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Condyloma in Pregnancy Is Strongly Predictive of Juvenile-Onset Recurrent Respiratory Papillomatosis

Michael J. Silverberg, PhD, MPH, Poul Thorsen, MD, PhD, Henning Lindeberg, MD, PhD, Linda A. Grant, PhD, MPH, and Keerti V. Shah, MD, DrPH
OBJECTIVE: To assess the risk of juvenile-onset recurrent respiratory papillomatosis conferred by a maternal history of genital warts in pregnancy, and to identify additional cofactors such as the method of delivery (cesarean versus vaginal) and procedures or complications during pregnancy. METHODS: A retrospective cohort design was used to evaluate maternal and infant characteristics associated with respiratory papillomatosis among Danish births between 1974 and 1993. Using data from Danish registries, we identied 3033 births with a maternal history of genital warts during pregnancy. Fifty-seven respiratory papillomatosis cases were identied by review of medical records from ear, nose, and throat departments. RESULTS: Seven of every 1000 births with a maternal history of genital warts resulted in disease in the offspring, corresponding to a 231.4 (95% condence interval 135.3, 395.9) times higher risk of disease relative to births without a maternal history of genital warts. In women with genital warts, delivery times of more than 10 hours were associated with a two-fold greater risk of disease. Cesarean delivery was not found to be protective against respiratory papillomatosis, and no other procedures or complications during pregnancy were observed to increase the risk of respiratory papillomatosis. CONCLUSION: A maternal history of genital warts in pregnancy is the strongest risk factor for respiratory papillomatosis in the child. Future studies should examine the efcacy of genital wart treatment for the prevention of disease. (Obstet Gynecol 2003;101:64552. 2003 by The American College of Obstetricians and Gynecologists.)

Juvenile-onset recurrent respiratory papillomatosis, also referred to as laryngeal papillomatosis, is a rare disease associated with low mortality but signicant morbidity.
From the Departments of Epidemiology and Molecular Microbiology & Immunology, Johns Hopkins University, Baltimore, Maryland; and Department of Epidemiology and Social Medicine, Aarhus University, and Oral Pathology Laboratory, Royal Dental College, Aarhus, Denmark. This research was supported in part by a National Cancer Institute grant (RO3 CA86170-01).

Lesions occur most often in the larynx, vocal cords, and oral and nasal mucosa, particularly at junctions of the squamous and ciliary epithelium.1 Incidence estimates range from two to 43 cases per 1,000,000 children and are dependent on the populations examined and methods used.27 Respiratory papillomatosis is the most common benign neoplasm of the larynx in children3,8 10 and causes childhood hoarseness, a change in voice, chronic cough, choking, recurrent respiratory infections, and failure to thrive. Derkay3 reported malignant progression of respiratory papillomatosis in less than 5% of cases and extralaryngeal spread in approximately 30% of cases. Treatment primarily consists of surgical removal, but recurrence is common. A tracheotomy may be performed to avoid life-threatening airway obstruction, and has been reported in 14% of juvenile cases.3 Case reports of respiratory papillomatosisassociated deaths are rare.11 The infectious nature of respiratory papillomatosis was rst demonstrated in 1923 when Ullman12 developed warts after inoculating himself with the laryngeal tissue from an infected 6-year-old boy. Subsequent case reports suggested that human papillomavirus (HPV) infection could be transmitted from mother to infant, resulting in respiratory papillomatosis.13,14 In addition, investigators have reported that over 50% of laryngeal papillomatosis cases have a maternal history of genital warts,15,16 thus suggesting an etiological association between genital warts and respiratory papillomatosis. The identication of HPV types 6 and 11 from both genital warts and respiratory papillomatosis1719 provided the denitive evidence for the etiological link between genital warts and respiratory papillomatosis. The Danish national registries are a valuable resource that allowed for an evaluation of factors associated with the development of respiratory papillomatosis among births over a 20-year period. All women with a history of genital warts during pregnancy were identied from the national registries. Respiratory papillomatosis cases were identied by a comprehensive medical record re-

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view from ear, nose, and throat departments. Our data allowed for the estimation of the absolute risk of respiratory papillomatosis in women with genital warts in pregnancy. We also evaluated the effect of young maternal age, nulliparity, and vaginal delivery, which were previously reported risk factors of disease.20 22 Additional potential risk factors available in the registry data were also evaluated, including increased delivery times and procedures and complications during delivery.

MATERIALS AND METHODS Between 1974 and 1993, the Danish Medical Birth Registry recorded 1,206,213 births in Denmark. We identied 3033 women who had genital warts during pregnancy by linking the data in the Danish National Hospital Registry with those in the Danish Medical Birth Registry. A representative sample (n 7902) of all births was selected by a simple random sample from the Danish Medical Birth Registry database to serve as a comparison group for the women with genital warts. We identied 57 cases of respiratory papillomatosis by review of medical records from ear, nose, and throat departments. A retrospective cohort design was used to identify risk factors for respiratory papillomatosis among Danish births. The data were extracted from the Danish National Registries, which have been described elsewhere.23,24 Briey, the Danish Medical Birth Registry23 contains data on all live births and stillborn fetuses by women living in Denmark and all infant deaths, dened as less than or equal to 1 year of age. From this database, we obtained sociodemographic information on the mothers and newborns, previous pregnancy and delivery histories of the mothers, and details of the delivery, including gestational age, birth weight, birth length, and delivery duration. The procedures performed and complications encountered during the delivery process were also included. The Danish National Hospital Registry24 includes detailed information on all hospital admissions. The registry can accommodate up to 20 discharge diagnoses per admission, which are coded according to the International Classication of Diseases. From this registry, we obtained all diagnoses of condylomata acuminata (International Classication of Diseases, 8th revision code 99.9) among pregnant women. The two national registries described above were linked using each mothers ten-digit Central Population Registry number, a unique identier that has been provided to all Danish citizens since 1968. The result was the identication of the earliest diagnoses of genital warts during pregnancy among women who gave birth between 1974 and 1993.

To identify respiratory papillomatosis cases, we contacted all Danish hospitals with an ear, nose, and throat department (n 22). Each hospital provided a list of patients who were admitted between January 1974 and December 1999 with a discharge diagnosis of benign neoplasm of the larynx, trachea, bronchus, or lung. Discharge diagnoses were based on the International Classication of Diseases, 8th revision before 1994 (International Classication of Diseases, 8th revision codes 508, 212, 231), and the International Classication of Diseases, 10th revision after 1994 (International Classication of Diseases, 10th revision codes J38, D14, D38). International Classication of Diseases, 9th revision codes were not implemented in Denmark. Medical records of all patients identied from the lists and born between 1974 and 1993 were reviewed. Diagnoses of respiratory papillomatosis were distinguished from other benign conditions, such as hemangiomas, bromas, chondromas, myxomas, neurobromas, polyps, and singers nodes, by the histopathologic report, which was included in the medical record. All cases identied in the medical record review with at least one histopathologically conrmed respiratory papillomatosis lesion were included in our study. We excluded cases with an adult onset, dened as 17 years of age or greater. The methods used to identify cases by medical record review were identical to the methods used by Lindeberg and Elbrond,5 who reported the incidence of respiratory papillomatosis in a subpopulation in Denmark from 1965 to 1984. We independently identied all 17 cases described in this earlier study that matched the criteria for our study, indicating that our surveillance was excellent. Approvals from the Danish Data Surveillance Authority, the ScienticEthics Committees in Denmark, the Johns Hopkins University, Bloomberg School of Public Health, and the Ofce for Human Research Protections of the United States Department of Health and Human Services were obtained to access the national registries and access the medical records of respiratory papillomatosis cases. Relative risks and 95% condence intervals (CIs) were calculated to compare the risk of disease among exposed children with a maternal history of genital warts in pregnancy with the risk of disease among two unexposed groups: 1) the random sample of children without a maternal history of genital warts and 2) all live births without a maternal history of genital warts. A population-attributable risk25 was also calculated to quantify the proportion of respiratory papillomatosis attributable to a maternal history of genital warts in pregnancy.

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Table 1. Characteristics of 11,853 Mothers and Newborns by Maternal History of Genital Warts in Pregnancy Characteristic Mean maternal age at delivery [y (range)] Previously pregnant (%) No. of previous live births (%) 0 1 2 2 Current smoker (at rst prenatal visit) (%) Not residing with newborns father (%) Gender of newborn (%) Female Male Preterm delivery (37 wk of gestation) (%) Cesarean delivery
* Random sample of all mothers without genital warts in pregnancy.

Genital warts (n 3033) 28.9 (18.243.7) 66.4 47.3 38.5 11.7 2.5 27.1 2.8 51.5 48.5 6.2 15.5

No genital warts (n 7902)* 30.9 (16.758.8) 66.4 47.2 38.6 11.3 2.9 26.6 3.4 51.3 48.7 5.5 15.0

Additional analyses to identify cofactors for disease development were performed using time-to-event procedures to account for different lengths of follow-up after birth. Data from all respiratory papillomatosis cases (n 57), and all births with a maternal diagnosis of genital warts (n 3033) were included. Unadjusted and adjusted relative hazards (similar interpretation to the relative risk) were computed using the Cox proportional hazards model.26 The outcome used in the Cox models was the time to respiratory papillomatosis diagnosis, which allowed for variable lengths of follow-up. Those subjects who ended follow-up without a diagnosis of respiratory papillomatosis were considered censored26 at December 31, 1999. Several groups of characteristics were evaluated, including maternal demographics and delivery history, newborn characteristics, procedures performed during pregnancy, and complications occurring during pregnancy. SAS 8.0 (SAS Institute Inc., Cary, NC) was used for all analyses.

RESULTS Of the 1.2 million live births in Denmark during the study period, we identied 57 respiratory papillomatosis cases, corresponding to an overall risk of 4.7 per 100,000 births and an overall rate of 3.5 per 1,000,000 personyears. There were no statistically signicant differences (P .05) of selected characteristics between the 3033 newborns identied from the Danish national registries with a maternal history of genital warts and the 7902 randomly selected sample of births without such a history in pregnancy (Table 1). In particular, the proportion of births with a cesarean delivery was similar in the two groups (P .51), suggesting that the presence of genital warts was not an indication for cesarean delivery in this population. Of the 57 respiratory papillomatosis cases, 21 were identied among the 3033 births with a maternal history of genital warts, and 36 were from the remaining births without a maternal history of genital warts (Table 2). No

Table 2. Juvenile-Onset Recurrent Respiratory Papillomatosis Risk by Maternal History of Genital Warts in Pregnancy Respiratory papillomatosis cases Respiratory papillomatosis risk* RR (95% CI) Population attributable risk (%)

n Reference group: random sample of births without a history of genital warts Genital warts No genital warts (random sample) Reference group: all births without a history of genital warts Genital warts No genital warts (all live births)

3033 7902 3033 1,203,180

21 0 21 36

6.9 0.0 6.9 0.03

1 231.4 (135.3, 395.9) 1

1.0

36.7

RR relative risk; CI condence interval. * No. of juvenile-onset recurrent respiratory papillomatosis cases per 1000 births.

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Table 3. Univariate Analyses Examining Maternal and Infant Characteristics as Risk Factors for Juvenile-Onset Recurrent Respiratory Papillomatosis Diagnosed with respiratory papillomatosis (%) Characteristic Maternal characteristics Younger maternal age (30 y) No previous deliveries Not living with newborns father Smoking at rst prenatal visit Previous pregnancy Previously complicated delivery Infant characteristics Female sex Low birth weight (2500 g) Preterm delivery (37 wk of gestation) Birth length (cm) 52 52 Delivery time (h) 10 10 Time from diagnosis of genital warts to birth (d) 30 30 No* (n 3012) 62.9 47.3 2.8 27.1 66.3 19.6 51.5 5.5 6.2 58.4 41.6 41.2 58.8 15.0 84.0 Yes (n 57) 75.0 37.5 8.9 26.8 71.4 19.6 38.6 3.6 0.0 57.1 42.9 50.9 49.1 9.5 90.5 Relative hazard 1.72 0.64 3.48 1.00 1.35 1.03 0.57 0.65 0.00 0.99 1 1.55 1 0.63 1 95% CI 0.94, 3.15 0.37, 1.11 1.39, 8.72 0.55, 1.82 0.74, 2.44 0.53, 1.98 0.33, 0.97 0.16, 2.67 Undened 0.58, 1.70 0.90, 2.66 0.15, 2.72

CI condence interval. * All births that did not result in juvenile-onset recurrent respiratory papillomatosis but had a maternal history of genital warts in pregnancy. Missing data on one case.

cases were identied from the 7902 randomly sampled births. The corresponding risk of respiratory papillomatosis was 6.9 cases per 1000 births among births with a maternal history of genital warts. Among births without a maternal history of genital warts in pregnancy, the corresponding risk was 0.0 cases per 1000 births in the random sample and 0.03 cases per 1000 among all live births without a maternal history of genital warts (Table 2). The risk of disease among births with a maternal history of genital warts in pregnancy was 231.4 (95% CI 135.3, 395.9) times higher than that among births without a maternal history of genital warts. Among births during the 20-year period, 37% of respiratory papillomatosis cases were attributable to a maternal history of genital warts during pregnancy (Table 2). Maternal genital warts in pregnancy were the overwhelming risk factor for respiratory papillomatosis. Thus, subsequent analyses evaluated cofactors of disease between all cases and all births with a maternal history of genital warts that did not result in respiratory papillomatosis. Univariate results are presented for maternal and infant characteristics in Table 3 and for procedures and complications in Table 4. The results of the nal multivariable model are listed in Table 5. The only statistically signicant (P .05) ndings in the univariate examinations (Tables 3 and 4) were a decreased risk of

respiratory papillomatosis among female infants (relative hazard 0.6; 95% CI 0.3, 1.0) and an increased risk if not living with the newborns father (relative hazard 3.5; 95% CI 1.4, 8.7) (Table 3). We did not identify any complications or procedures performed during pregnancy that were associated with a statistically signicant (P .05) increased risk of respiratory papillomatosis in our univariate models. Of note, elective cesarean, acute cesarean, and instrumentally assisted deliveries did not affect the risk of respiratory papillomatosis relative to the remaining vaginal deliveries. Several factors were associated with a slightly increased, although statistically insignicant (P .05) risk, including younger maternal age, deliveries with duration of 10 hours or more, cardiotopography, induced stimulation of labor (medical or rupture of membranes), breech presentation, shoulder dystocia, and a narrow maternal pelvis. In the multivariable model, deliveries longer than 10 hours in duration were associated with an increased risk of respiratory papillomatosis (relative hazard 2.0; 95% CI 1.1, 3.5). The duration of the second stage of labor, which may be a better surrogate for contact of the fetus with infective tissue, was not available in the registry data. We also observed an increased risk for not living with the newborns father (relative hazard 3.6; 95% CI 1.4,

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Table 4. Univariate Analyses Examining Procedures and Complications During Labor or Delivery as Risk Factors for Juvenile-Onset Recurrent Respiratory Papillomatosis Diagnosed with respiratory papillomatosis (%) Characteristic Procedures Method of delivery Elective cesarean Acute cesarean Instrumental Vaginal Cardiotocography Episiotomy or laceration of perineum Induced stimulation of labor (medical or rupture of membranes) Complications Any complication Breech presentation Shoulder dystocia Asphyxia Bleeding during delivery Prelabor rupture of membranes Rupture 4 h before delivery Rupture 4 h before delivery No prelabor rupture of membranes Umbilical cord prolapse Abnormal presentation of head Narrow maternal pelvis No* (n 3012) Yes (n 57) Relative hazard 95% CI

6.0 9.6 12.0 72.4 29.9 90.7 38.5 47.5 0.5 0.6 26.7 3.8 17.4 3.3 79.3 0.1 2.3 3.4

5.4 7.1 10.7 76.8 37.5 87.5 42.9 39.3 1.8 1.8 19.6 1.8 17.0 0.0 83.0 0.0 1.8 5.4

0.86 0.73 0.86 1 1.45 0.70 1.24 0.74 3.61 2.78 0.69 0.48 0.96 0.00 1 0.00 0.83 1.70

0.27, 2.76 0.26, 2.02 0.36, 2.02 0.84, 2.49 0.32, 1.57 0.73, 2.11 0.43, 1.28 0.50, 26.18 0.38, 20.18 0.36, 1.33 0.07, 3.47 0.47, 1.96 Undened Undened 0.12, 6.00 0.53, 5.43

CI condence interval. * All births that did not result in juvenile-onset recurrent respiratory papillomatosis but had a maternal history of genital warts in pregnancy. Missing data on one case.

9.1). Cesarean delivery, maternal age, parity, and gender were statistically insignicant (P .05). DISCUSSION The valuable resource of the Danish national registries allowed for the longitudinal evaluation of maternal and infant characteristics associated with respiratory papillomatosis. Fifty-seven respiratory papillomatosis cases occurring during a follow-up were identied by medical record review, corresponding to an overall rate of 3.5 per 1,000,000 person-years, which is similar to the rate reported by Lindeberg and Elbrond.5 A maternal history of genital warts in pregnancy was identied as the principal risk factor for the development of respiratory papillomatosis. Seven in every 1000 births with a maternal history of genital warts resulted in disease, corresponding to one case for every 144 births with maternal genital warts. Among births without a history of genital warts, the risks were three cases per 100,000 births or one case for every 33,421 births. Thus, maternal genital warts in pregnancy conferred a 231 times higher risk of disease relative to births without a maternal history of genital warts in pregnancy. Examinations of the oral cavity of

children and newborns using nasopharyngeal swabs have detected HPV deoxyribonucleic acid (DNA) in some studies,27,28 suggesting that HPV can be transmitted from mother to infant, but other studies have been negative.29 A higher risk of respiratory papillomatosis among women with clinical HPV disease conrms the mechanism of mother-to-infant transmission of infection. The small group of children (0.25% of all births) exposed to maternal genital warts accounted for 37% of disease. The remaining 36 cases of respiratory papillomatosis cases presumably resulted from HPV transmission from a mother with subclinical HPV infections. We did not have the data to estimate the risk of respiratory papillomatosis from subclinical maternal infections, but it is likely to be lower because of less virus shedding in subclinical infections than in clinical infections. We identied longer delivery times (at least 10 hours) and not living with the newborns father as additional cofactors among women with genital warts for the development of respiratory papillomatosis in the newborns. Mothers with more than 10 hours between onset of labor and delivery were twice as likely to transmit HPV resulting in respiratory papillomatosis. The increased risk for

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Table 5. Multivariable Analysis Examining Risk Factors for Juvenile-Onset Recurrent Respiratory Papillomatosis* Adjusted relative hazard 0.95 1 0.73 1.56 0.16 1 1.97 1 3.57 0.65

Characteristic Type of delivery Cesarean (elective or acute) Vaginal Maternal age (y) and parity Maternal age 30, nulliparous Maternal age 30, multiparous Maternal age 30, nulliparous Maternal age 30, multiparous Delivery time (h) 10 10 Not living with newborns father Female sex

95% CI 0.34, 2.66 0.34, 1.54 0.78, 3.11 0.02, 1.25 1.11, 3.51 1.41, 9.06 0.38, 1.14

CI condence interval. * No other variables were included in the model.

longer delivery times was likely a result of increased exposure to infection during delivery, providing evidence for intrapartum transmission of infection. Not living with the newborns father was associated with an increased risk of disease in both univariate and multivariable models. One explanation is that this factor may be correlated with unstable relationships, resulting in more recent exposures to sexually transmitted diseases such as HPV. Conrmation of these cofactors in other populations and settings is necessary. Of 57 cases in our study, seven (12.5%) were delivered by cesarean, of which only three were elective cesarean deliveries; this percentage was only slightly lower than the overall cesarean delivery rate among noncases (15.7%) and was not statistically signicant. Three previous studies by Shah and colleagues20 22 have examined method of delivery and other maternal cofactors for HPV transmission resulting in respiratory papillomatosis. Eight of 273 (2.9%) respiratory papillomatosis cases were delivered by cesarean in the three studies, which is lower than expected based on national statistics. Maternal young age (less than 20 years) and nulliparity were also more common among cases.20,21 We observed a slightly increased risk for younger maternal age, but not for parity or cesarean delivery. The discrepancies between studies may in part be explained by differences in both study design and the populations examined. First, our study used a cohort design, which reduces the inuence of recall bias, whereas previous investigations used a case control design using either a selected control group or national statistics for comparison. Furthermore, previous studies had no data on maternal genital warts. Finally, Denmark has substantially lower cesarean delivery rates than the United States, where the

previous studies were based. Thus, the power to detect a reduced cesarean delivery rate among respiratory papillomatosis cases in Denmark was limited, particularly with such a small case group. Fonnest et al30 have examined the incidence of neonatal herpes in this population, a disease with pathogenesis similar to that of respiratory papillomatosis. They reported 30 neonatal herpes cases among 862,298 births, corresponding to a risk of 3.5 per 100,000 births, a rate similar to the risk of respiratory papillomatosis found in our study (4.7 per 100,000 births). Cesarean delivery prevents transmission of herpes, although the protective effect was not observed when the amniotic membranes ruptured more than 4 6 hours before delivery.31 Primary maternal herpes infections32 and the use of fetal scalp electrodes33 increased the risk for neonatal herpes. We were able to evaluate the role of prelabor rupture of membranes and cesarean delivery for the risk of respiratory papillomatosis, although we did not have data on fetal scalp electrodes or primary versus recurrent HPV infections. A limitation of this study is the potential misclassication of genital warts. Friis et al34 examined women hospitalized for condylomata acuminata and noted that those with mild cases of disease would more likely seek treatment in an outpatient setting and would therefore be missed in studies of hospitalized cases. The misclassication may be somewhat reduced in our study because pregnant women were closely monitored throughout pregnancy and were hospitalized during labor and delivery. The result of any misclassication that did occur would be to dilute the observed association of genital warts and the risk of respiratory papillomatosis. The likelihood of the misclassication of respiratory papillomatosis cases is unknown. We had no information, for example, on mild cases that did not receive medical attention. However, in Denmark, all children with clinically relevant lesions in the aerodigestive tract would eventually be referred to an ear, nose, and throat specialist. It is also conceivable, although unlikely, that severe cases would be missed if they resulted in death before receiving medical care. Third, a common limitation of registry-based studies is the lack of investigator control of examined variables. We did not have data on genital wart treatments, use of fetal scalp electrodes, or duration of the second stage of labor, all of which may have an important role in the transmission process. Finally, as discussed, the small sample of cases makes it difcult to examine certain exposures, particularly if these exposures are rare, as in Denmark, which has a low rate of elective cesarean delivery. Nevertheless, larger case groups may be difcult to obtain without sacricing the high-quality data from national registries.

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Through the use of well-designed and maintained national registries, we evaluated cofactors for respiratory papillomatosis during pregnancy that had not previously been examined using a longitudinal, population-based design. These exposures were collected and recorded during the hospital admission, thus eliminating the possibility of recall bias. An additional benet of registrybased data was the independent collection of exposures and outcomes, avoiding some types of information and selection biases. Identication of respiratory papillomatosis cases was not inuenced by the method of delivery or the presence or absence of a maternal history of genital warts in pregnancy. In summary, we identied a maternal history of genital warts in pregnancy as the primary risk factor for respiratory papillomatosis. Increased contact between the fetus and mother, as measured by delivery time, was associated with an increased risk of respiratory papillomatosis, supporting an intrapartum transmission of HPV. However, considering the lack of a protective effect of cesarean delivery as well as a lack of association with complications, such as prelabor rupture of membranes, or procedures, such as instrumental delivery, in utero or postnatal transmission may be more common than previously suspected. Some studies have found HPV DNA in the amniotic uid and fetal membranes,28,35,36 which may have resulted from ascending infection from the maternal genital tract through unperceived tears in the fetal membranes. Additional studies are needed with a larger series of cases to clearly describe the effect of cesarean delivery. Other important factors that may affect the risk of respiratory papillomatosis also deserve further investigation, including location and size of the genital warts lesion in pregnant women, genital warts treatments used, and HPV subtype.

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Address reprint requests to: Michael Silverberg, PhD, MPH, Johns Hopkins University, Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Room E-7137, Baltimore, MD 21205-2179; E-mail: msilverb@ jhsph.edu. Received June 10, 2002. Received in revised form September 23, 2002. Accepted November 7, 2002.

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Maternal Risk Factors for JORRP

OBSTETRICS & GYNECOLOGY