivery
       Prelabor cesarean delivery23,688 (11.5)2193 (12.9)< .00011.15 (1.10–1.21)1.16 (1.09–1.23)
       Spontaneous labor111,523 (54.0)8921 (52.3)< .00010.86 (0.84–0.89)0.87 (0.84–0.90)
        Cesarean delivery after spontaneous labor18,835 (9.1)1749 (10.3).00031.10 (1.05–1.16)1.06 (1.00–1.12)
       Induction71,257 (34.5)5930 (34.8)< .00011.10 (1.06–1.13)1.10 (1.06–1.14)
        Cesarean delivery after induction14,746 (7.1)1381 (8.1)< .00011.22 (1.15–1.29)1.17 (1.10–1.24)
       All vaginal delivery149,199 (72.3)11,721 (68.8)< .00010.84 (0.81–0.87)0.84 (0.80–0.87)
       PPROM4596 (2.2)516 (3.0)< .00011.23 (1.12–1.36)1.18 (1.07–1.30)
       PROM14,379 (7.0)1212 (7.1).981.00 (0.94–1.07)0.99 (0.93–1.05)
       Breech presentation8785 (4.3)811 (4.8).011.10 (1.02–1.19)1.13 (1.05–1.22)
       Placental abruption3242 (1.6)380 (2.2)< .00011.27 (1.14–1.42)1.22 (1.09–1.36)
       Maternal hemorrhage13,423 (6.5)1292 (7.6).0011.11 (1.04–1.18)1.09 (1.03–1.16)
       Maternal pulmonary embolism114 (0.06)20 (0.12).0081.90 (1.18–3.07)1.71 (1.05–2.79)
       Maternal postpartum fever5531 (2.7)532 (3.1).351.05 (0.95–1.15)0.99 (0.90–1.09)
       Maternal ICU admission902 (0.6)73 (0.6).011.38 (1.08–1.76)1.34 (1.04–1.72)
       Maternal death18 (0.01)1 (0.01).70Not calculatedNot calculated
       Low birthweight, <2500 g16,551 (8.1)1815 (10.7)< .00011.26 (1.19–1.33)1.16 (1.10–1.23)
       Preterm birth, <37 wk23,618 (11.4)2526 (14.8)< .00011.25 (1.19–1.31)1.17 (1.12–1.23)
       Intrauterine fetal death1148 (0.6)110 (0.7).261.12 (0.92–1.38)1.07 (0.87–1.32)
      Women with and without asthma had following rates of missing data: 5.9% and 6.9% on vertex presentation, 24.0% and 21.3% on ICU admission, 8.5% and 11.0% on seizures, and 0.8% and 1.1% on birthweight, respectively. Analyses are based on singleton pregnancies from the Consortium on Safe Labor, 2002-2008.
      CI, confidence interval; ICU, intensive care unit; PPROM, preterm premature rupture of membranes; PROM, premature rupture of membranes.
      Mendola. Obstetric complications among US women with asthma. Am J Obstet Gynecol 2013.
      a All P values are based on generalized estimating equations that account for multiple pregnancies to the same woman. All P values are adjusted for site
      b Adjusted for site; maternal age; maternal race; marital status; insurance; prepregnancy body mass index; smoking during pregnancy; alcohol use during pregnancy; history of diabetes (except for gestational diabetes), human immunodeficiency virus, chronic hypertension (except for gestational hypertension, preeclampsia, eclampsia, or maternal seizure with hypertension), or thyroid disease; and parity (spontaneous labor, induction, cesarean delivery, and vaginal delivery adjusted for prior cesarean delivery instead of parity alone).

      Hypertensive disorders of pregnancy and maternal seizure

      Fully adjusted models indicate increased odds of superimposed preeclampsia (adjusted OR [aOR], 1.34; 95% confidence interval [CI], 1.15−1.56) and preeclampsia (aOR, 1.14; 95% CI, 1.06−1.22). Eclampsia was significantly associated with maternal asthma in site-adjusted models (OR, 1.61; 95% CI, 1.10−2.36) but the risk was attenuated after full adjustment (aOR, 1.41; 95% CI, 0.96−2.07). After observing a significant relationship between asthma and maternal seizure, we stratified seizures by hypertension status and found the increased risk of maternal seizure was primarily in the hypertensive group (aOR, 2.37; 95% CI, 1.40−4.02), suggesting that eclampsia may not have been fully captured in our dataset. Gestational hypertension was elevated in site-adjusted models but not significant after further adjustment.

      Other pregnancy complications

      Gestational diabetes (aOR, 1.11; 95% CI, 1.03−1.19) and placenta previa (aOR, 1.30; 95% CI, 1.08−1.56) were both increased, but chorioamnionitis was similar in pregnancies with and without asthma.

      Complications of labor and delivery

      Asthmatic pregnancies had an increased likelihood of being scheduled for prelabor cesarean delivery (aOR, 1.16; 95% CI, 1.09−1.23) or of being induced (aOR, 1.10; 95% CI, 1.06−1.14) compared to pregnancies without asthma. Asthmatic women were more likely to have a cesarean delivery than women without asthma regardless of whether they present in spontaneous labor (10.3 vs 9.1%, P = .0003) or undergo labor induction (8.1% vs 7.1%, P < .0001). As a result, pregnancies with maternal asthma had a lower odds overall of vaginal delivery (aOR, 0.84; 95% CI, 0.80−0.87).
      PROM was similar in pregnancies with and without asthma (7.1% vs 7.0%, P = .98) but PPROM was higher in asthmatics (3.0% vs 2.2%, P < .0001). Fetal presentation also varied by asthma status with more breech presentations among pregnancies complicated by asthma (aOR, 1.13; 95% CI, 1.05−1.22).
      With regard to severe complications, the odds of placental abruption (aOR, 1.22; 95% CI, 1.09−1.36), hemorrhage (aOR, 1.09; 95% CI, 1.03−1.16), pulmonary embolism (aOR, 1.71; 95% CI, 1.05−2.79), and maternal ICU admission (aOR, 1.34; 95% CI, 1.04−1.72) were all significantly increased in pregnancies with asthma but there was no difference in postpartum fever and maternal death.
      As anticipated, both low birthweight (aOR, 1.16; 95% CI, 1.10−1.23) and preterm delivery (aOR, 1.17; 95% CI, 1.12−1.23) were increased in pregnancies with asthma but the odds of intrauterine fetal death were not significantly higher compared to pregnancies without asthma. Restricting these analyses to nulliparas yielded similar findings (data not shown).
      With respect to preterm delivery (Table 4), we found no significant differences in prelabor cesarean deliveries (aOR, 1.06; 95% CI, 0.95−1.19), spontaneous labor (aOR, 0.93; 95% CI, 0.85−1.01), or induction (aOR, 1.04; 95% CI, 0.94−1.15) and women with asthma were no more likely than those without to have a cesarean delivery. However, further examination of the precursors of preterm delivery demonstrated that women with asthma had more medically indicated preterm deliveries (aOR, 1.14; 95% CI, 1.01−1.29) and were less likely to deliver preterm after a spontaneous process (labor or PPROM) (aOR, 0.89; 95% CI, 0.81−0.97).
      TABLE 4Precursors for preterm deliveries among US women with asthma
      VariableNo asthma n = 23,618 n (%)Asthma n = 2526 n (%)Site-adjusted P value
      P values are based on generalized estimating equations that account for multiple pregnancies to same woman–all P values are adjusted for site
      Site-adjusted odds ratio (95% CI)
      P values are based on generalized estimating equations that account for multiple pregnancies to same woman–all P values are adjusted for site
      Fully adjusted odds ratio (95% CI)
      P values are based on generalized estimating equations that account for multiple pregnancies to same woman–all P values are adjusted for site
      ,
      Adjusted for site; maternal age; maternal race; marital status; insurance; prepregnancy body mass index; smoking during pregnancy; alcohol use during pregnancy; history of diabetes, human immunodeficiency virus, chronic hypertension, or thyroid disease; and parity/prior cesarean section.
      Prelabor cesarean delivery4625 (19.6)511 (20.2).221.07 (0.96–1.19)1.06 (0.95–1.19)
      Spontaneous labor12,726 (53.9)1345 (53.3).080.93 (0.85–1.01)0.93 (0.85–1.01)
       Cesarean delivery after spontaneous labor3172 (13.4)359 (14.2).221.08 (0.96–1.22)1.07 (0.94–1.21)
      Induction6267 (26.5)670 (26.5).421.04 (0.95–1.15)1.04 (0.94–1.15)
       Cesarean delivery after induction1606 (6.8)176 (7.0).391.07 (0.91–1.27)1.02 (0.86–1.21)
      PPROM4596 (19.5)516 (20.4).861.01 (0.91–1.12)1.02 (0.92–1.13)
      Spontaneous process (labor or PPROM)15,359 (65.0)1609 (63.7).0090.89 (0.81–0.97)0.89 (0.81–0.97)
      Indicated3297 (14.0)404 (16.0).061.13 (1.00–1.27)1.14 (1.01–1.29)
      Elective or no recorded indication8824 (37.4)913 (36.1).981.00 (0.92–1.09)1.00 (0.91–1.09)
      Preterm delivery includes all singletons delivered <37 completed weeks from the Consortium on Safe Labor, 2002-2008.
      CI, confidence interval; PPROM, preterm premature rupture of membranes.
      Mendola. Obstetric complications among US women with asthma. Am J Obstet Gynecol 2013.
      a P values are based on generalized estimating equations that account for multiple pregnancies to same woman–all P values are adjusted for site
      b Adjusted for site; maternal age; maternal race; marital status; insurance; prepregnancy body mass index; smoking during pregnancy; alcohol use during pregnancy; history of diabetes, human immunodeficiency virus, chronic hypertension, or thyroid disease; and parity/prior cesarean section.

      Comment

      Women with asthma begin pregnancy with a less favorable profile of demographic, lifestyle, and clinical risk factors including increased obesity, increased smoking, and a higher burden of other chronic diseases. Even after adjustment for these and other risk factors, asthma was independently associated with higher odds for nearly all complications of pregnancy, labor, and delivery under study. Notably, asthmatic women experienced more serious complications including preeclampsia, preterm birth, cesarean delivery, placenta previa, placental abruption, hemorrhage, and pulmonary embolism, with a 34% increased odds of ICU admission. Neonates born to women with asthma were also more likely to be low birthweight.
      Our findings are consistent with the recent review and metaanalysis by Murphy et al
      • Murphy V.E.
      • Namazy J.A.
      • Powell H.
      • et al.
      A meta-analysis of adverse perinatal outcomes in women with asthma.
      that concluded risks were increased for preeclampsia, low birthweight, and preterm delivery in women with asthma. The literature on other complications of pregnancy is less consistent, although several studies reviewed by Dombrowski
      • Dombrowski M.P.
      Outcomes of pregnancy in asthmatic women.
      have reported increased risk for cesarean delivery and maternal hemorrhage.
      An observational cohort conducted by the Maternal-Fetal Medicine Units Network found increased risk for cesarean delivery but only observed increased risks for gestational diabetes and preterm delivery in women with severe asthma (but the number of cases with severe asthma was small: 8 for gestational diabetes mellitus and 16 for preterm delivery).
      • Dombrowski M.P.
      • Schatz M.
      • Wise R.
      • et al.
      Asthma during pregnancy.
      In contrast, in our fully adjusted models that have substantially more cases with asthma (927 with gestational diabetes mellitus and 2526 preterm pregnancies) but no information on severity, we observed an 11% increase in the odds of gestational diabetes and 17% increase in preterm birth compared to pregnancies without asthma.
      Results from prior large retrospective cohorts that examined obstetric complications have also provided conflicting results. Increased risk of miscarriage, hemorrhage, cesarean delivery, and anemia were reported in United Kingdom primary care health system records for pregnancies with asthma from 1988 through 2004
      • Tata L.J.
      • Lewis S.A.
      • McKeever T.M.
      • et al.
      A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma.
      but risk for placental abruption, placenta previa, hypertensive disorders, diabetes, and other chronic disease with the exception of depression were not elevated. Approximately 35% of women in the study contributed >1 pregnancy but the statistical modeling did not control for correlation between pregnancies to the same women and the rates of complications observed were generally lower than our findings. In contrast, a Medicaid-based study in Tennessee covering births from 1995 through 2003 observed higher risk for hypertensive disorders, hemorrhage, gestational diabetes, cesarean section, and low birthweight but not for preterm delivery.
      • Enriquez R.
      • Griffin M.R.
      • Carroll K.N.
      • et al.
      Effect of maternal asthma and asthma control on pregnancy and perinatal outcomes.
      Again, it was unclear how the authors controlled for multiple deliveries to the same women. Failing to control for the correlated pregnancies within women would likely overestimate the risks observed in these populations, but curiously, this was one of the few studies not to report a risk for preterm delivery.
      • Murphy V.E.
      • Namazy J.A.
      • Powell H.
      • et al.
      A meta-analysis of adverse perinatal outcomes in women with asthma.
      To our knowledge, no prior studies have examined risk for pulmonary embolism in relation to maternal asthma. Pulmonary embolism remains a leading cause of maternal mortality
      • Clark S.L.
      Strategies for reducing maternal mortality.
      and we observed twice as many cases in pregnancies complicated by asthma compared to those without asthma (12/10,000 vs 6/10,000 deliveries, respectively). It may be that this risk was secondary to the higher rate of cesarean delivery or thrombosis associated with preeclampsia but since the number of cases in our study was relatively small (n = 20 among women with asthma), the cause remains unknown. As embolism represents another vascular endpoint with serious consequences found to be associated with asthma, further research is needed to confirm this novel finding.
      Asthma is a complex chronic disease and the underlying immune dysfunction may increase the likelihood of poor placentation, resulting in both increases in gestational hypertensive disorders and placenta previa or abruption. Mothers with asthma have high-risk profiles, so their low likelihood of spontaneous labor (with more induction and prelabor cesarean section) may be expected but even when women with asthma labored, they were significantly less likely to have a vaginal delivery than their nonasthmatic counterparts. Perhaps the increased risk of pregnancy complications observed with asthma (eg, preeclampsia) also contributed to unsuccessful attempted vaginal delivery. Physician-diagnosed asthma increased risk for idiopathic preterm labor in a small case-control study from Quebec, Canada,
      • Kramer M.S.
      • Coates A.L.
      • Michoud M.C.
      • et al.
      Maternal asthma and idiopathic preterm labor.
      but the authors did not observe effects associated with methacholine challenge suggesting nonatopic, noncholinergic mechanisms. Our data suggest an increased risk of eclampsia, significant in a site-adjusted model, and given the high risk for maternal seizure when hypertensive disorders were noted in the medical record, cases of eclampsia likely were miscoded. This assumption is supported by the fact that very few women had epilepsy or other seizure disorders, so our finding that risk of maternal seizure or eclampsia is increased in women with asthma may be another indication of the confluence of factors leading from poor immunologic adaptation to pregnancy to preeclampsia/eclampsia.
      • Verlohren S.
      • Muller D.N.
      • Luft F.C.
      • Dechend R.
      Immunology in hypertension, preeclampsia, and target-organ damage.
      The strengths of this analysis include having clinical data from a large, contemporary US population. The number of women with asthma in the obstetric population continues to increase and as management of asthma continues to improve,
      National Asthma Education and Prevention Program
      Working group report on managing asthma during pregnancy: recommendations for pharmacologic treatment, update 2004.
      • Dombrowski M.P.
      • Schatz M.
      ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists number 90, February 2008: asthma in pregnancy.
      more recent data are valuable to examine the impact of maternal asthma on obstetric outcomes. The electronic medical records and discharge summaries provide a wealth of rich clinical data and the large sample size allows for rigorous analysis of less common, but more serious obstetric complications. With >17,000 pregnancies with asthma, we have one of the largest study populations to date. We are, however, limited by the data captured in the intrapartum records and discharge summaries. Not all clinical centers provided comparable data, but an intensive chart review of key variables compared to the electronic records found very good agreement
      • Zhang J.
      • Troendle J.
      • Reddy U.M.
      • et al.
      Contemporary cesarean delivery practice in the United States.
      and we conducted a series of sensitivity analyses to test the robustness of our findings (restricted to sites with lower variability in asthma prevalence, sites with complete data, patients with complete data, and only pregnancies with ICD-9-confirmed asthma) and found similar results.
      The major limitation of our study is the lack of information on asthma control, exacerbations, and treatment. Several studies have shown that adverse outcomes are more common (or only occur) in pregnancies with poor asthma control.
      • Enriquez R.
      • Griffin M.R.
      • Carroll K.N.
      • et al.
      Effect of maternal asthma and asthma control on pregnancy and perinatal outcomes.
      • Schatz M.
      • Dombrowski M.P.
      • Wise R.
      • et al.
      Spirometry is related to perinatal outcomes in pregnant women with asthma.
      • Bakhireva L.N.
      • Schatz M.
      • Jones K.L.
      • Chambers C.D.
      Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth.
      Presumably, the asthma cases in our study represent a mix of severity and treatment and we cannot evaluate how well our findings apply to the subgroup of women with well-controlled asthma. It is possible that records could be biased and more likely to include the diagnosis of asthma when complications arise, but the overall prevalence of asthma we observed (7.6%) was similar to the general population estimates of 10% for women of reproductive age and of asthma in pregnancy reported in the early 2000s (4-8%).
      • Kwon H.L.
      • Triche E.W.
      • Belanger K.
      • Bracken M.B.
      The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms.
      Our findings confirm that women with asthma have an increased risk of preeclampsia, preterm birth, and low birthweight.
      • Murphy V.E.
      • Namazy J.A.
      • Powell H.
      • et al.
      A meta-analysis of adverse perinatal outcomes in women with asthma.
      Since chronic inflammation is a hallmark of asthma and increases in proinflammatory cytokines are known to play an important role in triggering the spontaneous onset of labor,
      • Christiaens I.
      • Zaragoza D.B.
      • Guilbert L.
      • Robertson S.A.
      • Mitchell B.F.
      • Olson D.M.
      Inflammatory processes in preterm and term parturition.
      we considered the potential for spontaneous pathways leading to preterm delivery among women with asthma. However, when we examined the precursors of preterm delivery in our data, medically indicated delivery was more common in asthmatic pregnancies and women with asthma were less likely to deliver as a result of a spontaneous process (labor or PPROM). This suggests that the increased risk of preterm birth among women with asthma is not driven by spontaneous preterm labor but rather is due to their compromised medical condition. Inflammation related to asthma does not seem to be triggering preterm labor at the population level.
      We also found that asthma increased the risk of other serious obstetric complications including placental abruption, hemorrhage, pulmonary embolism, and maternal ICU admission as well as increasing risk for gestational diabetes, breech presentation, and cesarean delivery. The National Asthma Education and Prevention Program and ACOG have published guidelines for evaluation and treatment of asthma in pregnancy
      National Asthma Education and Prevention Program
      Working group report on managing asthma during pregnancy: recommendations for pharmacologic treatment, update 2004.
      • Dombrowski M.P.
      • Schatz M.
      ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists number 90, February 2008: asthma in pregnancy.
      and clinical strategies to manage women with asthma and improve outcomes have been well described.
      • Dombrowski M.P.
      • Schatz M.
      Asthma in pregnancy.
      Monitoring peak flow as an estimate of forced expiratory volume in 1 second (FEV1) is recommended and good control of asthma symptoms has been associated with improved outcomes, particularly for preterm birth. For example, >21% of women with poor spirometry across pregnancy (FEV1 <80% of expected) delivered preterm in the Maternal-Fetal Medicine Units Network study, compared to 15% when FEV1 was more favorable (≥80% of expected).
      • Schatz M.
      • Dombrowski M.P.
      • Wise R.
      • et al.
      Spirometry is related to perinatal outcomes in pregnant women with asthma.
      Asthma should be actively managed during pregnancy including objective assessment of symptoms and lung function, avoidance of asthma triggers, patient education, and step therapy to adjust the number and frequency of medications needed to control symptoms.
      • Dombrowski M.P.
      • Schatz M.
      Asthma in pregnancy.
      The importance of good asthma control for the well-being of the baby should be clearly communicated to the patient, particularly for those who may resist taking needed medication due to concern about the impact of pharmaceuticals on the fetus.
      Given that asthma is the most common chronic condition in pregnancy and the proportion of women of reproductive age with asthma is likely to increase for the foreseeable future, our findings are concerning. We observed a pattern of increased risk for nearly all outcomes studied in the general obstetric population, which likely included women with mild asthma and good asthma control. Since both asthma severity and control contribute to morbidity during pregnancy, more research is needed to determine factors that predict poor obstetric outcomes and determine if certain vulnerable women can benefit from targeted intervention to ameliorate their obstetric risks. Our data from a large, contemporary, nationwide US cohort suggest that we still have a long way to go to improve obstetric outcomes for women with asthma.

      Acknowledgments

      Institutions involved in the Consortium on Safe Labor include, in alphabetical order: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; EMMES Corp, Rockville, MD (Data Coordinating Center); Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Intermountain Healthcare and the University of Utah, Salt Lake City, UT; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH; Summa Health System, Akron City Hospital, Akron, OH; University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Houston, Houston, TX.

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