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Importance: Safety data on tetracycline antibiotic use during pregnancy are limited., Objective: To investigate the association between first trimester exposure to tetracyclines and the risk of major congenital malformations (MCMs)., Design, Setting, and Participants: This cohort study used data from nationwide registers for singleton infants live-born in Sweden from July 1, 2006, to December 31, 2018, with follow-up through December 2019. Tetracycline-exposed and unexposed infants were matched on propensity scores (ratio 1:10). Data analysis was performed from June 2023 to May 2024., Exposure: First trimester exposure to tetracyclines determined from maternal prescription fills, compared with no exposure., Main Outcomes and Measures: The primary outcome was any MCM diagnosed in the first year of life; secondary outcomes were 12 major malformation organ system subgroups and 16 individual malformations selected on the basis of prior safety signals and/or fulfillment of prespecified statistical power criteria. Malformations were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes aligned to the European Surveillance of Congenital Anomalies (EUROCAT) classification. Log binomial regression was used to estimate relative risks (RRs) with 95% CIs., Results: From a source cohort of 1 245 889 eligible infants (640 892 male [51.4%]), a propensity score-matched analytical cohort of 69 656 infants (35 903 male [51.5%]) was generated. Of 6340 infants exposed to tetracyclines during the first trimester (3325 male [52.4%]), 252 received a diagnosis of any MCM (39.75 cases per 1000 infants; 95% CI, 35.14-44.93 cases per 1000 infants) compared with 2454 of 63 316 unexposed infants (38.76 cases per 1000 infants; 95% CI, 37.27-40.30 cases per 1000 infants). Tetracycline exposure was not associated with any MCM (RR, 1.03; 95% CI, 0.90-1.16). The RRs for specific tetracycline substances were 1.07 (95% CI, 0.93-1.23) for doxycycline, 0.83 (95% CI, 0.60-1.15) for lymecycline, and 0.78 (95% CI, 0.32-1.92) for tetracycline-oxytetracycline. There was no increased risk for 10 of 12 malformation subgroups or for any of the 16 individual malformations analyzed. The higher RRs in the main analysis for nervous system anomalies (1.92; 95% CI, 0.98-3.78) and eye anomalies (1.76; 95% CI, 1.07-2.91) were attenuated in a sensitivity analysis with follow-up extended to age 3 years (nervous system anomalies, RR, 1.08; 95% CI, 0.52-2.24; eye anomalies, RR, 1.42; 95% CI, 0.88-2.29)., Conclusions and Relevance: In this cohort study, first trimester tetracycline exposure was not associated with increased risks of any MCMs. Additional studies are needed to rule out potential risks owing to power limitations for several MCM subgroups and individual malformations.

Background: In observational medication pregnancy safety studies, children are often followed from birth to 1 year of age. However, some major congenital malformations (MCM) may take longer to diagnose., Objectives: We aimed to investigate the proportion of children with detected MCMs at different lengths of follow-up and compare them to the proportion detected at 1 year after birth., Methods: This population-based register study included all singleton children liveborn in Sweden from 2006 to 2016. MCM were identified by ICD-10 codes in the Medical Birth Register and National Patient Register, aligned to the EUROCAT classification system. Cumulative proportion of children with detected MCM at birth, 90 days, 1, 2, and 3 years was calculated and compared between children born preterm and at term., Results: In 1,138,113 liveborn children, the cumulative proportion of children with a detected MCM increased from 1.9% at birth to 3.1%, 3.9%, 4.4% and 4.7% at 90 days, 1, 2, and 3 years after birth, respectively, and varied by MCM subgroup. MCMs of the eye, ear-face-neck, nervous system and genitals were detected with the longest delay, with 31%-59% more detected at 3- versus 1-year follow-up. Compared to children born at term, the proportion of children with any MCM was 2.5 times higher amongst preterm children, with a higher proportion detected over the first 90 days for most MCM subgroups., Conclusions: The proportion of children with a detected MCM varied by MCM subgroup and follow-up time. In pharmacoepidemiology studies of medication safety in pregnancy using Swedish national data, the length of child follow-up should be chosen in accordance with the expected age at detection if a specific subgroup of MCM is under investigation, for example, eye and genital MCM require longer follow-up for detection than abdominal wall and digestive system MCM. However, in most circumstances, 1 year of follow-up is sufficient., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Purpose: To present the main findings of a post-authorization safety study assessing pregnancy and infant outcomes after prenatal golimumab exposure in a real-world setting., Methods: This observational population-based cohort study included data from pregnancies ending in 2006-2018 (Finland) or 2019 (Denmark, Sweden). Infants born to women with rheumatic diseases or ulcerative colitis diagnoses were identified. Based on prescription fills from 90 days prior to pregnancy until delivery, infants were assigned to one of the four drug-exposure cohorts: golimumab, other anti-TNF biologics, other biologics, and nonbiologic systemic therapy, and the general population. Prevalence of adverse pregnancy outcomes, mortality, diagnoses of major congenital anomalies (MCA), and inpatient infections in the infants' first year of life were assessed. Odds ratios and 95% CIs were calculated for MCA and infection., Results: Among 134 infants in the golimumab cohort, none were stillborn or died in the first year of life. MCA were diagnosed in 4.5% of the infants in the golimumab cohort, versus 6.8%, 10.9%, 5.5%, and 4.6% in the other anti-TNF biologics, other biologics, nonbiologic systemic therapy and general population cohorts, respectively. Inpatient infections were diagnosed in 11% of golimumab-exposed infants, compared with 9%-11% of infants in the other cohorts. Unadjusted and selected adjusted comparisons showed no association between prenatal golimumab exposure and MCA or infection compared with the other exposure cohorts or general population., Conclusions: The number of infants with prenatal golimumab exposure was low, but results are reassuringly consistent with the evidence available for other anti-TNF biologics. Continued monitoring is needed., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths., Methods and Findings: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates., Conclusions: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MZA, JP, and EJS have performed other studies regarding antidepressants involving funding from Janssen Pharmaceutical via Phase4CPH. JP is also supervising a PhD student in the area of pregnancy outcomes and insulin funded by Novo Nordisk A/S. JTA, TF, and SMH have no relevant financial activities outside the submitted work in the past 36 months. HL and SPM are former employees of Eli Lilly and Company and are minor stockholders.

Objectives: To investigate the association between paternal use of antiepileptic drugs (AEDs) and adverse neurodevelopmental outcomes and major congenital malformations (MCM) in the offspring., Methods: Using nationwide Swedish registries, we included 1 144 795 births to 741 726 fathers without epilepsy and 4544 births to 2955 fathers with epilepsy. Of these, 2087 (45.9%) were born to fathers with epilepsy who had dispensed an AED during the conception period. Children who had both parents with epilepsy were excluded. The incidence rate of MCM, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and intellectual disability in offspring was analysed., Results: Offspring of fathers exposed to AEDs did not show an increased risk of MCM (adjusted OR 0.9, 95% CI 0.7 to 1.2), autism (adjusted HR (aHR) 0.9, 95% CI 0.5 to 1.7), ADHD (aHR 1.1, 95% CI 0.7 to 1.9) or intellectual disability (aHR 1.3, 95% CI 0.6 to 2.8) compared with offspring of fathers with epilepsy not exposed to AEDs. Among offspring of fathers with epilepsy who used valproate in monotherapy during conception, rates of autism (2.9/1000 child-years) and intellectual disability (1.4/1000 child-years) were slightly higher compared with the offspring of fathers with epilepsy who did not use AEDs during conception (2.1/1000 child-years autism, 0.9/1000 child-years intellectual disability), but in the propensity-score adjusted analyses, no statistically significant increased risk of adverse outcomes was found., Conclusions: Paternal AED use during conception is not associated with adverse outcomes in the offspring., Competing Interests: Competing interests: TT reports grants from Eisai, GSK, UCB, Bial, EU, Stockholm County Council, CURE, outside the submitted work and personal fees from Eisai, Sanofi, Sun Pharma, UCB, Sandoz., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Only few studies exist regarding the risk of a teratogenic effect of tramadol when used in early pregnancy. Using the Swedish Medical Birth Register, women (deliveries in 1997-2013) who had reported the use of tramadol in early pregnancy were identified. Maternal characteristics and concomitant drug use were analyzed. Among 1,682,846 women (1,797,678 infants), 1751 (1776 infants) had used tramadol, 96 of the infants had a congenital malformation and 70 of them were relatively severe. The adjusted odds ratio for a relatively severe malformation was 1.33 (95% CI 1.05-1.70). The odds ratios for cardiovascular defects (1.56, 95% CI 1.04-2.29) and for pes equinovarus (3.63, 95% CI 1.61-6.89) were significantly increased. The study suggests a teratogenic effect of tramadol but the risk increase is moderate., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Most previous studies have failed to demonstrate any effect of maternal use of 5-aminosalicylates (5-ASA) on malformation risk, but the number of infants studied have, in most cases, been low. The objective of the study was to get data from a large study with prospectively ascertained exposure information., Material and Methods: The study was based on data in the Swedish Medical Birth Register (1996-2011) where identification of maternal drug use is made from midwife interviews in early pregnancy. The presence of congenital malformations was ascertained from three national registers. Adjusted odds ratios were calculated by the Mantel-Haenszel methodology., Results: Among 1,552,109 women, 3651 with 3721 infants had reported the use of 5-ASAs in early pregnancy. The risk of a major malformation was increased (1.37, 95% confidence interval = 1.17-1.62) and still more for a cardiovascular defect (1.74, 1.37-2.22). This effect seemed to be influenced by concomitant use of systemic glucocorticosteroids or immunosuppressants but some confounding by indication may also exist. There was no marked difference between the four 5-ASA drugs studied., Conclusions: Infants born of women who use 5-ASA drugs in early pregnancy have an increased risk of a congenital malformation, notably a cardiovascular defect. This could be a drug effect or an effect of an active inflammatory bowel disease.

Purpose: To present concept, methods and use of a knowledge database providing assessments of potential fetal risks for all drugs on the Swedish market., Methods: Assessments of fetal risks are made primarily by analyzing prospective epidemiological data from the Swedish Medical Birth Register on drug intake in relation to birth outcome. This is complemented by evaluation of the scientific literature. Following standardized working procedures, a statement is compiled for each substance, which is also classified into one of three categories depending on the estimated risk level. The final documents include drug product names on the market, via linkage to a medicinal products register. The information is free and published on the website www.janusinfo.se . It can also be used as an integrated part of electronic health records., Results: The database covers assessments of fetal risks for close to 1,250 medicinal drug substances on the Swedish market. Each year, 96,000 searches are made, which might be compared to the around 100,000 children born in Sweden yearly. Apart from the Swedish Physicians' Desk Reference (Fass), the database is the most commonly used resource among specialists within gynaecology and perinatal medicine for information on drugs during pregnancy., Conclusions: A non-commercial knowledge base with assessments of fetal risk of different drugs is valued by health care professionals and is used extensively in Sweden. Based on analyses of national health registers, the database provides unique information on teratogenic drug risks.

Background: Earlier studies have shown that individuals with thalidomide embryopathy can have skeletal deformities, ear and eye aberrations, and facial palsy. This study aimed to survey the frequency and characteristics of facial palsy in this group of individuals., Participants: Thirty-one individuals with thalidomide embryopathy (age range, 45-47 years) and 25 healthy adults (age range, 41-56 years; mean age ± standard deviation, 49 ± 4.2 years)., Main Outcome Measures: Voluntary facial movements, lip force and three-dimensional lip motion analysis., Results and Conclusion: Four of the thalidomide embryopathy individuals (13 per cent) had congenital facial palsy. All four had eye aberrations, three had ear anomalies and one had a limb anomaly. Individuals with thalidomide embryopathy without a clinical diagnosis of facial impairment had significantly weaker lips and more restricted lip mobility than healthy controls. This study contributes to the overall knowledge of thalidomide embryopathy by adding a description of how facial expression can be affected in this condition.

Background: Concerns have been expressed about possible adverse effects of the use of antidepressant medication during pregnancy, including risk for neonatal pathology and the presence of congenital malformations., Method: Data from the Swedish Medical Birth Register (MBR) from 1 July 1995 up to 2007 were used to identify women who reported the use of antidepressants in early pregnancy or were prescribed antidepressants during pregnancy by antenatal care: a total of 14 821 women with 15 017 infants. Maternal characteristics, maternal delivery diagnoses, infant neonatal diagnoses and the presence of congenital malformations were compared with all other women who gave birth, using the Mantel-Haenszel technique and with adjustments for certain characteristics., Results: There was an association between antidepressant treatment and pre-existing diabetes and chronic hypertension but also with many pregnancy complications. Rates of induced delivery and caesarean section were increased. The preterm birth rate was increased but not that of intrauterine growth retardation. Neonatal complications were common, notably after tricyclic antidepressant (TCA) use. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) was verified. The congenital malformation rate was increased after TCAs. An association between use of paroxetine and congenital heart defects was verified and a similar effect on hypospadias was seen., Conclusions: Women using antidepressants during pregnancy and their newborns have increased pathology. It is not clear how much of this is due to drug use or underlying pathology. Use of TCAs was found to carry a higher risk than other antidepressants and paroxetine seems to be associated with a specific teratogenic property.

The effect of various antipsychotics during pregnancy has repeatedly been studied, but for most atypical antipsychotics, only little information is available. We identified from the Swedish Medical Birth Register 2908 women who had reported the use of any antipsychotic or lithium in early pregnancy and studied malformation rates with data also from the Register of Congenital Malformations and the Hospital Discharge Register. Comparisons were made with all births (n = 958,729) after adjustment for some confounders. Risks were expressed as odds ratios (ORs). Most women had used dixyrazine or prochlorperazine mainly because of nausea and vomiting in early pregnancy. Seventy-nine women had used lithium, and these outcomes are reported separately. Hence, the main analysis was restricted to 570 women (576 infants) using other antipsychotics. There was a statistically significant increase in the risk for a congenital malformation-after exclusion of some common and minor conditions, the OR was 1.52 (95% confidence interval, 1.05-2.19). Exclusion of infants exposed to anticonvulsants reduced the OR only slightly. Most of the increased risk was caused by cardiovascular defects, mainly atrium or ventricular septum defect. No certain drug specificity was found. Except for an increased risk for congenital malformations, a nearly doubling of the risk for gestational diabetes and a 40% increased risk for cesarean delivery was noted. Because there seems to be little drug specificity, it is possible that underlying pathology or unidentified confounding explains the excess risk.

Aim: To study delivery outcome including presence of infant congenital malformations after maternal use of loperamide in early pregnancy., Methods: Using the Swedish Medical Birth Register, women reporting the use of loperamide in early pregnancy were compared with other women for the period July 1, 1995-2004. Odds ratios (OR) or risk ratios (RR) were estimated after adjustment for some variables, which were associated with the use of loperamide (year of delivery, maternal age, parity, smoking, number of previous miscarriages)., Results: Characteristics of women using loperamide in early pregnancy were identified. An analysis of concomitant drug use indicated that only few of the women had inflammatory bowel disease. The risk of any congenital malformation was increased (OR = 1.43, 95% CI 1.04-1.96), based on 43 cases, but no major contributing type could be identified. The risk of hypospadias was significantly increased (RR = 3.2, 95% CI 1.3-6.6), based on seven cases. A statistically significant increase was seen also for placenta previa, large for gestational age and caesarean section., Conclusion: Maternal use of loperamide in early pregnancy may be associated with a moderate risk increase for a malformation in the infant. The finding should be evaluated from other large studies.

The use of antiepileptic drugs (AEDs) in pregnancy is associated with an increased risk of fetal malformations. Although it is known that AEDs may differ with respect to the type of malformations they can induce, earlier studies have generally lacked the power to demonstrate differences between AEDs in their overall teratogenic potential. Furthermore, there is an urgent need to assess the clinical teratogenic potential of the newer-generation AEDs. Epilepsy and pregnancy registries have been established to provide such information, which is essential for the rational management of women with epilepsy with childbearing potential. The registries also provide opportunities for additional studies of seizures observed during pregnancy and labor and, with the enrolled woman's consent, for separate studies on cognitive outcomes and pharmacogenetics. Although most are prospective, the existing registries vary somewhat in design, which needs to be considered when their results are compared. Some registries are driven by pharmaceutical companies (often compelled by national or international drug licensing agencies) and provide data on pregnancy outcome related to the sponsor's own product. Others are organized by independent research groups and are potentially more useful in that they publish comparative data. This review provides a critical discussion and comparison of important methodological aspects of AED and pregnancy registries along with a summary of results published so far.

Background: Exposure to Benzodiazepines (BZD) during foetal life has been suggested to contribute to neonatal morbidity and some congenital malformations, for example, orofacial clefts. Here we aimed to study the neonatal outcome and congenital malformations in neonates whose mothers reported use of BZD and/or hypnotic benzodiazepine receptor agonists (HBRA) during pregnancy., Methods: In the Swedish Medical Birth Register we identified 1979 infants whose mothers (n = 1944) reported use of BZD and/or HBRA in early pregnancy. An additional 401 infants were studied, born to 390 mothers who were prescribed such drugs during late pregnancy. Neonatal outcome including congenital malformations after exposure was compared with that of all births (n = 873 879)., Results: An increased risk for preterm birth and low birth weight was detected in the exposed population. The rate of relatively major congenital malformations was moderately increased among infants exposed in early pregnancy (adjusted OR = 1.24, 95%CI 1.00-1.55), not explained by known teratogenic maternal co-medication. A higher than expected number of infants with pylorostenosis or alimentary tract atresia (especially small gut) was found. This was, however, based on only seven infants for each group of malformation without association to any specific BZD or HBRA. The earlier proposed increased risk for orofacial clefts was not confirmed in our study., Conclusions: Maternal use of BZD and/or HBRA may increase the risk for preterm birth and low birth weight and cause neonatal symptoms, but does not appear to have a strong teratogenic potential. The tentative association with pylorostenosis and alimentary tract atresia needs confirmation.

Objective: To study the risk for congenital malformations among infants whose mothers used anti-asthmatic drugs during pregnancy., Materials and Methods: We studied 24,750 infants whose mothers reported the use of anti-asthmatic drugs in early pregnancy. Infants were identified from the Swedish Medical Birth Register where drug use reported at the first maternal health care visit is recorded. Congenital malformations among the infants born were identified from that register, the Swedish Register of Congenital Malformations, and the Hospital Discharge Register. Rates of malformations among infants exposed to anti-asthmatics were compared with the background population rate of malformations (4.7%) after adjustment for year of birth, maternal age, parity, smoking, and previous miscarriages., Results: A weak increase in the risk for a congenital malformation was seen (odds ratio =1.09, 95% CI=1.03-1.15) which could not be explained by the confounders studied. The risks for three specific types of malformations appeared to be increased: relatively severe cardiac defects, orofacial clefts and specifically median cleft palate, and anal atresia. For the two last mentioned groups, use of anti-asthmatics with inhaled corticosteroids showed a higher odds ratio than use of other anti-asthmatics, but the differences could be random., Conclusions: Maternal asthma and use of anti-asthmatic drugs carry no major risk for congenital malformations in the offspring, but a slight teratogenic effect cannot be excluded. It may be due to asthma, and arguments for a stronger effect of inhaled corticosteroids than of other anti-asthmatics are weak.

Background: Maternal use of selective serotonin re-uptake inhibitors (SSRIs) has recently been associated with an increased risk for certain malformations., Methods: Using the Swedish Medical Birth Register, we identified women who had reported the use of SSRIs in early pregnancy and studied their infants, born between July 1, 1995 and the end of 2004. Congenital malformations were identified from that register, from the Register of Congenital Malformations, and from the Hospital Discharge Register. The effect of drug exposure was studied after adjustment for a number of identified maternal characteristics that could act as confounders., Results: We identified 6,481 women who reported the use of SSRIs in early pregnancy and their 6,555 infants. There was no general increase in malformation risk. An increased risk for cystic kidneys was seen, but this was based on only nine malformed infants, and the pathology varied between these cases. An in-depth study of cardiovascular defects identified an association between such defects and notably ventricular and atrial septum defects and maternal use of paroxetine but not other SSRIs. No support for a postulated association between SSRI use and infant craniostenosis or omphalocele was found., Conclusions: Use of SSRIs in early pregnancy does not seem to be a major risk factor for infant malformations. The association between paroxetine use and infant cardiovascular defects may be a result of multiple testing, but is supported by other studies.

Objective: To investigate major congenital and neural crest malformations (NCM; craniofacial and conotruncal defects) in the offspring of laboratory employees., Methods: Data for 1951 females was linked to the Medical Birth Register (3003 pregnancies). Exposure information was based on questionnaires. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated., Results: The prevalence of "major malformations" were 2.3% (n = 41; exposed) and 1.9% (n = 23; unexposed). For the major malformations, solvent exposure before the third trimester gave an OR of 1.8 (CI = 1.0-2.9); "laboratory work in general," of 1.2 (CI = 0.7-2.0) unadjusted. OR for benzene use around conception/organogenesis was 5.3 (CI = 1.4-21.1) for NCM., Conclusion: No significant risk for laboratory work in general was seen, but there was an increased ratio for NCM relative to solvents, especially benzene. These results are based on small numbers and should be interpreted cautiously.

Animal studies indicate male-mediated teratogenicity for certain carcinogens/mutagens. Nevertheless, paternal occupational determinants of malformations in humans have been sparsely investigated. Data on male employees at Swedish universities from 1970 to 1989 were linked to the Medical Birth Register. The relationship between major malformations and exposure to laboratory work and to specific laboratory agents/techniques before the third trimester were analyzed using logistic regression. For major malformations, "laboratory work in general" (n = 3237) gave an adjusted odds ratio (OR) of 1.3 (95% CI = 0.8-2.1) and carcinogenic solvent use (n = 2489) of 2.0 (95% CI = 0.8-4.9) around the time of conception. For carcinogenic solvents and neural crest malformations, OR was 4.9 (95% CI =1.5-15.8). In conclusion, the prevalence of congenital malformations was not increased in offspring of males with laboratory work in general (1970-1989). Paternal work with agents such as carcinogens could, however, be of concern.

Objective: To study the association between maternal drug use in early pregnancy and orofacial cleft in the infant., Design: Register analysis based on prospectively collected information., Patients: All delivered women in Sweden July 1, 1995, through December 31, 2001., Main Outcome Measure: Presence of orofacial cleft in infant., Results: Prospective information on maternal drug use during the first trimester, as reported in early pregnancy, was studied in 1142 infants with orofacial clefts, isolated or with other malformations, excluding chromosome anomalies. Any drug use was not associated with clefts (odds ratio [OR] = 0.98, 95% confidence interval [95% CI] = 0.85 to 1.13), with isolated clefts (OR = 0.92) with isolated median cleft palate (OR = 1.03, 95% CI = 0.79 to 1.36) or with isolated cleft lip with or without cleft palate (OR = 0.86, 95% CI = 0.71 to 1.05). Reported use of multivitamins, folic acid, or B(12) was not associated with a decrease in orofacial cleft risk (OR = 1.00, 95% CI = 0.63 to 1.52). ORs above 2 were seen for some drugs: sulfasalazine, naproxen, and anticonvulsants, but only a few exposed cases occurred. An association between glucocorticoid use and infant cleft was indicated and seemed to be strongest for median cleft palate., Conclusion: Maternal drug use seems to play only a small role for the origin of orofacial clefts, at least in Sweden.

The purpose of the paper is to identify maternal drug use that may be associated with an increased risk for cardiac defects in the offspring. A case-control study was performed with cases (cardiovascular defects without known chromosome anomalies) being identified from three Swedish health registers (n=5015) and controls being all infants born in Sweden during the period 1 July 1995-2001 (n=577,730). Information on drug exposure was obtained by interview in early pregnancy. Associations between maternal drug use and infant cardiovascular defect were identified for insulin, antihypertensives, fertility drugs, erythromycin, naproxen, anticonvulsants, nitrofurantoin, clomipramine, and budesonide in nasal preparations. Some of these associations are probably due to confounding from underlying disease or complaint, some may be due to multiple testing, some may be true drug effects. Further studies are needed to verify or reject these associations.

In some countries, including Sweden, no risk is considered to exist with the use of meclozine for nausea and vomiting in pregnancy (NVP), but in other countries warnings against use during pregnancy are given. Rat tests indicate a teratogenic risk and published epidemiological studies are of restricted size. Delivery outcome was studied in 16,536 women who reported the use of meclozine in early pregnancy and was compared with all 540,660 women who gave birth. Information on drug usage was obtained prospectively in early pregnancy. Risk factors for using meclozine were young maternal age, to have had a previous child, not to smoke, to have a low body mass index. The use of some other drugs (antihypertensives, thyroxine, anticonvulsants) decreased the use of meclozine. Maternal diagnoses of preeclampsia or diabetes were less frequent when the woman had used meclozine. The twinning rate was increased and the sex distribution of the infants low (female excess). Preterm birth, low birth weight, short body length, and small head circumference occurred at a reduced rate after meclozine use, notably for boys. Also the rate of congenital malformations was reduced. If anything, delivery outcome is better than expected when the mother used meclozine. These beneficial effects are probably secondary to NVP. Meclozine can apparently be used without risk at this condition.

Background: The aim of the study was to evaluate congenital malformations and functional anomalies in the offspring of Swedish parents with thalidomide embryopathy (TE)., Methods: Sixty-four children (29 girls, 35 boys) with ages ranging from 0-18 years, born to 34 Swedish parents (14 women, 20 men) with TE, were studied. Data on malformations and dysfunction were collected from medical records at maternity and child healthcare units, delivery units, hospitals, outpatient clinics and schools., Results: Five children had both a mother and father with TE, 23 had a mother suffering from TE, and in 36 children the father had TE. One girl had a major malformation consisting of pulmonary stenosis, and single cases of minor physical features and positional deformities were observed. One boy had autism. Four children were born preterm, all to a TE mother. One child died within 24 hr after birth. Seven spontaneous abortions were registered, five of them in TE mothers. The cesarian section rate was 39% among the TE mothers, compared to 14% among the non-TE mothers., Conclusions: Malformations or functional anomalies similar to those typical for TE were not found in this group of children born to Swedish parents with TE. Cesarian sections were more frequently performed in TE mothers, partly because of pelvic and uterine malformations., (Copyright 2002 Wiley-Liss, Inc.)

A study was performed of congenital malformations in infants whose mothers used nonsteroidal anti-inflammatory drugs (NSAIDs) in early pregnancy. Data were obtained from an ongoing prospective recording of drug use during the first trimester. During the period July 1, 1995 through December 31, 1998, 2557 infants were born to women who reported the use of NSAIDs in early pregnancy. The OR (after consideration of maternal age, parity, and smoking habits) for any congenital malformation was 1.04 (95%CI 0.84-1.29), but the OR for cardiac defects reported to the Medical Birth Registry was 1.86 (1.32-2.62) based on 36 instances, and for orofacial clefts 2.61 (1.01-6.78) based on only six instances. By using other information sources, another four infants with cardiac defects were identified. There was no drug specificity for cardiac defects but among six mothers of infants with orofacial clefts, five had used naproxen.

Objectives: To evaluate the magnitude of possible fetal risks involved in maternal use of omeprazole during pregnancy., Study Design: Infants whose mothers used omeprazole during pregnancy were identified from the Swedish Medical Birth Registry. A total of 955 exposed infants born in 1995-1999 were identified: 863 of which were exposed in early pregnancy and 131 later in pregnancy and 39 who had been exposed both in early and late pregnancy. Delivery outcome was studied: presence of congenital malformations, perinatal survival, low birth weight, low Apgar score and hospitalization up to the end of 1997., Results: No clear-cut indication of ill effects were seen. Five infants were stillborn and the rate of congenital heart defects was slightly increased, but both effects may be random., Conclusions: The present dataset and previously published data give no reason for concern after exposure for omeprazole during pregnancy.

Objective: To study delivery outcome after maternal use of acid-suppressing drugs during early pregnancy., Design: Cohort study of women identified by interview in early pregnancy., Population: Sweden women giving birth from 1995 to early 1997., Methods: Comparison of infants exposed to acid-suppressing drugs with all births in 1995-1996., Main Outcome Measures: Presence of congenital malformations., Results: Proton pump blockers were used by 275 women, H2 receptor antagonists by 255 women, and both categories of drugs by 20 women. No effect of the use of omeprazole or H2-receptor antagonists on the rate of congenital malformations could be demonstrated., Conclusions: Though a teratogenic effect of these drugs cannot be completely ruled out, the individual risk after exposures during the first trimester seems to be negligible.

Parental exposure in chemical industry may represent a risk for pregnancy outcome. Using a population-based medical birth registry, linked to census for 3 years (1976, 1981, 1986), delivery outcome has been studied in women who worked as factory workers in chemical industry or whose cohabiting partners had such work. As a group of reference were used all women who worked in industry and all women whose partners worked as factory workers, respectively. No increased rate of abnormality was seen in infants fathered by men working in chemical industry. Infants born of women working in such industry showed a high rate of low birth weight and short gestational length and also of infant death. The latter phenomenon was only seen among infants born in 1976.

Women with epilepsy giving birth during 1973 to 1991 were identified by record linkage of Swedish health registries. Among 3,625 identified infants, 9 had spina bifida. A nested case-control study was performed, comparing drugs used in early pregnancy in the 9 cases and in 18 controls, matched for year of delivery, maternal age, and parity. Six of the spina bifida mothers had used carbamazepine and two had used valproic acid. Among the controls, 5 women used carbamazepine and one valproic acid. There is an apparent excess risk for spina bifida after use of either of these two drugs, but it is not statistically significant when the analysis is restricted to drug-using women. The findings support earlier reports in the literature of an association between carbamazepine and spina bifida.

A prospective ophthalmological study was done in 86 out of a total of 100 Swedes with established thalidomide embryopathy. Forty-six (54%) of all examined individuals had eye findings, which made the eye the second most commonly affected organ in thalidomide embryopathy only surpassed by upper limbs (81%). Forty-three patients (50%) had ocular motility defects, mostly incomitant strabismus. Facial palsy and abnormal lacrimation each occurred in 17 (20%) individuals. One patient had coloboma of the uvea and optic disc and another two had coloboma of the optic disc. Infrequent anomalies were microphthalmos, congenital glaucoma, lipodermoid, and large refractive errors. The observed ocular motility defects, facial palsy and abnormal lacrimation occurred with early induced defects in thalidomide embryopathy, but not with isolated late occurring anomalies. This suggests that thalidomide exerts its effects on the development of these structures early in the teratogenic period, probably mainly during the fourth week of development.

Our study of individuals with thalidomide embryopathy reaffirms many of the principles of clinical teratology concerning sensitivity of developing structures and specificity of action. It also highlights important features of ocular teratology that differ from those of other organ systems. Because malformations of the eye and associated structures do not significantly threaten the survival of the embryo, fetus, or neonate, any variation in prevalence in older individuals is not due to the nature of the ocular malformation but may be significantly modified by "the company they keep," the systemic malformations occurring at the same time as the original insult, whether it be an environmental, a genetic, or a local disturbance. Additionally, the presence of clusters of malformations caused by a teratogen at a specific time supports the concept of a common pathogenic mechanism and provides suggested avenues for further research into the cause of these malformations.

Abnormalities (dysmorphism, mental retardation etc) were reported (The Lancet 1987; i: 108-9) in children of mothers using high doses of benzodiazepines regularly during pregnancy in the area of Sweden with the highest use of benzodiazepines (Gothenburg). This signal was investigated in Sweden by use of available drug data bases, and in the USA by use of computerized health care data in Medicaid, including drugs and diagnoses. Neither the Swedish survey, nor the preliminary analysis of the pediatric profiles in the US-Medicaid population supported the occurrence of drug-associated abnormalities as described in The Lancet. Also, no significant findings were seen in a survey in Czechoslovakia on behavioural changes in children, whose mothers used diazepam during the second part of their pregnancy. Although available pharmacoepidemiology data do not confirm the hypothesis, this review points to existing geographic differences in use of benzodiazepines during pregnancy (frequency of chronic use and dosage level) and their potential clinical consequences. (Fig. 1, Ref. 25).

A summary is given of experiences in the use of the Swedish registries of birth defects for causal epidemiological studies. Case-control studies and cohort studies are described and exemplified. The application of case-control techniques to cohorts of women selected for probable or possible exposure is also described. The importance of using large-scale registry studies in the search for common but low-risk teratogens is stressed.

Prescription data have been analysed in order to study drug exposure of women before, during and after pregnancy as compared to non-pregnant controls. During full term pregnancy (n = 341) drug exposure increased markedly, mostly due to prescription of drugs such as iron and vitamins. Excluding these drugs, the increase was statistically significant only for one third of the women whose case records revealed some intercurrent disease during pregnancy. Women whose pregnancy ended in a spontaneous abortion (n = 29) did not differ significantly from controls in terms of drug exposure before, during or after pregnancy. In an induced abortion group (n = 60), drug exposure was more pronounced before pregnancy than in the other pregnant patients or controls. On comparing the drug history obtained from delivery records with that obtained in this study it was found that only diuretics and urinary tract chemotherapeutics had been noted fairly consistently in the former records.

By record-linkage of the 1975 Swedish census and the Medical Birth Register of infants born in 1976, 1,161 infants were identified who were born to women coded as laboratory workers in the census. These infants were compared to all 98,354 infants born in Sweden in 1976. There was a higher than expected number of infants who died neonatally and/or had congenital malformations. Twenty-six singleton infants who either died or had serious malformations were selected for further study. To each of the cases, 2 controls were selected among the 1,161 infants. A questionnaire was sent to the 26 cases and 50 controls (2 cases had only 1 control each) asking about work during pregnancy. No specific type of laboratory work was found to be more common among the cases than controls.

A questionnaire on pregnancy outcome was distributed to 782 women engaged in laboratory work at some time between 1968 and 1979. The response rate was 95%. Reported data on miscarriages, malformations and birth weights were compared to data in hospital records and central registers. Twelve per cent of the reported miscarriages could not be verified. Work with solvents was more frequently reported for these miscarriages as compared to those which could be verified or those which were anamnestically recorded. Fifty per cent of the malformations reported in the questionnaires were also found in registers or hospital records. Regarding birth weights, 28% of the infants had different birth weights reported in questionnaires than were found recorded in the Swedish Medical Birth Register. It is suggested that questionnaire data should be completed with information from sources having a higher validity when the influence of environmental factors on pregnancy outcome is studied.

We describe a material of 577 infants born of epileptic women treated with anticonvulsants in monotherapy during early pregnancy and collected from France, Italy, and Sweden. The incidence of major malformations is increased compared with the general population but no definite difference in risk can be demonstrated between the various anticonvulsants, but valproic acid was associated with a doubling of the average risk. The increased risk for facial clefts and for cardiac malformations, described from most studies on epilepsy during pregnancy, cannot be seen in this material. Unusually many cases of penis abnormalities (micropenis, hypospadias) were noted. An effect on fetal growth can be demonstrated and is apparently more pronounced for carbamazepine than for the other drugs. It results in a reduced birth weight in spite of normal gestational length, reduced body length and head circumference. The possible biological significance of this finding is discussed.

Retrospective studies, performed in 6 hospitals in Sweden, demonstrated that severe congenital malformations occurred more frequently in neonates born to mothers who used hexachlorophene soaps, 10--60 times a day by handwashing and hand-creams during at least the first trimester of pregnancy (25 severe malformations in 460 neonates), when compared to neonates born to similarly employed mothers who did not use hexachlorophene soaps (0 severe malformations in 233 neonates). Minor congenital anomalies were also more commonly noted in the hexachlorophene-exposed group when contrasted with controls. Other known adverse influences, such as age, infections during pregnancy, other drug usage, or smoking habits did not appear different in the two groups.

Clustering of malformations and especially of spina bifida in Sweden was studied using the Register of Malformations and the Medical Birth Records Register. The incentive to this study was provided by the observation of a cluster of malformations, notably spina bifida, and perinatal deaths, locally thought to be related to the use of herbicides in forestry. This cluster was verified but it was shown that a high rate of spina bifida existed in the region before the introduction of herbicides in forestry. Some other clusters of spina bifida were identified and also a number of clusters of other malformations. Case-history studies were performed but revealed no lead to an explanation. Principles in the origin of the clusters and their analysis are discussed.

Results froma prospective study in Malmö performed in 1963-65 are used to discuss the possible role of hormonal drugs in human fetal maldevelopment. Appr. 2 per cent of all women had a child born were treated with gestagens during early pregnancy and slightly more had used Primodos as a pregnancy test. No harmful effect on embryonic development can be demonstrated.

The thalidomide catastrophy in the early 1960th clearly demonstrated the need of accurate epidemiological data of birth defects. Since 1963 there is in Sweden like in many other countries a continuous registration of congenital malformations in order to provide data for the early detection of changes in frequencies or patterns of defects and thus also to facilitate early identification of new environmental teratogens. During the more than 20 years period the Swedish register has been in operation an increase in the incidence of certain malformations such as omphalocele, hypospadia and Down's syndrome in the offspring of young mothers has been observed. Despite rather extensive studies no explanation for these changes has so far been found. Due to the great concern in the public about the relation between environmental factors and the occurrence of congenital malformations it is of great importance that the register can be used to elucidate the situation when there has been a suspicion of increased teratogenic risks in certain areas of Sweden or when pregnant women have special working conditions. The rate of malformations has been found to be higher among infants born to women coded as laboratory technicians than in the rest of the Swedish population. So far, no specific teratogenic factor has been identified. In Sweden no relation has been found between the incidence of congenital malformations and socioeconomic conditions. The incidence of neural tube defects has been found to be higher than expected in a count in Western Sweden.(ABSTRACT TRUNCATED AT 250 WORDS)

A study was made of the delivery outcome in women working in medical occupations in Sweden. One cohort of approximately 1500 women who worked in 31 hospitals for chronic diseases during the period 1965-1975 and who gave birth during those years was studied. Also all women working in medical occupations and delivered during the years 1973-1975 were investigated by matching existing data registers. It was found that caesarian sections and vacuum extractions were used more frequently than expected. A significantly increased perinatal death rate was noted in 1973, but could not be related to any specific occupational exposure known to represent an increased risk. No general increase in malformation rate was seen, but a local cluster, occuring at certain hospitals in the Gothenburg area in 1973-1974 was identified. No support was obtained for the hypothesis that the use of soap containing hexachlorophene is associated with an increased risk of perinatal death or malformation.

Strategies in dealing with data obtained from malformation monitoring based on experiences with the Swedish monitoring systems, operating since 1965 (Register of Congenital Malformations) and 1973 (Medical Birth Register) are discussed. The importance of checking data that have sounded an alarm is stressed. Experience has shown that false alarms due to artefacts, such as changed diagnostic routines, changed reporting or registration of malformations, or random fluctuations, comprise most suspected changes in incidence. If a true increase in malformation frequency or a local cluster is observed, a hint of possible aetiological factors can be obtained from studies of maternal age distribution, seasonal viriation, geographical distribution, etc. The last step of the analysis consists of a case-control or a cohort study, aimed at revealing a specific teratogen. The importance of locating limited research resources to well-defined problems using high quality data is stressed.

Pregnancy outcome was studied in three parishes situated around a chemical factory from which air and water pollution was considered to have occurred. Data on health variables were mainly obtained from registries supplemented with hospital record information. No definite reproductive hazards could be demonstrated but an unusually high perinatal death rate among twins born in the area was noticed. The paper discusses principles involved in the design of a study of this type.