1 Department of Clinical Epidemiology, Aarhus and Aalborg University Hospitals, DK-8000 Aarhus C, Denmark; 2 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, 90110 Thailand; 3 Department of Clinical Microbiology, Aalborg Hospital, DK-9000 Aalborg, Denmark
Received 23 May 2003; returned 8 July 2003; revised 6 August 2003; accepted 7 August 2003
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Abstract |
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Methods: The association between use of sulfamethizole and adverse birth and neonatal outcome was investigated in a casecontrol and a cohort study in Denmark. We used data from the Prescription Database, the Birth Registry and the Hospital Discharge Registry in North Jutland County to study any association between sulfamethizole use and first recorded miscarriage. The cohort analysis included 3484 women who received a prescription for sulfamethizole from 30 days before conception to date of delivery, and 60 175 women who did not use a sulphonamide-containing drug during pregnancy or 30 days before conception. The casecontrol analysis included 3347 women who had a miscarriage, of whom 90 had taken sulfamethizole, and 22 599 primiparous controls who had a live birth.
Results: Among women who received prescriptions for sulfamethizole, adjusted odds ratios and 95% confidence intervals for adverse birth outcome were: malformation 1.17 (0.951.43); low birth weight 0.69 (0.490.98); pre-term birth 1.12 (0.971.30); stillbirth 1.02 (0.611.68); neonatal jaundice 1.14 (0.383.46); and for receiving a prescription for sulfamethizole within 1 week before miscarriage 1.66 (0.922.99).
Conclusions: We found no increased risk of congenital malformation, stillbirth or pre-term birth, and no association between use of sulfamethizole late in pregnancy and risk of neonatal jaundice. There was an increased risk of miscarriage after exposure to sulfamethizole during the week before miscarriage, but further studies are needed to evaluate whether this increased risk is causal.
Keywords: malformation, pre-term delivery, low birth weight, miscarriage
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Introduction |
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Materials and methods |
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We conducted our research in the Danish County of North Jutland (population 490 000). The study included data on all women who had a live birth or a stillbirth after the 28th week of gestation, or who had a miscarriage (including missed abortion), between 1991 and 2001. The data were obtained from the Danish Medical Birth Registry and the countys Hospital Discharge Registry. The risk of adverse birth outcome (congenital malformation, low birth weight, pre-term birth, stillbirth and jaundice) was examined in a cohort analysis, and the risk of miscarriage was examined in a casecontrol analysis.11
Use of sulfamethizole
Women prescribed sulfamethizole were identified through the population-based North Jutland Pharmaco-Epidemiological Prescription Database.12 The database was initiated on 1 January 1989, with complete coverage from 1 January 1991. It covers all prescriptions made by general practitioners (GPs) and hospitals in the county. North Jutland is served by pharmacies equipped with electronic accounting systems that are used primarily to secure reimbursement from the National Health Service. The health service provides tax-supported healthcare for all inhabitants in Denmark, i.e. 50% of all expenditure on a wide range of prescribed drugs, including sulfamethizole, and sulfamethizole is only available on prescription. Information including the customers civil registration number, the type of drug prescribed according to the Anatomical Therapeutical Chemical classification system, and the date of dispensing the drug is transferred from the pharmacies to the Prescription Database.
Outcome data
The Danish Medical Birth Registry. The Danish Medical Birth Registry contains computerized records of all births in Denmark since 1 January 1973.13 Data are recorded by the midwives or the doctors responsible for the deliveries. The main variables in the registry include maternal age, parity, birth weight, gestational age, maternal smoking status and data about delivery.
The County Hospital Discharge Registry. The data on miscarriages, malformations and neonatal jaundice were obtained from the County Hospital Discharge Registry,14 from which data are transferred to the national Danish Hospital Discharge Registry. The national registry comprises data on 99.4% of all discharges from Danish hospitals and includes civil registration number, dates of admission and discharge, the surgical procedure(s) performed and up to 20 discharge diagnoses, classified according to the Danish version of the International Classification of Diseases (ICD), 8th revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter. The registry does not cover contacts with GPs.
All congenital malformations were recorded at birth or during the first year of age. The codes for congenital malformation were 740759 in ICD-8, and Q00Q99 in ICD-10. Congenital dislocation of the hip and undescended testes were excluded due to expected poor validity of these diagnoses.15 Data on jaundice of the newborn were included in the analysis only if the diagnosis was made within 14 days after birth. The codes for neonatal jaundice were 774, 775, 778.91 and 778.99 in ICD-8, and P5759 in ICD-10. The ICD-8 and ICD-10 codes for miscarriage were 634.61, 643.89, 645.1 and O02, and O03, respectively.
Record linkage between prescription and outcome data
A 10-digit civil registration number is assigned to all Danish citizens shortly after birth by the Central Office of Civil Registration, and this was used to link the exposure and outcome data.
Study design
Cohort analysis. The association between use of sulfamethizole and adverse birth and neonatal outcome was studied in the cohort of women who had a live birth or a stillbirth after the 28th week of gestation. Women who used sulfamethizole were classified into three groups according to the time at which they were exposed. (i) The early pregnancy group comprised women who received a prescription from 30 days before conception until the end of the first trimester. (ii) The entire pregnancy group comprised women who received prescriptions at any time during pregnancy. (iii) To study the association with neonatal outcome, separate analyses were conducted in a third group of women, the late pregnancy group, who received a prescription within either 14 or 30 days before delivery. Non-exposed control women were all women in the study group who did not take up a prescription for sulfamethizole or any sulphonamide-containing drug during the preconceptual and pregnancy period.
Casecontrol analysis. We used a casecontrol design to study the association between redeeming a prescription for sulfamethizole and first recorded miscarriage. Cases were defined as women with a first lifetime recorded miscarriage between 1 January 1991 and 31 December 2000, and no previous birth noted. The control group comprised primiparous women who had a live birth during the same period.
Any imbalance in gestational age between cases and controls might introduce bias and the optimal design was to stratify or match on gestational age. In the birth registry, we had data on gestational age for the controls, but in the hospital discharge registry, gestational age was not recorded. Therefore, we drew 100 random cases with miscarriages from the registry and reviewed their medical paper records in order to determine their gestational age. We assumed that the distribution of their gestational age was representative for the distribution among all cases. The controls were then selected by stratified sampling based on this gestational age distribution. For example, we found that 1% of miscarriages occurred at a gestational age of 4 weeks, so in this study we examined sulfamethizole exposure before week four of gestation in 1% of the controls.
Sulfamethizole exposure was determined as redemption of a prescription for sulfamethizole during the 12 weeks before the miscarriage (cases) or the assigned week of pregnancy (controls).
Statistical analysis
Cohort analysis. We performed logistic regression to estimate the risk of malformation, low birthweight (<2500 g), pre-term birth (<37 weeks), stillbirth and jaundice in children born to mothers who redeemed a prescription for sulfamethizole compared with other pregnant women. We adjusted for maternal smoking status (smoker or non-smoker), parity and maternal age (<25, 2530 and >30 years), and for neonatal jaundice we also adjusted for gestational age, using design variables. Only full-term births were included in the analysis of low birthweight.
Casecontrol analysis. We performed logistic regression analyses to estimate the relative risk of miscarriage associated with sulfamethizole exposure. Since high maternal age and previous miscarriage are risk factors for miscarriage, we limited the analysis to first lifetime miscarriage and adjusted for maternal age.11 We also adjusted for one or more prescriptions for anti-diabetic agents and prescription for anti-epileptics, since diabetes and epilepsy are risk factors for birth defects and probably fetal loss. We assessed exposure during four different gestational periods (1st, 2nd3rd, 4th7th, 8th12th weeks) before the day of discharge after the miscarriage and the corresponding day in controls. All risk estimates were presented with 95% confidence intervals (CI), and the analyses were performed with the SAS System, v. 8.2.
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Results |
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A total of 3484 women who had a live birth or stillbirth after the 28th week of gestation received 4004 prescriptions for sulfamethizole. A total of 2173 women received prescriptions during the first trimester or 30 days before, 105 women in the last 30 days of their pregnancy and 40 within the 14 days before delivery (Table 1). There were no substantial differences in study variables between the women who received a prescription for sulfamethizole and those who did not.
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Casecontrol study
Among 3347 cases of miscarriage, 90 were exposed to sulfamethizole within the 12 weeks before hospitalization, and among the 22 599 primiparous women who had a live birth, 624 were exposed to sulfamethizole (Table 3). There was a higher proportion of women over 30 years of age in the miscarriage group, but no differences in the prevalence of diabetes or epilepsy. Table 4 shows the OR for miscarriage compared with pregnancies resulting in a live birth in women who received a prescription for sulfamethizole. The adjusted OR was 1.66 (95% CI 0.932.98) for women exposed within the week before miscarriage. For women exposed more than 1 week before miscarriage, the ratios were close to 1.
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Discussion |
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Since the registration of prescriptions and birth outcome is complete and independent, we did not expect selection bias or differential information bias, but our study design did not allow us to identify malformation detected at prenatal examinations that led to subsequent elective abortion. The hospital discharge registry does not cover women are seen by their GP. The vast majority of Danish women with a miscarriage are hospitalized; however, it is possible that we have missed some very early cases.
In the casecontrol study, the exposure data were recorded routinely and were independent of the diagnosis; thus, there was no risk of recall bias. Because of our reliance on prescription information, we do not know whether the women actually took the drugs prescribed. However, as the patients were required to pay part of the costs, misclassification due to non-compliance was probably limited.
The data on congenital malformation obtained from the Hospital Discharge Registry are regarded as acceptable for general surveillance and epidemiological research. A recent study from our dataset in the County of North Jutland has estimated that the predictive value and completeness of data on congenital abnormalities in the Hospital Discharge Registry are 88.2% (range 85.990.5%) and 89.9% (range 87.792.1%), respectively.15 Any misclassification of discharge diagnoses is probably unrelated to exposure to sulfamethizole.
Data about potential confounders, such as maternal smoking status, parity and maternal age, were available in the cohort study. Smoking is a risk factor for spontaneous abortion,16 but we were unable to adjust for smoking in our casecontrol analysis because we did not know the smoking status of the women with miscarriage. However, there was no major difference in the prevalence of cigarette smoking between the different groups in the cohort study. If sulfamethizole was a teratogen, it would probably cause a few specific malformations and not increase the risk of malformation in general.17 Thus, a large number of these specific malformations would be needed to give a significant increase in congenital malformation overall. This study had somewhat limited statistical power, but there was no trend in the distribution of congenital malformation that would suggest a causal association.
Sulfamethizole is widely used in women of childbearing age in Denmark, but, because of the risk of neonatal jaundice, it is not recommended in the ninth month of pregnancy.4 Our epidemiological findings do not provide major evidence for this recommendation, and further data are needed to obtain a higher precision in the calculation of the risk estimates.
Our study suggested an increased risk of miscarriage after exposure to sulfamethizole during the week before miscarriage. This association of sulfamethizole with miscarriage may reflect confounding by indication, since urinary tract infection is associated with premature labour,18 and this might also be associated with miscarriage. It is also possible that the symptoms of miscarriage were erroneously interpreted as symptoms of a urinary tract infection and, thus, given antibiotic treatment. Further studies are needed to evaluate whether this suggested increased risk of miscarriage is causal or due to confounding or chance.
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Acknowledgements |
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Footnotes |
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References |
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