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Monitoring of maternal drug use and infant congenital malformations. Does loratadine cause hypospadias?
Abstract
The Swedish Medical Birth Registry was used for the monitoring of maternal drug usage in early pregnancy and the occurrence of congenital malformations in infants. An association between maternal use of the anti-allergic drug loratadine and infant hypospadias was noticed. Continued monitoring suggested that this was probably not a chance phenomenon, but a biological mechanism which could explain the association is unknown. Comparisons with the outcome after exposure for other anti-allergic drugs suggested a drug specificity.
... Loratadine is a non-sedating antihistamine commonly used for seasonal allergies [18]. In 2001, a report from Sweden suggested an association between maternal use of loratadine and infant hypospadias [19]. Having considered year of birth, maternal age, and parity, the odds ratio (OR) for hypospadias in relation to loratadine exposure was 2.39 (95% confidence interval [CI]: 1.43-3.38). ...
... (95% confidence interval [CI]: 1.43-3.38). The study also compared the occurrence of hypospadias after the use of other antihistamines. The OR for having a diagnosis of hypospadias in the Swedish Medical Birth Registry (MBR) after maternal use of loratadine compared with maternal use of other antiallergic anti-histamines was 4.0 (95% CI:1.42-12.9) [19]. Neither a recent study from Israel including 210 pregnant women exposed to loratadine [20] nor a study that used data from four countries and included 161 pregnant women exposed to loratadine [21] found an increased risk of hypospadias. However, these studies had limited power and due to the low prevalence of hypospadias not one case c ...
... In fact, the risk point estimates for hypospadias were higher with maternal exposure to other antihistamines compared with loratadine. Thus, our risk estimates do not corroborate the findings in the Swedish study [19] that initiated the hypospadias debate. However our risk estimates had limited statistical precision and an effect similar to that in the Swedish study cannot be ruled out entirely. ...
To examine the risk of hypospadias after exposure to loratadine and other antihistamines during pregnancy, we conducted a population-based case-control study in four Danish counties, which account for 30% of the Danish population (approximately 1.6 M). We obtained data on maternal use of antihistamines from prescription databases, and data on birth outcomes from the Danish Medical Birth Registry (MBR) and the Hospital Discharge Registry (HDR). A total of 65,383 male births with a full prescription history of the mother in the study period from 1989-2002 were available for analysis. Within this cohort, we identified cases with a diagnosis of hypospadias, and 10 selected controls per case without such a diagnosis (matched on birth month, gender and year of birth). We identified 227 cases of hypospadias recorded in the HDR within six months postpartum and 2270 controls. One case (0.4%) and eight (0.4%) controls were exposed to loratadine in the first trimester and up to 30 days before the time of conception. The adjusted odds ratio (OR) for hypospadias among users of loratadine relative to non-users was 1.4 (95% CI: 0.2-11.2) and the corresponding OR for other antihistamines was 1.9 (95% CI: 0.7-5.7). In this study, maternal exposure to loratadine did not appear to be associated with an increased risk of hypospadias when compared with other antihistamines, although it should be noted that the statistical precision of the risk estimates might be limited.
... Congenital malformations in infants were identified with the use of three nationwide registers: the Medical Birth Register, the Congenital Malformation Register, and the Hospital Discharge Register (up to 2006) [11]. Beginning in 1994, maternal use of drugs during pregnancy has been registered [12]. This information is based on the midwife interview at the first antenatal visit (90% of women attend before week 12) and therefore mainly refers to first trimester exposure. ...
... This information is based on the midwife interview at the first antenatal visit (90% of women attend before week 12) and therefore mainly refers to first trimester exposure. Information on drugs prescribed for antenatal care during the whole pregnancy [12] is also available. All types of drugs are recorded, including prescription, over-the-counter, herbal, and homeopathic drugs. ...
To investigate the association between maternal use of antihypertensives in early pregnancy and delivery outcome, notably infant congenital malformations.
A cohort study of 1,418 women who had used antihypertensive drugs in early pregnancy but had no diabetes diagnosis were identified from the Swedish Medical Birth Register.
There was an excess risk for placental abruption, caesarean section, delivery induction, and post-delivery hemorrhage in women taking hypertensives. Infants were more often than expected born preterm, were small for gestational age, and had an excess of various neonatal symptoms. Cardiovascular defects occurred with an adjusted odds ratio of 2.59 (95% CI 1.92-3.51). The results were similar when the woman had used ACE inhibitors or other antihypertensives, notably beta blockers. Stillbirth rate was increased (risk ratio 1.87, 95% CI 1.02-3.02), again without any clear drug specificity.
There seems to be little drug specificity in the association between maternal use of antihypertensives and an increased risk for infant cardiovascular defects.
... In a recent issue of International Journal of Medical Sciences, a study was published based on a prescription register in Denmark which indicated an absence of an association between maternal use of loratadine and an increased risk for hypospadias in the offspring [1]. The reason for that study was a report we wrote [2] which described a system for an ongoing monitoring of maternal drug use and infant congenital malformations. As an example we presented the finding that maternal use of loratadine in early pregnancy was associated with a roughly doubled risk for infant hypospadias. ...
... Our study is – like our previous study -based on the nationwide Swedish Medical Birth Register which contains information on maternal use of drug as reported and registered in early pregnancy [2, 8]. This information is based on interviews performed by midwifes and the system has been working since July 1, 1994 which makes it possible to collect a large number of pregnancies where the women used a drug (prescription or over-the counter) and to study offspring for various characteristics, including congenital malformations. ...
The original report published in 2001 on a possible association between maternal use of loratadine and an increased risk of infant hypospadias, based on data in the Swedish Medical Birth Register 1995-2001, has been followed up by continued surveillance in the same register. The original "signal" was based on 15 infants with hypospadias among 2780 loratadine-exposed infants born, representing an adjusted odd ratio of about 2.3, statistically significant. Since then another 10 cases have been identified, and 12.5 expected. For the period 2001-2004, another 1911 loratadine-exposed infants have been identified and only two had hypospadias (4 expected). Our present position is that the primary finding was a "signal" which had occurred by chance and the follow-up agrees with independent studies which indicate an absence of an association. This illustrates the care with which apparent statistically significant increases have to be handled when no prior hypothesis exists.
... A collection of severe congenital neural system malformations known as NTDs are caused by the failure of closing of the neural tube during neurulation (19), the curving of the neck, especially at E15 treated with 0.2 mg/kg of Dexamethasone , which forms spherical-shaped embryos, and the curvature of the head toward the chest of embryo , the nervous system malfunction was used to explain the deformities in the head region, and this was confirmed by (20). This study also described how dexamethasone treatment during pregnancy altered the development of synapses in the central nervous system (21). ...
Current study includes an investigation of the effects of Dexamethasone (Dex) drug on neural tube development. A total of 60 pregnant mice were allocated into four groups at random, with 15 mice each group, While the control group received injections of a Normal Saline 0.9 %, each group's members were given a specified dose of Dexamethasone drug and at different times. All of the animals received their doses through tail intravenous injection at a specific periods of pregnancy then the embryos isolated at specific embryonic days . The results of various doses of dexamethasone reveal that the number and concentration of doses have an increasing of negative effects on the neural tube development of mouse embryos, neural tube abnormalities (NTDs), Spina bifida, a convoluted body and tail, spina bifida cystica, and a porous longitudinal section in the neural tube, the general external morphological characteristics of embryos that were also influenced by Dex. Dex has a harmful effects on the development of the neural tube, particularly when the dexamethasone administered over an extended period of time and in many dosages.
... Тем не менее анализ Шведского медицинского реестра показал повышенный риск гипоспадии у мальчиков [15]. Однако данные не были подтверждены дальнейшими исследованиями [16,17]. ...
Results of examination of 64 pregnant women with allergic dermatosis. Provides results of the efficacy, tolerance and safety study of the loratadinum drug in pregnant women with allergic dermatosis.
... Some studies conducted on pregnant women using loratadine suggest that the use of loratadine during pregnancy increases the risk of hypospadias [42][43][44][45]. However, other prospective studies and many systematic analyzes revealed that the use of loratadine in pregnancy is not associated with the development of hypospadias [46]. ...
Allergy incidence in pregnancy is about 20% and frequently observed as rhinitis and asthma. Asthma often
coexists with allergic rhinitis in adults, and severe nasal findings are present in one out of every three
pregnant women. Asthma and allergic rhinitis may worsen or remain unchanged in pregnancy. Allergic
reactions can also worsen the course of pregnancy. Appropriate drug selection should be made for asthma
and other allergic diseases, and possible risks should be explained to the pregnant woman. Increased risk
perception of drug use may cause the pregnant woman to stop taking the drug suddenly and the disease to
worsen. The purpose of the treatment in pregnancy is controlling the mother's disease while ensuring a
normal course of fetal development. Treatment should be started with the least number of drugs and the
lowest dose possible. Inhaled beta-2 adrenergic agonists and theophylline can be used as bronchodilators
during pregnancy. Chlorpheniramine, loratadine and cetirizine may be preferred in allergic conditions
requiring antihistamine use. Prednisone and also pseudoephedrine can be used during pregnancy, if
necessary. The use of alpha-adrenergic drugs other than pseudoephedrine and epinephrine should be
avoided except for anaphylaxis.
... Another second generation H 1 antihistamine with a structure similar to TCAs is loratadine, an over-the-counter second generation H 1 antihistamine. Källén and Olausson (2001) found a correlation between exposure to loratadine and hypospadias. Furthermore, loratadine was reported to exert estrogen-like effects and disrupt penile development in mice resulting in offspring with hypospadias, when administered doses of 1 and 3 mg/kg/day (Willingham et al., 2006), although McIntyre et al. (2003) found no correlation between perinatal loratadine exposure and hypospadias in male rats. ...
Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Δ5-steroids and significant decreases in Δ4-steroids were observed, indicating an inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in up-regulation of 3β-HSD and 17β-HSD, whereas CET only resulted in up-regulation of 3β-HSD. This indicated that the decrease in steroids downstream from 3β-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3β-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded.
... Data were obtained from the Swedish Medical Birth Register, where information on maternal drug use is obtained from midwife interviews in early pregnancy (usually in week 10-12) [6]. The register also contains information on maternal characteristics which may confound the analysis [7]. ...
... To this group also belongs the Swedish Medical Birth Register where drug use in early pregnancy, both prescription and OTC drugs, is registered. It is based on interviews by midwives at the first prenatal care visit, usually towards the end of the first trimester [5]. ...
The article discusses possible effects of the use of analgesics during pregnancy. It summarizes the pertinent literature and reports some previously unpublished data from the Swedish Medical Birth Register. Most likely the use of analgesics does not cause spontaneous abortion. Only small malformation risk increases are seen after the use of opioids and perhaps non-steroid anti-inflammatory drug (NSAID) use. If possible, the latter should be avoided during the first trimester. If exposure has occurred there is no reason to consider an interruption of the pregnancy. Continued use of analgesics may increase the risk of preeclampsia and of preterm birth, especially valid for opioids. Use of acetylsalicylic acid (ASA) in late pregnancy should be avoided because of the risk of bleeding and (valid also for NSAIDs) premature closure of the ductus arteriosus. A small risk for neonatal abstinence syndrome may exist after the use of opioids for chronic pain, notably during the third trimester and long-lasting effects on child development can possibly occur. For a woman with chronic pain, adequate use of pain killers during pregnancy is needed. It is prudent to avoid ASA and NSAIDs towards the end of the pregnancy, while acetaminophen is an acceptable option all through pregnancy. If continued use of opioids is necessary, the associated risks are low. Triptans can be used for migraine during pregnancy. If possible sumatriptan is preferable to other triptans as data for the latter are largely lacking. Ergots are preferably avoided as not enough data are available.
... Een Zweedse studie rapporteerde in 2001 inderdaad een prevalentie van hypospadie die twee keer verhoogd was ten opzichte van de algemene populatie na gebruik van loratadine in het eerste trimester. 3 Echter, in 2003 werden in twee studies van Teratologie Informatie Services geen gevallen van hypospadie gevonden. 4,5 Een jaar later werd de mogelijke associatie onderzocht in een Amerikaans patiënt-controleonderzoek waarbij geen statistische associatie werd gevonden tussen loratadine en hypospadie. ...
... Risk estimates for specific malformations after maternal use of tramadol in early pregnancy; conditions with at least four cases exposed to tramadol are included. nal use of drugs in early pregnancy, based on interviews made by midwives at the first antenatal care visit of the pregnant woman, in most cases during weeks 10-12 [12]. The interviews are structured and the records for registration are identical in all prenatal care centers. ...
... Two sources were used for the identification of women who used ondansetron in early pregnancy. One was the midwife interviews at the first antenatal care visit of the pregnant woman (usually during weeks 10-12) when she was asked what drugs she had used since she became pregnant [7]. The stated drug use was recorded in clear text and was later centrally transferred to ATC (anatomic, therapeutic, chemical) codes and entered into the Medical Birth Register [8]. ...
... 4 Most studies that have considered specific drugs in relation to specific defects have generally identified no associations between maternal use of antihistamines and major birth defects. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] However, positive associations have been reported for diphenhydramine in relation to cleft palate, 25 cleft lip with or without cleft palate, neural tube defects, spina bifida, limb reduction defects, and gastroschisis; 26 loratadine in relation to hypospadias; 27,28 chlorpheniramine in relation to eye defects, ear defects, 29 spina bifida, and cleft lip with or without cleft palate; 26 doxylamine in relation to oral clefts, 30 pyloric stenosis, 31,32 hypoplastic left heart syndrome, spina bifida, and neural tube defects. 26 Using data from the Slone Epidemiology Center Birth Defects Study (BDS-also known as the Pregnancy Health Interview Study), we tested the previously-reported associations between specific birth defects and first trimester exposure to antihistamines and explored whether there might be associations between specific antihistamines and other common specific major congenital malformations. ...
Background
Several studies have reported an association between use of specific antihistamines in early pregnancy and certain specific birth defects.
Objective
To test 16 previously hypothesized associations between specific antihistamines and specific birth defects, and to identify possible new associations.
Methods
We used 1998-2010 data from the Slone Epidemiology Center Birth Defects Study, a multicenter case-control surveillance program of birth defects in North America. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors, and details on the use of prescription and nonprescription medications. We compared first trimester exposure to specific antihistamines between 13,213 infants with specific malformations and 6982 nonmalformed controls by using conditional logistic regression to estimate odds ratios and 95% confidence intervals (CIs), with adjustment for potential confounders, including indication for use.
Results
Overall, 13.7% of controls were exposed to antihistamines during the first trimester. The most commonly used medications were diphenhydramine (4.2%), loratadine (3.1%), doxylamine (1.9%), and chlorpheniramine (1.7%). When estimates were stable, none supported the previously hypothesized associations. Among more than 100 exploratory comparisons of other specific antihistamine-defect pairs, 14 had odds ratios ≥1.5, of which 6 had 95% CI bounds excluding 1.0 before but not after adjustment for multiple comparisons.
Conclusion
Our findings do not provide meaningful support for previously posited associations between antihistamines and major congenital anomalies; at the same time, we identified associations that had not been previously suggested. We suspect that previous associations may be chance findings in the context of multiple comparisons, a situation that may also apply to our new findings.
... They were asked about all drug use since they became pregnant. 4 The drug names were recorded in clear text and then transferred to ATC codes (Anatomical, Therapeutic, Chemical classification system). A total of 12 050 women reported the use of SSRI; 2014 the use of benzodiazepines; 1503 the use of hypnotic benzodiazepine receptor agonists (HBRA); and 1003 the use of other sedatives/hypnotics, the largest group of which used hydroxyzine (n=819). ...
To investigate the proposed synergistic teratogenic effect of use of selective serotonin receptor inhibitors (SSRI) together with sedatives or hypnotics, primarily benzodiazepines, during pregnancy.
Cohort study of congenital malformations after maternal use of SSRI, sedatives/hypnotics or the combination of the two drug categories.
Swedish national health registers.
A total of 10 511 infants born of women who had used SSRI drugs but no other central nervous system (CNS)-active drug, 1000 infants born of women who had used benzodiazepines and no other CNS-active drug, and 406 infants whose mothers had used both SSRI and benzodiazepines but no other CNS-active drug.
None of the three groups showed a higher risk for any relatively severe congenital malformation or any cardiac defect when comparison was made with the general population risk (adjusted risk ratio (RR) for the combination of SSRI and benzodiazepines and a relatively severe malformation=1.17 (95% CI 0.70 to 1.73). Similar results were obtained for the combination of SSRI with other sedative/hypnotic drugs.
The previously stated increased risk associated with the combined use of these drug categories, notably for a cardiac defect, could not be replicated.
... Most therapeutic drugs, such as corticosteroids, antibiotics, antipsychotics, antifungal and anti-asthmatic drugs, do not seem to be associated with hypospadias, although some studies may suffer from under reporting (Czeizel and Rockenbauer, 1997;Czeizel et al., 2001;Brouwers et al., 2007Brouwers et al., , 2010Källén and Otterblad, 2007;Carter et al., 2008;Carmichael et al., 2009a). Based on data from the Swedish Medical Birth Register 1995, Källén and Olausson (2001 reported 15 hypospadias cases in 2780 infants born after maternal use of loratadine, an antihistamine, during pregnancy but in 2001-2004 only two cases were identified among 1911 infants exposed to loratadine, indicating that the primary finding occurred by chance (Källén and Olausson, 2006). Other studies also failed to find an association between loratadine and hypospadias (CDC, 2004;Pedersen et al., 2008). ...
Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias.
Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995.
The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent.
Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.
... This register was started in 1973 and contains information on antenatal care, delivery, and neonatal conditions, since 1982 based on copies of the original medical records. Information on drug use was included from July 1, 1994 [153]. Nearly all women attend the antenatal care system and the first visit usually takes place before the end of the first trimester, the majority between weeks 10 and 12. ...
To compare interview data on drug use during pregnancy with data identified from a register of prescriptions.
We compared information from the Swedish Prescribed Drug Register with the Swedish Medical Birth Register on antidepressant use. In order to evaluate the clinical significance of the difference in ascertainment with the two methods, the rate of preterm births among singletons and of neonatal symptoms were studied.
During the year before the last menstrual period, 1.5% of the women filled prescriptions for antidepressants each month. Already before the pregnancy was known, the rate of filled prescriptions decreased and reached 0.5% towards the end of the pregnancy. Twenty-two percent of first-trimester use of antidepressants was unidentified using interview data and prescriptions during the 2nd and 3rd pregnancy months covered only 55% of actual use. When women who filled prescriptions 1 or 3 months before the last menstrual period were included, 17 and 43% respectively of women were included who probably did not use the drugs in the first trimester. Prescriptions gave a more complete ascertainment of drug use after the first trimester than data from antenatal care, which seemed to overestimate drug use.
Interview data seem to give the most valid results on early use. When interview data are not available, prescription data could be used, but should not include prescriptions given earlier than 1 month before the last menstrual period. Studies of drug use later in pregnancy are best based on prescription data in the absence of interview data.
... I det svenska födelseregistret finns också uppgifter om läkemedel som den gravida kvinnan tagit vilket resulterat i flera studier för att t. ex. analysera risker med att ta astmaläkemedel (budesonid) och allergimedel (loratadin) under graviditet (14,15). Studierna har resulterat i att man bedömt att budesonid inte var farligt att ta under graviditet, men att allergimedlet loratadin visat på en varningssignal för missbildningen hypospadi som nu närmare följs upp av såväl svenska som europeiska läkemedelsverk. ...
... Drug data are available from July 1, 1995, to the present. The data collection methodology is described by Källén and Otterblad Olausson (2001). ...
To test the hypothesis that maternal drug use or treatment for infertility is related to the occurrence of infant craniostenosis. DESIGN AND MATERIAL: Maternal drug use and infertility treatment were studied in 398 cases of craniostenosis, identified from various Swedish health registers. Exposure information was ascertained in early pregnancy, and comparisons after adjustment for some confounders were made with all infants born. In order to validate some findings, data from the Central-East France Registry were studied for first trimester drug exposure in 235 infants, and use of ovarian stimulation in 315 infants with craniostenosis.
A statistically significant association between maternal use of anticonvulsants and infant craniostenosis was found (risk ratio [Swedish data], 6.9; 95% confidence interval, 1.10 to 7.94). With the Swedish data, an association was found with three nitrosatable drugs (risk ratio, 3.4; 95% confidence interval, 1.10 to 7.94), previously associated with the occurrence of craniostenosis, but this was based on only five exposures, and no such exposure occurred in the French data set. No association with subfertility (odds ratio, 0.72; 95% confidence interval, 0.60 to 1.86) or infertility treatment (odds ratio, 1.06; 95% confidence interval, 0.60 to 1.87) was found in the Swedish data and no statistically significant increase in the use of ovulation stimulation in the French data.
A strong association was found between the maternal use of anticonvulsants and infant craniostenosis, and a tentative association was found with the use of nitrofurantoin and two other nitrosatable drugs. There was no association with maternal subfertility or infertility treatment.
... The Swedish Medical Birth Registry, for example, contains prospectively collected information on drug use as reported by the pregnant woman at her first visit to the antenatal care system, 6 and this information has been used for evaluation of pregnancy outcome after exposure to drugs. 7,8 The second type of registry is designed as an ongoing case-control study. Each case is matched with a control, which is often defined as the next nonmalformed birth of the same sex as the case. ...
The International Clearing-house for Birth Defects Surveillance and Research, formerly known as International Clearinghouse of Birth Defects Monitoring Systems, consists of 40 registries worldwide that collaborate in monitoring 40 types of birth defects. Clearinghouse activities include the sharing and joint monitoring of birth defect data, epidemiologic and public health research, and capacity building, with the goal of reducing disease and promoting healthy birth outcomes through primary prevention.
We discuss 3 of these activities: the collaborative assessment of the potential teratogenicity of first-trimester use of medications (the MADRE project), an example of the intersection of surveillance and research; the international databases of people with orofacial clefts, an example of the evolution from surveillance to outcome research; and the study of genetic polymorphisms, an example of collaboration in public health genetics.
In connection with the considerable increase of prevalence of allergic diseases (AD) there all more often are situations, when it will be to decide the question of management of patients a doctor with an allergy during pregnancy. Prevalence of AD (allergic rhinitis/conjunctivitis, allergic phenotypes of bronchial asthma and hives, atopic dermatitis, food/drug/insect allergy, anaphylaxis) among pregnant women can arrive 30 %. It is possible to distinguish three types of influence of pregnancy on clinical motion of AD: 1) presence of pregnancy does not affect motion of AD; 2) on a background pregnancy comes remission of AD; 3) on a background pregnancy arise up intensifying of AD and their motion are burdened. It is difficult to predict exactly how the course of AD will occur during pregnancy, while the nature of treatment of a pregnant woman with AD and the level of their control are extremely important. At pregnancy diagnosis of AD is based on data of allergic anamnesis, food diary, physical inspection. Thus realization of skin and provocative tests with allergens contra-indicated. Application of provocative tests is also forbidden with a histamine, а methacholine and an acetylcholine. At treatment of pregnant from AD must be taken into account possible side effects of antiallergic drugs. Setting of modern medicinal facilities allows in most cases to control motion of allergic pathology for pregnant and avoid development of side effects of drugs. Treatment of AD during pregnancy the best result must provide for a mother and child. Medical workers must inform the women of reproductive age and pregnant of potential risks and present/absent proofs of unconcern/ununconcern of diagnostic and curative events.
In this chapter, we give a comprehensive review of the currently available literature on environmental factors involved in the etiology of hypospadias. We begin with a description about the prevalence of hypospadias, the clustering of hypospadias in families, the testicular dysgenesis syndrome, and the estrogen hypothesis. We focus the remainder of this chapter on the evidence for environmental factors that may be involved in the etiology of hypospadias and divided the chapter in several parts: exogenous exposure to estrogens, endogenous hormone levels, clinical factors, behavioral factors, occupational factors, and living environment. We summarized the results in a quick overview table. We used the review article that we published in 2012 as basis and updated it with new information and references. We focused on the etiology of isolated hypospadias in humans. Therefore, we did not systematically review animal studies.KeywordsEtiologyAssociationEnvironmentHypospadiasRisk factor
Background
It is estimated that approximately 10–15% of pregnant women report antihistamine use during pregnancy. Although antihistamines are generally considered safe during pregnancy, results from published studies are inconsistent.
Methods
Using a case–control study design we analyzed 41,148 pregnancies (30,091 cases and 11,057 controls) from the National Birth Defects Prevention Study (1997–2011). Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals for 64 birth defect groupings in relation to early pregnancy exposure to 14 distinct antihistamines. Models were adjusted for maternal age, race, parity, education level, prenatal care, folic acid use, smoking and alcohol use, and study site.
Results
Approximately 13% of cases and controls were exposed to an antihistamine during early pregnancy. Analyses were restricted to those defects where more than five cases were exposed to the antihistamine of interest, generating 340 analyses which yielded 20 (5.9%) significant positive associations (adjusted ORs ranging from 1.21 to 4.34).
Conclusions
Only a few of our findings were consistent with previous studies. There is a lack of strong evidence to conclude that birth defects are associated with exposure to antihistamines during early pregnancy.
Most likely there is no or very little teratogenic risk from using antihistamines for allergy in early pregnancy. It should, however, be noted that there is a large number of such drugs and the possibility that some are associated with an increased risk, perhaps of a specific malformation, remains but has so far not been demonstrated.
Maternal use of drugs can be ascertained in different ways – retrospectively by questionnaires or interviews, prospectively already in early pregnancy, or by linkage with registers of prescriptions. Each method has its limitations which are discussed in the chapter. The least reliable method is retrospective ascertainment perhaps months after the delivery when a recall bias may occur, and often a large percentage of nonparticipants may cause further bias. If other methods can be applied they are preferable. The use of prescription registers will have the uncertainty that the woman may not have used the prescribed drug during the pregnancy.
A single study can seldom definitely identify a hazard. Publication of an observed association may result in studies from other scientists in order to verify or reject the observation. Such studies must have enough power to detect the suggested association. Some examples are described in the chapter. Meta-analyses try to summarize a number of different studies, but this methodology is often not suitable for epidemiological studies, for instance, of drug exposure and pregnancy outcomes. More important than to calculate a common odds or risk ratio is to methodologically evaluate large studies.
The study extends a previous investigation on the use of oral decongestants during pregnancy with another 1 000 women (1 017 infants) who reported the use of such drugs in early pregnancy and 1 125 women (1 145 infants) who had such drugs prescribed later in pregnancy. The results on the beneficial delivery outcome after late use of the drugs with a reduced rate of preterm birth and low birth weight were verified and it was also shown that the rates of large-for-gestational age and heavy infants were increased. After early use of such drugs, no increased risk of congenital malformation was seen and previously published data on an association with certain malformations, thought to be due to vascular disruption, could not be supported. It is suggested that pregnancy rhinitis as an indication for the use of oral decongestants could be associated with a well functioning placenta and a good delivery outcome.
The cost, complexity, and risk of selection bias often associated with primary data collection has led to the use of disease registries and databases as an alternative data source for studies of many epidemiological and clinical questions. Medical registries and administrative databases are attractive options. They often contain information on large study populations, and they can provide information on exposures, disease outcomes, and some potential confounding factors for subjects in those populations. Thus medical databases can be very useful for the efficient study of etiologic associations in large populations, and for the evaluation of utilization, effectiveness and safety of medical interventions in clinical settings. This chapter presents an approach for teaching use of routine medical databases covering teaching objectives, teaching method and format, and assessing students' achievements.
This chapter describes the pharmacology and toxicology of antiallergic drugs during pregnancy. These drugs include antihistamines, glucocorticosteroids, mast cell therapy, and immunotherapy. Antihistamines, or H1-blockers, are substances that competitively block the action of histamine on the histamine receptors. H1-antihistamines are mostly used in antiallergy therapy; some are used as antiemetics and some as sedatives. The less sedating antihistamines are preferred for antiallergy therapy. Allergen immunotherapy (allergy shots) is an antiallergy therapy in which continuously increasing doses of an allergen are injected subcutaneously. This therapy stimulates the production of immunoglobulins that bind the allergen before it can react with the mast cells. After immunotherapy, the allergic reaction on exposure to the allergen is diminished because less histamine is released by the mast cells. Immunotherapy is often effective for those allergic patients in whom the symptoms persist despite optimal environmental control and drug therapy. Glucocorticosteroids and mast cell therapy are briefly looked upon in the chapter.
Pregnant women often have an allergic disease. The treatment of allergic diseases in pregnancy does not differ much from the treatment in general population. More important is allergen avoidance and health education of pregnant woman. Double blind placebo controlled trials of the treatment of allergic diseases in pregnancy are extremely rare. Use of drugs that have been on the market for longer time is recommended, because there is more information available on the safety of these drugs. Drugs for local use are generally safer than systemic drugs. It is recommended that nasal decongestants should be avoided. Among antihistamines the drugs of choice are cetirizine and loratadine. Among inhaled corticosteroids the drug of choice is budesonide. The treatment of anaphylaxis is the same as in general population.
Introduction:
Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2-receptor antagonists.
Areas covered:
This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post hoc because of several previously published meta-analyses and commentaries on this medication.
Expert opinion:
The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: i) selection of appropriate study population; ii) ascertainment of antihistamine exposures; and iii) ascertainment of birth defect outcomes. Selected antihistamines have been very well studied (e.g., loratadine); others, especially H2-receptor antagonists, require additional study before an assessment of safety with respect to birth defect risk could be made.
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 previous studies from the Swedish Medical Birth Register, a possible association between erythromycin therapy and an increased risk for cardiovascular defects was found. Other studies using different methodology have not verified this observation. The finding resulted in a warning for the use of erythromycin in early pregnancy, followed by a marked decline in such use. The present study was conducted to follow up on the previous observations and to find methodological explanations for the variation in results in these different published studies.
Data on Swedish women who gave birth during the period 1996-2011 were studied using the drug information in the Medical Birth Registry, obtained from midwife interviews conducted toward the end of the first trimester. Data on the presence of congenital malformations were ascertained from national health registers. Odds ratios were then determined using the Mantel-Haenszel methodology.
A persistent association was seen between erythromycin use and the occurrence of cardiovascular defects, with a risk estimate of 1.70 (95 % confidence interval (CI): 1.26-2.39), of similar strength during the first and last 8 years of observation. We discussed the contradictory findings of the other published studies and pointed out possible methodological problems that may explain the absence of an effect in studies based on prescription registers.
Our study verified an association between early pregnancy erythromycin use and infant cardiovascular defects; most defects were mild. The cause of this association is unclear.
H1-antihistamines are inverse agonists that combine with and stabilize inactive conformation of H1-receptors. Thus they interfere with actions of histamine at H1-receptors. They are widely used for treatment of allergic rhinitis, allergic conjunctivitis, urticaria, coughs, colds and insomnia. H1-antihistamines are classified as older 'first generation' and newer 'second generation'. First generation H1-antihistamines have poor receptor H1-receptor selectivity, and cross blood-brain-barrier. They have a lot of adverse events such as anti-muscarinic, anti-α-adrenergic, anti-serotonin, and sedative effects. In contrast, second generation H1-antihistamines were highly selective for the histamine H1-receptor, do not cross the blood brain barrier, and have minimal adverse events. The risks of first-generation H1-antihistamines have been clearly underestimated, particularly when purchased as nonprescribed over the counter medications by public. This review summarizes curent literature to evaluate antihistamines including their mechanism, indications and side-effects.
In order to evaluate the previously published association between maternal use of selective serotonin re-uptake inhibitors (SSRI) and persistent pulmonary hypertension in the neonate (PPHN), we used data from the Swedish Medical Birth Register for the years 1997–2005. Infants were identified from discharge diagnoses, and maternal exposure to drugs from interviews performed in early pregnancy and from prescriptions from the antenatal care service. Putative confounders were studied: an increased risk for PPHN was indicated for high maternal age, for first parity, for maternal BMI, and possibly for maternal smoking. Adjusting for these variables and year of birth, an association between maternal use of SSRI and PPHN in births after 34 completed weeks was identified with a risk ratio of 2.4, 95%CI 1.2–4.3 when based on women who reported the drug use in early pregnancy. When a subgroup of the women were studied who also had prescriptions for SSRI from the antenatal care later in pregnancy, the risk estimate was 3.6, 95%CI 1.2–8.3. The risk estimates were lower than that described previously in the literature, but both estimates could come from the same about 4–5 times increased risk. The mechanism behind the association between SSRI and PPHN is unclear but an increased risk for respiratory problems after maternal use of SSRI is well known, and PPHN could be a rare part of this association. Copyright © 2008 John Wiley & Sons, Ltd.
Routine data are data collected continuously or at least repeatedly with some time intervals. They could be collected in various
ways, e.g. registration by the health services or by interviews with patients or population groups. For epidemiological purposes,
it is necessary that the disease cases collected can be related to a specified population base, thus providing the ability
to calculate different epidemiological measures as incidence, prevalence etc. The data could then be stored and administered
in registers. Health data or disease registers are restricted to persons with diseases or health-related events. The coverage
can vary from a total registration to a sample of the population and from national to regional coverage. Data can be routinely
collected for various reasons, from economic and administrative purposes to more strict epidemiological purposes.
The use of drugs for migraine during pregnancy may have adverse effects on delivery outcome, and warnings exist for such drugs regarding use during pregnancy. Most information in the literature concerns triptans.
The aim of the study was to describe the delivery outcome when a woman had used drugs for migraine during pregnancy.
A register study where exposure for drugs was obtained partly by interview conducted by the attending antenatal care midwife and medical records from antenatal care (1995-2008) and partly by linkage to the Prescribed Drug Register (2005-8).
All deliveries in Sweden (1 211 670 women) recorded in the Medical Birth Register with data from antenatal care.
Women using triptans or ergots during pregnancy were identified and compared with all women who did not use drugs for migraine.
Pregnancy complications, pregnancy duration and birthweight, neonatal morbidity and mortality, and congenital malformations.
Use of ergots or triptans during early pregnancy (first trimester) occurred in 3286 women with 3327 infants, while use after the first trimester occurred in 1394 women with 1419 infants. Women using such drugs for migraine were older than other women, were more often of parity 1 (no previous infant) and more often had a high body mass index. Women using drugs for migraine had not previously had more miscarriages than expected. There was an increased risk for pre-eclampsia (odds ratio [OR] 1.44; 95% CI 1.17, 1.76). An increased risk for preterm birth was seen after use of drugs for migraine later in pregnancy (OR 1.50; 95% CI 1.22, 1.84). There was no increased risk for stillbirth or early neonatal death. No certain signs of teratogenicity were found for any of the drug types when compared with women not using such drugs (OR for any malformation 0.95; 95% CI 0.80, 1.12).
Our data suggest that the risk of adverse effects on pregnancy outcome associated with the use of drugs for migraine is low but data for triptans other than sumatriptan are still few.
Question:
Many of my pregnant and breastfeeding patients suffer from allergies and frequently ask me about the safety of antihistamines during pregnancy and breastfeeding. Should I advise them to use the older sedating medications? I have heard that they might be safer than the newer nonsedating class of drugs. Or have the newer ones been studied as well?
Answer:
First-generation antihistamines are considered safe to use during pregnancy. There are relatively fewer data on the nonsedating second-generation antihistamines; however, published studies are reassuring. All antihistamines are considered safe to use during breastfeeding, as minimal amounts are excreted in the breast milk and would not cause any adverse effects on a breastfeeding infant.
Antihistamines are commonly used during pregnancy. There is little evidence that they have teratogenic effects, but there are knowledge gaps with respect to newer products, as well as the relationship between specific antihistamines and specific birth defects.
Using the National Birth Defects Prevention Study (1997-2003), the authors examined associations between maternal use of 14 antihistamines during early pregnancy and 26 isolated major birth defects. A Bayesian analysis incorporating prior knowledge about the relationships between antihistamines, birth defects, and measured covariates was conducted.
Of the 364 associations investigated, 24 had 95% posterior intervals excluding 1.0. All 24 associations were positive; 23 associations were of weak to moderate magnitude (posterior OR < 3.0) and one was strong (OR > 6.0) but very imprecise. Of the 24 associations, 20 were with noncardiac defects. Eight associations involved the antihistamine diphenhydramine.
The results of this study generally were consistent with no association between birth defects and antihistamine use during early pregnancy. Several of the findings might warrant further investigation, although the observed elevated associations should be interpreted in the context of the number of associations investigated and the analysis of retrospective, self-reported data.
Background: Loratadine, a second-generation antihistamine, is commonly used to treat seasonal allergies. Some studies have suggested that use of loratadine by pregnant women increases the risk of hypospadias in male offspring.
Objective: This meta-analysis was designed to assess the strength of the association between loratadine and hypospadias.
Methods: To locate pertinent articles published in any language from January 1989 until August 2007, we searched electronic databases (MEDLINE, OVID, EMBASE, SCOPUS, TOXLINE Special, ReproTox, TERIS, CINAHL and others), conference proceedings and bibliographies. Studies were eligible for this analysis if they were cohort, case-control or case series studies that reported the incidence of hypospadias in the offspring of women who were or were not exposed to loratadine during pregnancy. Two authors independently extracted information on study design, participant characteristics, measures of outcome, control for potential confounding factors and risk estimates using a standardized data collection form. The Newcastle-Ottawa Scale was then used to assess the quality of each study. We used a random-effects meta-analysis model to combine the risk data.
Results: In 1402 potentially relevant titles, we found three case-control studies and seven cohort studies that reported the incidence of hypospadias or other congenital malformations in offspring of women who did or did not use loratadine during pregnancy. Together the studies in our meta-analysis provided information about 453 053 male births in Brazil, Canada, Denmark, Israel, Italy, Sweden, the UK and the US.
Loratadine is a second-generation histamine H(1)-receptor antagonist, used in the treatment of allergic conditions. No prospective controlled trials on loratadine in human pregnancy have been published to date.
To determine whether the use of loratadine or other antihistamines (OAH) is associated with an increased risk of major anomalies.
Callers who were counseled by the Israeli Teratogen Information Service in regard to loratadine or OAH exposure during pregnancy were prospectively collected and followed up. Pregnancy outcome was compared among three exposure groups: loratadine, OAH, and a control group of patients who were counseled for nonteratogenic exposure, nonteratogenic controls (NTC). The OAH included astemizole, chlorpheniramine, terfenadine, hydroxyzine, promethazine, and dimetindene.
We followed up 210 pregnancies exposed to loratadine (77.9% in the first trimester) and 267 pregnancies exposed to OAH (64.6% in the first trimester) and compared pregnancy outcome with that of 929 NTC. The rate of congenital anomalies did not differ among the groups [loratadine: 4/175 (2.3%), OAH: 10/247 (4.0%), NTC: 25/844 (3.0%), P =.553, relative risk (RR), 0.77; 95% confidence interval (CI), 0.27 to 2.19, (loratadine vs NTC); RR, 0.56; 95% CI, 0.18 to 1.77, (loratadine vs OAH)]. The rate did not differ between those exposed to antihistamines in the first trimester and the control patients [loratadine: 1/126 (0.8%), OAH: 7/146 (4.8%), NTC: 25/844 (3.0%), P =.152, RR, 0.27; 95% CI, 0.04 to 1.94, (loratadine vs NTC); RR, 0.17; 95% CI, 0.02 to 1.33, (loratadine vs OAH)].
This study on the use of loratadine in human pregnancy suggests that this agent does not represent a major teratogenic risk. The study was powered to find a 3-fold increase in the overall rate of major anomalies.
Normal pre- and postnatal male reproductive development and function is dependent upon testicular androgen production and is sensitive to antiandrogenic perturbations. It was of interest to determine if the H(1) histamine antagonist loratadine had the potential to alter androgen-mediated reproductive development in the rat, a sensitive species for detecting antiandrogenic effects. Loratadine was administered orally by gavage to pregnant Sprague-Dawley rats at doses of 4, 12 or 24 mg/kg from gestation day 7 to postnatal day 4, encompassing the period of androgen-dependent male reproductive development. Vehicle control rats received 0.4% aqueous methylcellulose. Dams were allowed to deliver naturally and rear their offspring until postnatal day 21. On postnatal day 21 male offspring were retained for further evaluation of androgen-dependent endpoints and the female offspring were euthanized and their sex confirmed internally. Males were necropsied from postnatal day 72 to 85. Dams administered 24 mg/kg of loratadine exhibited a transient 45% decrement in maternal body weight gain at the initiation of dosing (gestation days 7-9). Mean pup body weight on postnatal days 1 and 4 were approximately 4% lower than controls. No other effects on offspring growth were observed. Anogenital distance on postnatal day 1 was unaffected by loratadine exposure. Loratadine exposure did not induce the retention of nipples in male rats, affect preputial separation, or induce external malformations, including hypospadias. Seminal vesicle and prostate weights were not decreased by loratadine exposure. These data clearly demonstrate that systemic loratadine exposure, in multiples up to 26 times clinical exposure levels, does not exhibit in vivo antiandrogen activity, as evidenced by the absence of alterations or malformations in androgen-dependent reproductive tissues in male rats exposed to loratadine during the critical period of androgen-dependent development.
Normal pre- and postnatal male reproductive development and function is dependent upon testicular androgen production and is sensitive to antiandrogenic perturbations. It was of interest to determine if the H1 histamine antagonist loratadine had the potential to alter androgen-mediated reproductive development in the rat, a sensitive species for detecting antiandrogenic effects. Loratadine was administered orally by gavage to pregnant Sprague–Dawley rats at doses of 4, 12 or 24mg/kg from gestation day 7 to postnatal day 4, encompassing the period of androgen-dependent male reproductive development. Vehicle control rats received 0.4% aqueous methylcellulose. Dams were allowed to deliver naturally and rear their offspring until postnatal day 21. On postnatal day 21 male offspring were retained for further evaluation of androgen-dependent endpoints and the female offspring were euthanized and their sex confirmed internally. Males were necropsied from postnatal day 72 to 85. Dams administered 24mg/kg of loratadine exhibited a transient 45% decrement in maternal body weight gain at the initiation of dosing (gestation days 7–9). Mean pup body weight on postnatal days 1 and 4 were approximately 4% lower than controls. No other effects on offspring growth were observed. Anogenital distance on postnatal day 1 was unaffected by loratadine exposure. Loratadine exposure did not induce the retention of nipples in male rats, affect preputial separation, or induce external malformations, including hypospadias. Seminal vesicle and prostate weights were not decreased by loratadine exposure. These data clearly demonstrate that systemic loratadine exposure, in multiples up to 26 times clinical exposure levels, does not exhibit in vivo antiandrogen activity, as evidenced by the absence of alterations or malformations in androgen-dependent reproductive tissues in male rats exposed to loratadine during the critical period of androgen-dependent development.
An increase in dizygotic twinning rate after folic acid supplementation has previously been described, but in a recent study from China, no such effect was seen.
To further investigate the association between use of folic acid supplement and dizygotic twinning.
Using the Swedish Medical Birth Registry, the rate of dizygotic twinning among infants of women who reported the use of folic acid was studied, taking a number of confounders into consideration. Comparisons were made with all women recorded in the register.
Unlike-sexed twin pairs were used as representatives of dizygotic twinning.
A number of confounders for the association between folic acid use and twinning were identified and taken into consideration. Women who were immigrants (who used less folic acid and had slightly lower twinning rates than women born in Sweden) and women who reported subfertility problems or treatment for subfertility (who had a high use of folic acid and a high twinning rate) were excluded, and adjustment was then made for year of birth, maternal age, parity, and smoking in early pregnancy. Folic acid use and twinning risk increased with maternal age and decreased with parity. Smokers used less folic acid than nonsmokers. Concomitant use of other drugs was no important confounder except for those used at subfertility. The odds ratio (OR) for dizygotic twinning after folic acid supplementation was then 1.71 (95%CI=1.21-2.42) and for the years 2000-2001 even 2.09 (95%CI=1.39-3.12).
There is an increase in twinning rate after folic acid supplementation in a Western population which should be taken into consideration when folic acid supplementation or food fortification is recommended.
This review summarizes and discusses the use of central health registers in studies of causes of congenital malformations. The review is illustrated using data from the Swedish Medical Birth Register with adjacent registers and gives examples of different methods to identify environmental exposures. The review stresses the usefulness of this approach but also the inherent problems of which the researcher must be fully aware.
The review presented here discusses and exemplifies problems in epidemiological studies of drug teratogenesis according to methodology: case-control studies, cohort studies, or total population studies. Sources of errors and the possibility of confounding are underlined. The review stresses the caution with which conclusions have to be drawn when exposure data are retrospective or other possible bias exists. It also stresses the problem with the multiple testing situation that is usually present in the studies. It is therefore difficult to draw any firm conclusion from single studies and still more difficult to draw conclusions on causality. As randomized studies are in most cases out of the question, one has to rely on the type of studies which can be made, but the interpretation of the results should be cautious. The ideal study, next to a randomized one, is a large prospective study with detailed exposure information and detailed and unbiased outcome data. Even so, such a study can mainly be used for identifying possible associations which have to be verified or rejected in new studies. Nearly every finding of a risk increase, if not extremely strong, should only be regarded as a tentative signal to be tested in independent studies.
Allergic rhinitis is the most common allergic disease. Pharmacological interventions are often not used in pregnancy because of alarming information in drug labels and patient information, even when evidence for safety exists.Low-risk therapies could include immunotherapy, intranasal sodium cromoglycate (cromolyn sodium), beclometasone, budesonide and first-generation antihistamines. In a meta-analysis examining the safety of first-generation antihistamines in pregnancy, 200 000 first trimester exposures failed to show increased teratogenic risk. Loratadine is the most studied second-generation antihistamine (with a total patient cohort of 2147 women who were exposed) and does not appear to increase the risk of major congenital malformations; however, it has not been as well studied as the earlier antihistamines. Since desloratadine is the principal metabolite of loratadine, it can be assumed that a similar safety profile would fit for desloratadine as was described for loratadine although no direct human studies have been done. Decongestants have not been conclusively proven to affect the fetal outcome and may be used for short-term relief when no other safer alternatives are available. Intranasal corticosteroids have not been associated with an increase in congenital malformations in humans. Based on efficacy and the fact that there would be little systemic absorption, they can be considered a first-line treatment over oral antihistamines, decongestants and mast cell stabilisers; however, the number of controlled trials in pregnancy is limited. Intranasal corticosteroids are associated with minimal systemic effects in adults and are the most effective therapy for allergic rhinitis. Benefit-risk considerations must, therefore, be done but favour their first-line use during pregnancy. Because fetal safety is paramount, recommendations should be based both on the safety of the drugs during pregnancy and the comparative efficacy of the agent in the treatment of the underlying condition. This review exemplifies the fact that there are many safe treatment options for the clinician when dealing with allergic rhinitis during pregnancy.
Hypospadias is a developmental anomaly of the penis and urethra that can be steroid mediated. It is characterized by a urethral opening occurring below the normal location at the tip of the penis. The link between loratadine, the active ingredient in a common over-the-counter antihistamine, and hypospadias, the most common congenital abnormality, has been the subject of controversy. We examined the effect of in utero exposure to an over-the-counter loratadine syrup on urethral development, and expression of androgen and estrogen receptors.
We orally gavaged pregnant dams with the equivalent of a daily dose of loratadine syrup, with 3 times that dose or with a corn oil gavage control from GD 12 through GD 17. Using gross and histological assessment and 3D reconstruction, we looked for urethral abnormalities in fetal GTs at E 19. We also used real-time quantitative PCR to characterize the expression levels of steroid receptor mRNA in the GT at E 19, a critical stage for completion of urethral and penile development in this species.
Loratadine syrup disrupted normal urethral development in the mouse, based on gross morphology and histological assessment, and also disrupted steroid receptor expression, producing an expression profile similar to that resulting from in utero exposure to ethinyl estradiol.
In utero exposure to over-the-counter loratadine syrup can result in hypospadias in this model, and creates changes in the steroid receptor mRNA expression profile similar to those elicited by a synthetic estrogen.
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.