September 20, 2007
Acute and Chronic Respiratory Diseases in Pregnancy
By Getahun, Darios Ananth, Cande V; Oyelese, Yinka; Peltier, Morgan R; Et al
Abstract Objective. To examine whether acute and chronic respiratory diseases are associated with an increased risk of spontaneous premature rupture of the membranes (PROM).
Results. The incidence of PROM was 5%, and rates of acute and chronic respiratory conditions were 2.1 and 9.5 per 1000 pregnancies, respectively. Chronic bronchitis was associated with a reduced risk of PROM (RR 0.39, 95% CI 0.31, 0.48). Asthma was significantly associated with PROM at preterm (RR 1.15, 95% CI 1.14, 1.17) and term (RR 1.27, 95% CI 1.23, 1.30). Stratification by race showed that acute upper respiratory disease was associated with preterm PROM in whites (RR 1.90, 95% CI 1.71, 2.11) and blacks (RR 6.76, 95% CI 5.67, 8.07). Viral/bacterial pneumonia was associated with preterm PROM in blacks and term PROM in both races. Asthma was associated with term PROM in blacks but not whites.
Conclusions. Acute respiratory diseases and asthma during pregnancy are associated with spontaneous PROM, with substantially stronger association among blacks than whites. We speculate that timely diagnosis and treatment, coupled with closely mentoring of pregnant women may help reduce the rate of PROM and associated complications.
Keywords: Respiratory disease, asthma, bronchitis, spontaneous premature rupture of membranes
In the USA, premature rupture of the membranes (PROM) complicates about 10% of pregnancies and most cases occur spontaneously without apparent cause [1,2]. Of all singleton preterm births at <37 weeks, approximately 10% are attributable to PROM . PROM is associated with an increased risk for obstetrical complications such as oligohydramnios and placental abruption [4-6]. Infants delivered preterm following PROM are also at increased risk for bronchopulmonary hypoplasia , neonatal sepsis, and neonatal death [5,8,9].
Despite the speculative etiology, epidemiologic studies have documented risk factors associated with PROM, including young maternal age , black race , multiparity , maternal smoking and cocaine use [13,14], previous PROM or preterm birth , multiple gestation , cervical incompetence , and obstetrical procedures such as cervical cerclages [5,15]. A significant proportion of PROM cases have an underlying inflammatory etiology following sexually transmitted diseases  and upper genital tract infections [17,18].
Despite the widespread use of antimicrobial therapy and advances in respiratory therapy, respiratory conditions during pregnancy remain important risk factors for maternal and fetal morbidity and mortality . The incidence of communityacquired pneumonia during pregnancy is approximately 1.5 to 2.7 per 1000 pregnancies , with rates similar to that in the general population . However, if contracted during pregnancy, pneumonia portends a virulent course , and is associated with an increased risk of delivering preterm [19,23], delivering small-for-gestational age , and neonatal mortality .
Asthma is a ubiquitous yet a serious medical condition, complicating pregnancy  with an estimated prevalence of 3.7% to 8.4% among pregnant women in the USA . Uncontrolled asthma may lead to reduced oxygenation and/or an asthma-related inflammatory response at the maternal-fetal interface, which may be associated with increased risk of adverse pregnancy outcome. Asthma during pregnancy is associated with an increased risk of preeclampsia and preterm birth .
We hypothesized that acute and chronic respiratory diseases are associated with increased risk of spontaneous PROM through bacteremia and increased levels of proinflammatory cytokines. Therefore, we examined the association between acute and chronic respiratory conditions and spontaneous PROM to test our hypothesis using a large population-based cohort of singleton pregnancies in the USA.
We used the National Hospital Discharge Survey (NHDS) data  assembled by the National Center for Health Statistics (NCHS). This survey comprises discharges from non-institutional hospitals in the USA between 1993 and 2004, exclusive of federal, military, and Veterans Administration hospitals, located in the 50 States and the District of Columbia. Short stay (average length of hospitalization <30 days) general, as well as pediatric general hospitals participated in the annual survey. Discharge diagnosis and medical procedures, as well as demographic characteristics such as age, gender, race, marital status, adequacy of prenatal care, smoking, cocaine use, geographic location, and type of insurance coverage were extracted. In the NHDS dataset, self-reported maternal race was grouped as white, black, American Indian/Eskimo, Asian/Pacific Islander, and Others' irrespective of the Hispanic origin. Thus, white race includes both white nonHispanics and white Hispanics. Similarly, the black race group includes both black non-Hispanics and black Hispanics. We excluded American Indian/ Eskimo and Asian/ Pacific Islander from the analysis due to small counts.
The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were utilized to identify pregnancies complicated with the following respiratory tract conditions: acute respiratory conditions including acute upper respiratory diseases (ICD-9-CM 465.8 and 465.9), acute bronchitis (ICD-9-CM 466.0-466.19), and viral/ bacterial pneumonia (ICD-9-CM 480.0-487.0), as well as chronic respiratory conditions including chronic bronchitis (ICD-9-CM 491.0-492.8 and 495.9-506.0) and asthma (ICD-9-CM 493.0-493.9). Women who had both conditions in a pregnancy were excluded from all analyses due to the very small count (<0.01% in the cohort). Data on singleton births (ICD-9-CM V270, V271, V301, V302, V3000, and V3001) and spontaneous premature rupture of membranes (ICD-9-CM 658.10-658.23) were also extracted. Spontaneous PROM was denned as the rupture of membranes at any given time during pregnancy prior to the onset of labor.
The distributions of socio-demographic and behavioral characteristics of women with acute and chronic respiratory tract conditions were compared using Chi-square tests. Multivariable logistic regression analysis was performed to examine the association between acute and chronic respiratory conditions and spontaneous premature rupture of membranes after controlling for potential confounders. These included maternal age (categorized as 14-24, 25-34, and 35-49 years), maternal race (white, black, and others), marital status (married or unmarried), adequacy of prenatal care (adequate or inadequate), maternal smoking (yes or no), cocaine use (yes or no), insurance type (Medicare, Medicaid, indemnity, uninsured, and others), geographic location (Northeast, Midwest, South, and West) and birth year (1993-94, 1995-96, 1997-98, 1999- 2000, 2001-02, and 2003-04).
We repeated the analysis after stratifying the data on whether PROM occurred at preterm (<37 weeks) or at term, as well as maternal race categories. Relative risks (RR) and 95% confidence intervals (CI) were used to describe the associations. Under the rare disease assumption, the odds ratio can be considered a valid estimate of the relative risk. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC, USA).
The study was approved by the Institutional Review Board of UMDNJ- Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
After incorporating the sampling weight, there was a total of 41 250 539 singleton pregnancies between 1993 and 2004 in the USA. The overall rates of PROM and acute and chronic respiratory conditions were 50, 2.1 and 9.5 per 1000 singleton pregnancies, respectively. Of all singleton births, 16.3% preterm and 4% at term were attributable to PROM. Hospitalized pregnant women with acute and chronic respiratory conditions were more likely to be young, unmarried, smoke cigarettes, use cocaine, be enrolled in the Medicaid program, and to be residents of Northeast and Midwest geographic regions (Table I). While white women were more likely to have acute respiratory conditions, black women were more likely to have chronic respiratory conditions.
Table II shows the associations between acute (acute upper respiratory diseases, viral and bacterial pneumonia, and acute bronchitis) and chronic (chronic bronchitis and asthma) respiratory conditions and spontaneous PROM based on the overall cohort. Of the acute respiratory conditions, acute upper respiratory disease and viral and bacterial pneumonia were associated with PROM, but not acute bronchitis. Of the chronic respiratory conditions, asthma was associated with PROM, but chronic bronchitis was not.
Table I. Distribution of maternal characteristics among women with acute and chronic respiratory conditions: USA, 1993-2004. Figure 1 shows the associations between acute and chronic respiratory conditions at preterm and term gestations using the overall cohort. A strong association was observed between acute upper respiratory disease and PROM at preterm (RR 1.67, 95% CI 1.56, 1.78), but not at term gestations. Viral and bacterial pneumonia was strongly associated with PROM at term (RR 2.28, 95% CI 2.16, 2.42), but not at preterm gestations. Acute bronchitis was not associated with PROM at preterm and term gestations. Among the chronic respiratory conditions, asthma was strongly associated with PROM both at term (RR 1.27, 95% CI 1.23, 1.30) and preterm (RR 1.15, 95%> CI 1.14, 1.17) gestations, but chronic bronchitis was associated with reduced risk at term gestation.
The association between acute and chronic respiratory conditions and spontaneous PROM for white and black women at preterm and term gestations is shown in Table III. Although acute upper respiratory disease was associated with preterm PROM in both races, the strength of association was substantially higher for blacks than for whites. Viral and bacterial pneumonia was significantly associated with preterm PROM among blacks only. In both races, viral and bacterial pneumonia was associated with term PROM. Acute upper respiratory disease was significantly associated with term PROM among blacks, but not among whites. Among whites, acute bronchitis was associated with term PROM. Of the chronic conditions, maternal asthma was associated with term PROM among black women only.
In this population-based study, we found that acute respiratory tract conditions and asthma during pregnancy increased the risk of spontaneous PROM. More importantly, acute upper respiratory tract diseases were associated with preterm PROM, whereas viral and bacterial pneumonia was associated with term PROM. In addition, these associations demonstrated strong race-disparity. Relative risks for spontaneous preterm PROM among those with acute respiratory tract conditions, and at term gestation among asthmatic women were substantially higher for black than for white women.
It has been hypothesized that ascending bacterial infections at the maternal-fetal interface are a significant component in the primary pathophysiologic mechanism leading to PROM [5,17,18]. Recent evidence suggests that inflammatory processes at sites remote from the genital tract may lead to increased levels of proinflammatory cytokines at the maternal-fetal interface  . This is perhaps best studied for periodontitis and adverse pregnancy outcomes including preterm birth, preterm PROM, etc. Increased levels of inflammatory markers such as interleukin (IL)- 6 and IL-8 in amniotic fluid are correlated with colony-forming units of periodontal pathogens in subgingival plaque of pregnant women [27,28] . Increased levels of fetal cord IgM have also been documented in response to microorganisms known to be associated with periodontitis , suggesting that these organisms can stimulate an immune response at the maternal-fetal interface. It is possible that similar inflammatory changes can occur at the maternal-fetal interface in response to acute and chronic inflammatory respiratory conditions. Thus, it is conceivable that both respiratory tract infections and periodontal inflammatory processes predispose to PROM through a common process: increased intrauterine concentrations of various proinflammatory cytokines, prostaglandins, and matrix metalloproteinease [5,27,28]. Another mechanism may be by infective inflammatory respiratory conditions causing systemic dissemination of the microorganisms that may consequently lead to intrauterine inflammation.
Table II. Associations between maternal acute and chronic respiratory conditions and spontaneous premature rupture of membranes: USA, 1993-2004.
Figure 1. Relative risk for spontaneous premature rupture of membranes at preterm (left panel) and term (right panel) gestations and respiratory disease among singleton pregnancies: USA, 1993- 2004. Relative risks were adjusted for maternal age, race, marital status, prenatal care, insurance, geographic location, birth year, smoking, and cocaine use. [dagger]The small number of cases precluded subgroup analysis.
Table III. Associations between maternal acute and chronic respiratory conditions and spontaneous premature rupture of membranes by maternal race at preterm and term gestation: USA, 1993- 2004.
Our findings of an increased risk of PROM among women with asthma during pregnancy corroborate previous findings , but are at variance with others studies. Sorensen et al.  reported the absence of association between maternal asthma and risk of preterm PROM (OR 1.63, 95%> CI 0.50, 5.33), contradicting our findings. Nonetheless, closer examination of our data shows that the association between asthma and PROM is present only for black women when spontaneous PROM occurs at term gestations. Despite advances in knowledge regarding potential risk factors and pathophysiologic mechanisms for asthma and advances in therapy, the prevalence, severity, and mortality from asthma have increased over the past decade with a disproportionately higher rate among blacks , The increased risk for spontaneous PROM among asthmatic black women could be consistent with disparity in access to health care that may have resulted in a higher asthma hospitalization rate among blacks relative to whites [32,33]. This suggests that black women are perhaps disproportionately affected by relatively severe forms of asthma in their pregnancy, and consequently PROM.
The reduced risk of PROM among women with acute and chronic bronchitis may be driven by the widespread use of antibiotics. Antibiotics are generally thought to be ineffective in preventing preterm births. But studies on monkeys suggest they can be effective if given prior to the start of uterine contractions . Similarly, frequent use of antibiotics to treat respiratory tract infections may have an unintended benefit of removing undiagnosed subclinical infections at the maternal-fetal interface that could cause PROM. Further studies are needed to ascertain the mechanisms by which upper respiratory tract disease, pneumonia, and asthma exert their effect on the risk of PROM and also the potential protective effect of acute and chronic bronchitis. Policies that are designed to increase the awareness of patients and care takers for early recognition and management, and implementing preventive methods such as active immunization or prophylactic therapy are of importance.
It is important to recognize the limitations of large administrative databases. Foremost among them is the possibility of data on the prevalence of respiratory diseases being underreported in the NHDS data. Women hospitalized for any respiratory conditions during pregnancy (remote from the delivery-related hospitalization) or those who received outpatient treatment may not have been captured in the study. Thus, our reported associations are modestly conservative.
Data on maternal race were missing for up to 20%> of records between 1995 and 2001, and in up to 30% of records thereafter . The NCHS reported that counties with non-reporting hospitals have higher proportions of whites compared to counties with reporting hospitals, suggesting differential reporting of race in the NHDS data . We excluded discharge records with missing data on race in our race-stratified analysis and this exclusion may have resulted in an overestimation of rates of acute and chronic respiratory diseases among whites. In order to assess whether missing data on maternal race had biased the findings of our analysis on race- disparities in the association between acute and chronic respiratory conditions and PROM, we conducted a sensitivity analysis after assigning all missing values to white race. The result of the sensitivity analysis did not differ substantially from the results found after excluding the missing values on race from the analysis. Since our study was based on the data of women who required hospitalizations, the reported prevalences of respiratory tract conditions are likely underestimated, limiting generalizability to pregnant women seen as outpatients. However, these results do underscore the need for careful monitoring and timely treatment of respiratory conditions in order to prevent PROM. The discharge survey is based on random samples of hospitals and may not be representative of all non-federal short-term hospitals. Since the dataset lacks temporality between onset of respiratory conditions and PROM, it is unlikely to establish a cause-and-effect relationship. Because information about medications during pregnancy is not well documented in the NHDS data it is difficult to determine if the increased risk of PROM in an asthmatic woman is a result of the disease or anti-asthmatic drugs. Furthermore, the risk of PROM due to these drugs at prophylactic doses remains unknown. However, previous studies have reported the risk associated with asthma medications used during pregnancy to be minimal compared to the risks associated with largely uncontrolled asthma [36-38]. Only a small fraction of an administered dose of inhaled corticosteroid reaches the lung, and therefore this is considered safe during pregnancy . Asthmatic pregnant women generally have poor asthma knowledge and skills . Patient education on self-management and timely diagnosis and treatment, coupled with closely mentoring this pregnant population may help to reduce the rate of PROM and associated complications.
On the other hand, the strengths of the study include its large sample size, a population-based cohort, and control for potential confounding factors. Previous studies have reported that the precision of coding of diagnoses and procedures in the dataset exceeds that of other datasets from the NCHS. Coding errors for procedures and diagnosis were estimated to be about 0.9% [41,42]. Pregnancies complicated by acute respiratory tract conditions and asthma requiring hospitalization are associated with PROM, especially among blacks. We speculate that patient education, timely diagnosis and treatment, and closely mentoring this pregnant population may help reduce the rate of PROM.
DG, CVA, and JCS are partly supported through a grant (HD038902) from the National Institutes of Health awarded to CVA.
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DARIOS GETAHUN1, CANDE V. ANATH1, YINKA OYELESE2, MORGAN R. PELTIER2, JOHN C. SMULIAN2, & ANTHONY M. VLNTZILEOS2
1 Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences,
UMDNJ-Robert Wood Johnson Medical School, NJ, USA and 2 Division of Maternal-Fetal Medicine, Department of
Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, NJ, USA
(Received 9 January 2007; revised 30 May 2007; accepted 15 June 2007)
Correspondence: Darios Getahun, MD, MPH, Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08901-1977, USA. Tel: +1 732 235 5178. Fax: +1 732 235 6627. E-mail: [email protected]
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