Objective
The objective of the investigation was to study the possible association between uterus uni- or bicornis in pregnant women and structural birth defects (ie, congenital abnormalities) in their offspring.
Study Design
There were 22,843 cases with congenital abnormality recorded in the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. These subjects were matched to 38,151 controls without any defect. Prevalence of medically recorded uterus uni/bicornis in the prenatal maternity logbook in the mothers of subjects with different congenital abnormalities and of their matched controls without any defect were compared.
Results
Fifty-seven (0.25%) subjects and 67 (0.18%) controls had mothers with uterus uni/bicornis. There was a significant association of uterus uni/bicornis in pregnant women with a higher risk of total group of congenital abnormalities (adjusted odds ratio, 1.5; 95% confidence interval, 1.1–2.2) explained mainly by a significantly higher risk of clubfoot and particularly postural deformity association in their children (adjusted odds ratio, 4.7; 95% confidence interval, 2.4–9.1).
Conclusion
Pregnant women with a uni/bicornis uterus have a significantly higher risk of clubfoot and postural deformity association.
Structural birth defects (ie, congenital abnormalities of uterus, such as uterus uni- or bicornis [uni/bicornis]) in pregnant women are associated with a higher risk of miscarriages and preterm births. However, the possible association of uterus uni/bicornis in pregnant women with the risk of different congenital abnormalities in their children has not been reported often in the literature. Thus, the aim of the study is to assess the impact of uterus uni/bicornis in pregnant women on risk of different congenital abnormalities in their offspring.
Materials and Methods
The study was based on the comparison of prevalence of uterus uni/bicornis as exposure in the mothers of cases affected with congenital abnormalities and controls without congenital abnormality in the database of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
Cases with congenital abnormalities were selected from the Hungarian Congenital Abnormality Registry for the HCCSCA. The report of cases with congenital abnormality is mandatory for physicians from birth until the first birthday and most congenital abnormalities are reported by obstetricians or pediatricians. Autopsies were obligatory for all infant deaths and was usually (about 80%) performed on stillborn fetuses during the study period. Pathologists sent a copy of the autopsy report to the registry if defects were identified in stillborn fetuses or infant deaths. Fetal defects diagnosed by prenatal diagnostic centers with or without elective termination of pregnancy have also been reported to the Hungarian Congenital Abnormality Registry since 1984.
Two main categories of cases with congenital abnormalities were differentiated: isolated (only 1 organ is affected) and multiple (concurrence of 2 or more abnormalities affecting at least 2 different organ systems) congenital abnormalities. The total (birth plus fetal) prevalence of cases with congenital abnormalities diagnosed from the second trimester of pregnancy through the age of 1 year was 35 per 1000 informative offspring (ie, live-born infants, stillborn fetuses, and electively terminated malformed fetuses) in the Hungarian Congenital Abnormality Registry, 1980-1996, and about 90% of major congenital abnormalities were recorded during the 17 years of the study period.
Three exclusion criteria were used in the selection of cases with congenital abnormality from the Registry to the HCCSCA: (1) cases reported after 3 months of birth or elective termination of pregnancy (23% of the total, including mainly mild congenital abnormalities), in addition to cases (2) with 3 mild congenital abnormalities as congenital dysplasia of the hip based on Ortolani click, congenital inguinal hernia, major hemangioma, and (3) with congenital abnormality–syndromes caused by major gene mutations or chromosomal aberrations (with preconceptional origin) were excluded.
Controls were identified from the National Birth Registry of the Central Statistical Office for the HCCSCA on the basis of the list of cases with different congenital abnormalities in the Hungarian Congenital Abnormality Registry, and this list was provided for the coworkers of National Birth Registry by the coworker of the HCCSCA as a part of contract between these 2 institutions. Controls were defined as newborn infants without congenital abnormality and in general two controls were matched with every case according to sex, birth week in the year when cases were born, and district of parents’ residence. The name and address of these control mothers were sent to the coworkers of the HCCSCA.
Exposure and confounding data were obtained from 3 sources. The first is medically recorded prospective data. Mothers of cases and controls were asked in a mailed explanatory letter to send us their prenatal maternity log book and other medical records (mainly discharge summaries of their deliveries) regarding their diseases and related treatments during the study pregnancy and their child’s congenital abnormality. During the study period, prenatal care was provided to all pregnant women. The first visit was between the 6th and 12th gestational weeks. The task of obstetricians was to record all pregnancy complications, maternal diseases, and related drug prescriptions in the prenatal maternity logbook.
The second is retrospective maternal information. A structured questionnaire together with a list of diseases and drugs and a printed informed consent was also mailed to the mothers immediately after the selection of cases and controls. To standardize the answers, mothers were asked to read the enclosed list of diseases and medications as a memory aid before replying. Mothers were asked to sign an informed consent, which authorized us to record the name and address of their children in the HCCSCA. The period between birth or elective termination of pregnancy and return of information package (questionnaire, logbook, informed consent, etc) in our prepaid envelop was 3.5 ± 1.2 and 5.2 ± 2.9 months for cases and controls, respectively.
The third is supplementary data collection. Regional nurses were asked to visit all nonrespondent mothers of cases at home, to help mothers to fill in the same questionnaire, and to evaluate available medical documents. In addition, nurses were asked to obtain data regarding lifestyle (smoking, drinking, illicit drug use) through a personal interview of the male partner and/or other close relatives of mothers living together. The data about lifestyle were collected only in this subsample visited at home because of the unreliability of retrospective maternal information. Nurses visited 200 nonrespondent and 600 respondent control mothers as part of 2 validation studies because the ethics committee considered that this follow-up would be disturbing to the parents of healthy children. Regional nurses used the same method in these control mothers as in nonrespondent case mothers.
Thus, data were collected for 96.3% of cases (84.4% from reply, 11.9% from visit) and 83.0% of controls (81.3% from reply, 1.7% from visit). Informed consent was signed and returned by 98.4% of mothers.
The procedure for data collection changed in 1997 because regional nurses visited and questioned the mothers of all cases and controls. However, data from 1997 onward have not been validated at the time of this analysis; thus, only the data set of the 17 years between 1980 and 1996 are evaluated here.
Congenital abnormalities of uterus have a number of anatomical manifestations. This study evaluates only isolated uterus unicornis or bicornis (with both uni- or bicollis and uterus didelphys or uterus duplex) with or without vaginal congenital abnormality. Pregnant women with uterus arcuatus and uterus septate/septus-subseptus and syndromic uterus congenital abnormalities (eg, Müllerian duct and renal agenesis and cervical thoracic somatic dysplasia association) were excluded. Pregnant women with uterus uni/bicornis were evaluated based on prospective physician-recorded diagnoses in the prenatal maternity logbook.
Statistical analysis
The software package SAS version 8.02 (SAS Institute Inc, Cary, NC) was used. First, the characteristics of pregnant women with or without uterus uni/bicornis (the latter as reference) were compared using Student t test for quantitative and χ 2 statistics or odds ratios (ORs) with 95% confidence interval (CI) for categorical variables. The prevalence of uterus uni/bicornis in mothers who had cases with different congenital abnormality groups was compared with the frequency of uterus uni/bicornis in the mothers of all matched controls, and adjusted OR with 95% CI were evaluated in a conditional logistic regression model.
Potential confounding factors included in the statistical analyses were maternal age, birth and pregnancy order, marital and employment status (as indicator of socioeconomic status because it correlated well with the level of education and income ), maternal diseases, and related drug treatments and the use of pregnancy supplements (mainly folic acid).
Results
Of 22,843 cases, 57 (0.25%) had mothers with uterus uni/bicornis. Of these 57 cases, 37 had mothers with uterus bicornis, whereas 20 cases were born to mothers with uterus unicornis. The method of diagnoses (hysteroscopic or hysterosalpingographic examinations) was recorded in 27 women with uterus bicornis and 10 mothers with uterus unicornis, whereas the diagnostic method was not mentioned in the other 20 pregnant women. Among 38,151 controls, 67 (0.18%) were born to mothers with uterus uni/bicornis. Of these 67 controls, 40 had mothers with uterus bicornis, whereas 27 controls were born to mothers with uterus unicornis. The diagnosis of uterus bicornis and unicornis was based on the previously mentioned imaging techniques in 32 and 13 control mothers, respectively, whereas the remaining 22 pregnant women had no description of the diagnostic methods. However, it is necessary to mention that there was no request regarding the diagnostic method of uterus uni/bicornis in the prenatal maternity logbook.
The maternal characteristics of case and control mothers with uterus uni/bicornis and without uterus uni/bicornis as reference are shown in Table 1 . The mean maternal age was somewhat higher, whereas their mean birth order was lower in the groups of mothers with uterus uni/bicornis. However, the mean pregnancy order (including previous births and miscarriages) was nearly similar in the study groups. A greater difference (0.5) between mean birth and pregnancy order in case and control mothers with uterus uni/bicornis indicates a higher rate of previous fetal loss (ie, miscarriages) than in the previous pregnancies of case and control mothers without uterus uni/bicornis (0.2). The proportion of professional and managerial women was higher in pregnant women with uterus uni/bicornis, particularly in control mothers.
