Teratogen Information Service Research Articles

Profile of calls and activities of the first Teratogen Information Service in Latin America through 32 years

Profile of calls and activities of the first Teratogen Information Service in Latin America through 32 years

A descriptive analysis of calls to the NSW Teratogen Information Service regarding use of anti-infectives during pregnancy.

BackgroundMotherSafe is a free telephone-based counseling service for Australian consumers and health-care providers concerned about drug exposures during pregnancy and breastfeeding. Anti-infectives are the most commonly prescribed drugs for pregnant women. This study aims to provide a descriptive analysis of prospectively collected calls received by MotherSafe regarding anti-infective exposures during pregnancy between 2000 and 2020. Aggregate data were examined by type of caller, reason for call, pregnancy category and exposure type. Inductive thematic analysis of the comments recorded by MotherSafe counsellors at the time of call was undertaken.ResultsOver the study period, 25,890 calls related to exposure to anti-infectives during pregnancy (antibiotic, antiviral, and antifungal medications). Calls from patients were dominated by low-risk exposures (pregnancy category A) to drugs while calls from health care professionals related to drugs with limited human information (pregnancy category B3). Analysis of MotherSafe counsellor comments revealed over 200 instances of concerns relating to health care professional advice to the patient. Three themes emerged: incorrect or conflicting advice, poor counselling, and refusal to treat, prescribe or dispense. It is likely that these comments are biased to the negative as patients would not call MotherSafe if they were happy with HCP advice. However, the findings are concerning as they reveal an underlying lack of knowledge in some health care professionals which may have led to undertreatment of patients. This study reinforced the importance of Teratogen Information Services such as MotherSafe in providing counselling and clear communication of evidence-based information to guide decision-making, reducing potential emotional distress in pregnant women, and optimizing maternal, pregnancy and infant outcomes.

COVID-19 vaccine hesitancy and acceptance among pregnant people contacting a teratogen information service.

Pregnant people are at increased risk of severe illness from SARS‐CoV‐2 infection and are more likely to be admitted to an intensive care unit, be put on a mechanical ventilator, and die, if infected. Having COVID‐19 during pregnancy also increases the risk of preterm delivery. Vaccination is a critical tool for controlling the COVID‐19 pandemic; however, to date, just over 30% of pregnant people in the United States have been vaccinated. It is important to identify any barriers to acceptance of the COVID‐19 vaccine among the pregnant population so that specific hesitancy concerns can be addressed. Our objective was to identify the proportion of pregnant people who are unsure or not planning to be vaccinated against COVID‐19 and collect information about their reasons for hesitancy. A questionnaire examining views on COVID‐19 vaccine interest was administered to 299 pregnant people who contacted MotherToBaby 3/1/21–7/23/21. Questions obtained information about the perception of COVID‐19 risk in pregnancy, interest in receiving a COVID‐19 vaccine while pregnant, and reasons for acceptance or hesitancy. Within the sample, 21% had already been vaccinated against COVID‐19, 43% were planning to get vaccinated, 9% were not planning to receive the vaccine, and 27% were undecided. Women who were not planning to get vaccinated and those that were undecided both said their concern was ‘not enough safety information for pregnancy’. Individuals aged 18–25, those who made less than $50,000/year, and those who lived in the Northeast were more likely to be hesitant. Based on these data, continued efforts to collect and communicate high‐quality and understandable information to pregnant people about vaccine safety should be a key priority in efforts to increase vaccine acceptance among this group.

The safety of pranlukast and montelukast during the first trimester of pregnancy: A prospective, two-centered cohort study in Japan.

For leukotriene receptor antagonists (LTRAs), especially pranlukast, safety data during pregnancy is limited. Therefore, we conducted a prospective, two-centered cohort study using data from teratogen information services in Japan to clarify the effects of LTRA exposure during pregnancy on maternal and fetal outcomes. Pregnant women who being counseled on drug use during pregnancy at two facilities were enrolled. The primary outcome of this study was major congenital anomalies. The incidence of major congenital anomalies in women exposed to montelukast or pranlukast during the first trimester of pregnancy was compared with that of controls. Logistic regression analysis was performed to analyze the effects of maternal LTRA use during the first trimester of pregnancy on major congenital anomalies. The outcomes of 231 pregnant women exposed to LTRAs (montelukast n=122; pranlukast n=106; both n=3) and 212 live births were compared with those of controls. The rate of major congenital anomalies in the LTRA group was 1.9%. Multivariable logistic regression analysis revealed that LTRA exposure was not a risk factor for major congenital anomalies (adjusted odds ratio, 0.78; 95% confidence interval, 0.23-2.05; p=0.653). In addition, no significant difference was detected in stillbirth, spontaneous abortion, preterm birth, and low birth weight between the two groups. The present study revealed that montelukast and pranlukast were not associated with the risk of major congenital anomalies. Our findings suggest that LTRAs could be safely employed for asthma therapy during pregnancy.

Queries on medication use during pregnancy: characterisation of the Swiss Teratogen Information Service database.

Limited information on medication safety may result in concerns on how to treat pregnant and breast-feeding patients. The Swiss Teratogen Information Service (STIS) provides information to healthcare professionals about medications during pregnancy and breast feeding. Our objective was to describe the queries addressed to the STIS over the past two decades. The STIS maintains a database of queries on pregnancy outcomes after exposure to various substances, which may be a valuable source of information. We initially analysed the general characteristics of all queries. Thereafter, we focused on exposure to medications during singleton pregnancies and associated health-related aspects. From 2000 to 2019, 7148 queries were entered into the database. An increasing number of queries was recorded over the study period, with an average of 357 queries entered into the database per year. Most of the enquirers were physicians; more specifically, gynaecologists/obstetricians (2389/7148; 33.4%) and psychiatrists (1007/7148; 14.1%). Two thirds (4747/7148; 66.4%) of the queries addressed medication intake during pregnancy; the next most frequent queries concerned planned medication in the context of pregnancy (928/7148; 13.0%) or medication use during breast-feeding (873/7148; 12.2%). In more than 50% (3611/7148) of cases, women were treated with more than one drug; altogether, 15193 medications (taken alone or in combination) were identified. The most frequent queries concerned medicines for the nervous system (ATC group N, n = 7042), with selective serotonin reuptake inhibitors (n = 1271) in the leading position, followed by benzodiazepine derivatives (n = 1102) and other antidepressants (n = 780). The next most frequently mentioned drug classes were anti-infectives for systemic use (J, n = 1586) and drugs for the alimentary tract and metabolism (A, n = 1205). Analysis of follow-up information on cases of medication exposure during singleton pregnancies (n = 2672) revealed an offspring malformation rate of 4.2%. The organ system most often affected was the musculoskeletal system, followed by the circulatory system; congenital malformations of the nervous system and chromosomal abnormalities were also seen. The three most frequently documented congenital diagnoses were malformations of cardiac septa, the brain and major arteries. Healthcare professionals often have concerns regarding the treatment of pregnant women with medication, and require professional counselling in this area. A variety of drugs are mentioned in queries addressed to the STIS, of which psycholeptics and psychoanaleptics are the most frequent. Proper guidelines on their use during pregnancy appear particularly urgent.

Women and babies are dying from inertia: a collaborative framework for obstetrical drug development is urgently needed

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.

Adherence with prescription drugs in pregnant and breastfeeding women consulting with the Israel Poison Information Center Teratology Service

Introduction During pregnancy and breastfeeding, many women require prescription medications. Concerns about drug effects on the fetus or breastfed infant may lead to decreased adherence. Our objective was to evaluate the adherence of pregnant and breastfeeding Israeli women to prescription drugs, the information they received regarding drug safety, and the women’s awareness and pattern of the use of Teratogen Information Services (TIS) in Israel. Methods We conducted a prospective observational cohort study among pregnant and breastfeeding women who had contacted the Israel Poison Information Center (IPIC) to consult about prescription medications. In a follow-up telephone call, we assessed adherence (defined as medication initiation by the time of the follow-up call) and the patients’ recollection of the safety information given by the prescribing physician. In an additional cohort of post-partum women, we assessed their awareness about TIS in Israel. Results We included 59 pregnant women (62 prescriptions), 75 breastfeeding women (80 prescriptions), and 49 postpartum women. About two-thirds of all prescriptions were for antimicrobial drugs. By the time of the follow-up call, most participants (89% of pregnant and 89% of breastfeeding women) had initiated medications. Eight (11%) breastfeeding women stopped breastfeeding their babies while using the medication. Patients reported receiving explicit and unequivocal information concerning medication safety by the prescriber for 50% and 55% of prescriptions to pregnant and breastfeeding women, respectively. 70% of postpartum women interviewed in the maternity ward were not aware of TIS in Israel. Discussion and conclusions We observed high adherence rate to prescription medication therapy among pregnant and breastfeeding women in our cohort. Only about half of the women reported receiving comprehensive drug safety information by the prescriber. Raising awareness of the importance of medication safety counseling among both physicians and patients may contribute to the quality of medical care of pregnant and breastfeeding women in Israel.

Syphilis prevalence in the Brazilian population and calls to Brazilian Teratogen Information Service

Syphilis prevalence in the Brazilian population and calls to Brazilian Teratogen Information Service

Calls to a Major Teratogen Information Service Regarding Exposures During Breastfeeding.

Background: MotherSafe is a free telephone-based counseling service for Australian consumers and health care providers concerned about drug exposures during pregnancy and breastfeeding. Calls relating to breastfeeding are relatively common and a source of significant distress to the breastfeeding mother, particularly if there is a lack of clarity regarding possible adverse effects of drug exposure on the infant. This study seeks to identify the medication exposures of concern for breastfeeding mothers and the information available to address these concerns. Aims: To review calls to MotherSafe about breastfeeding drug exposures during the 19-year period from 2000 to 2018 and to highlight drugs of concern and counseling issues. Materials and Methods: A retrospective descriptive assessment of a prospectively collected Access database was undertaken. Phone counseling records identified the medication (and other) exposures of concern regarding breastfeeding. The information about medication exposures via breastfeeding provided in consumer and product information (PI) was also reviewed. Results: Of a total of 315,158 calls received at MotherSafe between 2000 and 2018, 116,876 (37.1%) were regarding drug exposure via breastfeeding; 30% of these calls related to nonsteroidal anti-inflammatory drugs, antihistamines, antidepressants, simple analgesics, and antibiotics, and 5% were regarding an exposure specifically contraindicated when breastfeeding. Conclusions: Queries about medication exposures via breastfeeding represent a significant proportion of all the counseling calls to MotherSafe. This study demonstrates the inconsistent and often misleading information about breastfeeding exposures found in consumer and PI sheets and online and highlights the important role of Teratogen Information Services like MotherSafe in providing evidence-based information to both consumers and health care providers.

From abortion-inducing medications to Zika Virus Syndrome: 27 years experience of the First Teratogen Information Service in Latin America.

In 1990, the first Teratogen Information Service in Brazil (SIAT) was implemented in the Medical Genetics Service at Hospital de Clinicas de Porto Alegre. SIAT is a free-to-use information service both to health professionals and the general population, especially to women who are pregnant or planning pregnancy. The main objective of this paper is to present the activities of SIAT in its initial years (1990-2006), compared to those in the last decade (2007-2017). In addition we review the scientific contribution of SIAT in the field of human teratogenesis. Since 1990, SIAT received 10,533 calls. Use of medications were the main reason for concern, accounting for 74% of all questions, followed by other chemical exposures (occupational, cosmetics, environmental), and maternal infectious diseases. Among its main contributions to scientific knowledge was the collaboration for the identification of two new human teratogens: misoprostol in the 1990s and Zika virus in 2015/16. In conclusion, SIAT is still evolving, as is the Medical Genetics Service that hosts it. Through its 27 years of existence more than 300 undergraduate and graduate students have rotated at SIAT. Presently, SIAT is expanding the research to experimental teratogenesis and to investigation of molecular mechanisms of teratogens.

Medications and pregnancy: The role of community pharmacists - A descriptive study.

BackgroundSafe use of medications during pregnancy requires a comprehensive understanding of risk-benefit profiles for individual treatments. Pharmacists are supported in this aspect by clinical information agencies (e.g. MotherSafe, a telephone-based teratogen information service) and reference texts. To what extent and for what reasons Australian pharmacists utilise these services/resources are yet unknown. Further, debate on replacement of conventionally defined medication safety in pregnancy categories (A, B1-3, C, D, X) by narratively stated safety evidence may affect pharmacists’ routine practice. This study aimed to gauge pharmacists’ experiences and resource needs in undertaking support roles regarding gestational drug use.MethodsSemi-structured interviews (audio-recorded or documented using field notes) were performed with community pharmacists in Australia and transcribed verbatim. Inductive thematic analysis was conducted using the NVivo software (Version 11, QSR International).ResultsData saturation was achieved with 24 interviews. Qualitative data yielded 5 emergent themes: barriers to effective counselling, patient trust, risk perception, role definition and practice support needs. Overall, participants relied on pregnancy categories, were risk averse and cautious in offering advice. Currently available data for unclassified and category B therapeutic agents (limited human data) were deemed inadequate. Reluctance to use the proposed narrative system was also expressed.DiscussionThis study highlights key barriers in the provision of maternal care by pharmacists and the potential tension present if the existing category system is replaced by a narrative one. These need to be addressed through training and development of practice support resources to enhance pharmacists’ skills in evidence-based risk estimation and communication.

Counselling regarding paternal exposures: Can we do better?

MotherSafe is a free telephone-based counselling service for the general public and healthcare providers concerned about exposures during pregnancy and breastfeeding. Calls relating to paternal exposures are less common, but can cause distress to the person concerned. This review seeks to identify the key concerns and what information is available to address these concerns. To review calls made to MotherSafe about paternal exposures to teratogens during the 16year period, 2000-2015, and to document any patterns or changes in calls over the period. A retrospective descriptive assessment of a prospectively collected database (2000-2015) was undertaken. Telephone counselling records identified the drugs of concern regarding paternal exposures. The information about paternal exposures provided in consumer and production information was also reviewed. Of a total of 253103 calls received at MotherSafe between 2000 and 2015, 1072 calls (0.4%) were regarding paternal exposures. The majority of these calls related to immunomodifiers (19%), hair loss products (11%) and antidepressant medications. Paternal exposures represent a small proportion of all the counselling calls made to MotherSafe. The study highlighted the deficient and often misleading information about paternal exposures found in most consumer and product information sheets or via the internet. The study indicates the important role of Teratogen Information Services like Mothersafe in providing evidence-based information to both consumers and healthcare providers.

Zika virus infection and congenital anomalies in the Americas: opportunities for regional action.

The Zika virus (ZIKV) was identified in 1947 in the Zika forest in Uganda, but recently it has emerged as a public health threat. The first evidence of human infection occurred in 1952, but only in April 2007 was the first outbreak in humans recognized. In the Americas, a ZIKV outbreak began in Brazil in 2015, and from the second half of 2015 onward, a substantial number of newborns with severe microcephaly began to be reported to health authorities. In February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases in areas affected by ZIKV constituted a Public Health Emergency of International Concern. Seldom has there been such a resultingly vast production of scientific literature in record time. In this report we discuss the impact of ZIKV infection during pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action. We consider this to be a unique opportunity for countries in the Region of the Americas to develop, strengthen, and improve surveillance systems for congenital anomalies and teratogen information services. Creating health needs assessment tools for low- and middle-income countries may help them to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. Such initiatives will be useful for ZIKV congenital syndrome control and also for having a much wider impact on a significant proportion of preventable and manageable congenital conditions.

Mycophenolate mofetil embryopathy: A newly recognized teratogenic syndrome

Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.

Calls to a teratogen information service regarding potential exposures in pregnancy and breastfeeding.

BackgroundMotherToBaby Utah is a teratogen information service that provides support for pregnant and breastfeeding women and healthcare providers regarding risks of exposures to medications, infections, herbals, homeopathic and dietary medications, chemicals and other substances. Calls are anonymous and free of charge. This study was undertaken to examine the volume and classification of calls regarding exposures during pregnancy and breastfeeding.MethodsData were extracted from calls requesting information about medication use and other exposures to pregnant and breastfeeding women, between January 1 2009 and December 31 2012. Descriptive statistics were calculated.ResultsA total of 27,299 calls regarding 46,031 exposures were identified in this study population. The majority of calls were made by the exposed individual (82.1 %); 13.0 % were made by a healthcare provider and 4.9 % were made by a family member or acquaintance. The majority of calls concerned pregnancy (65.8 %) versus breastfeeding (34.2 %). Exposure during the current pregnancy was the subject of 88.6 % of calls. For calls where trimester information was available, the percentage of calls for first, second and third trimesters were 44.1, 32.5 and 23.4 %, respectively.ConclusionThis study found analgesics, cold medications, herbals, homeopathic, and dietary medications were of the topic of concern for the majority of the calls regarding exposure during pregnancy and/or breastfeeding. Teratogen information services gather and provide important educational resources for both patients and healthcare providers. As the majority of calls concern nonprescription drugs and vaccines, these data provide insight into a lack of education on these subjects that should be addressed during prenatal care.

Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study.

Perinatal psychological stress has been associated with unfavorable maternal and neonatal outcomes. We aimed to assess the impact of perinatal stress on infant development at 1year of age. We recruited pregnant women calling North American Teratogen Information Services or attending outpatient clinics at CHU Sainte Justine (Montreal) between 2008 and 2010 and their spouses. To be part of our study, women had to be (1) >18years of age, (2) <15weeks of gestational age at recruitment, (3) living within 250-km radius of Montreal, and (4) taking antidepressants or non-teratogenic drugs. Stress was assessed using the telephone-administered four-item perceived stress scale during pregnancy in mothers and at 2months postpartum in both parents. Child development at 1year of age was evaluated with the Bayley III scales. Socio-demographic and potential confounders were collected through telephone interviews. Multivariable linear regression models were built to assess the association between perinatal parental stress and child development. Overall, 71 couples and their infants were included. When adjusted for potential confounders, maternal prenatal stress was positively associated with motor development (adjusted β = 1.85, CI 95% (0.01, 3.70)). Postpartum maternal and paternal stresses were negatively associated with motor and socio-emotional development, respectively (adjusted β = -1.54, CI 95% (-3.07, -0.01) and adjusted β = -1.67, CI 95% (-3.25, -0.10), respectively). Maternal and paternal postnatal stress seems to be harmful for the motor and socio-emotional development in 1-year-old children. No association was demonstrated between parental stress and cognitive, language, and adaptive behavioral development. However, prenatal maternal stress appears to improve motor skills.

Review of calls to an Australian teratogen information service regarding psychotropic medications over a 12‐year period

Telephone counselling services are increasingly utilised by consumers to obtain contemporary and confidential information about perinatal drug and toxin exposure. The use of such services in regard to psychotropic agents is unknown. To determine the frequency and types of calls to a New South Wales (NSW)-based telephone counselling service regarding perinatal psychotropic agent exposure between 2000 and 2011. Retrospective analyses of MotherSafe call data between two epochs: I (2000-2005, n=46,277) and II (2006-2011, n=118,587), total 164,864 calls. 25,698 (15.6%) calls were made about psychotropic agents: 16,218 (9.8%) about antidepressants, 3,145 calls (1.9%) about mood stabilisers/antiepileptic agents, 2,878 (1.7%) about benzodiazepines and 3,457 (2.1%) about antipsychotic drugs. Calls regarding psychotropic agents doubled in epoch II (18,231 vs 7,467, epoch I) but decreased as a proportion of total calls (I: 16.1% vs II: 15.4%, P<0.001). Selective serotonin inhibitors (SSRIs) were the most common drugs of concern (>44% of total psychotropic calls). The proportion of calls regarding particular agents changed significantly between epochs, for example paroxetine (epoch I: 14.8% vs epoch II: 6.7% of all antidepressant calls, P<0.001) and quetiapine (epoch 1: 10.6% vs epoch II: 34.7% of all antipsychotic calls (P<0.001). Calls from rural areas of NSW increased from 22.6 to 24.7% (P<0.001). Consumer demand for information about the use of psychotropic agents for women of child-bearing age has increased considerably over the last decade, particularly in rural areas of Australia. This indicates a need to review current existing services, particularly for rural consumers.

Continuation of pregnancy after first‐trimester exposure to mifepristone: an observational prospective study

To report the follow-up of continuing pregnancies after first-trimester exposure to mifepristone. Observational prospective study. France. Patients exposed to mifepristone during the first 12 weeks of pregnancy. Women were included in the study when they or their doctors asked a French pharmacovigilance centre or the Paris Teratogen Information Service about the risk of mifepristone exposure in early pregnancy. Exclusion criteria were requests received after 22 weeks of gestation or subsequent elective termination of pregnancy without a pathological examination of the fetus. Data on maternal history and drug exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. Rate of major congenital malformations. A total of 105 pregnancies were included, with 46 exposed to mifepristone alone, and 59 exposed to both mifepristone and misoprostol. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI 1.2-10.4%), with two cases among 38 patients exposed to mifepristone alone, and two cases among 57 patients exposed to both mifepristone and misoprostol. This first prospective study found that the rate of major malformations after first-trimester exposure to mifepristone is only slightly higher than the expected 2-3% rate in the general population. Such findings provide reassuring data for risk evaluation for continuation of pregnancy after mifepristone exposure.

Rates of Major Malformations in Infants Following Exposure to Duloxetine During Pregnancy

Method. In this observational multicenter cohort study, data on duloxetine exposure were collected prospectively from either women or their health care providers who had requested information regarding the use of duloxetine during pregnancy. These data came mainly from national teratogen information services that provide evidence-based information regarding the safety of and risks associated with drugs and other exposures during pregnancy. The data were collected from March 2010 to April 2012 and were from Canada, France, Israel, England, Italy, Australia, Switzerland, and Finland. French data were collected from several pharmacovigilance centers, which use procedures similar to those of teratogen information services, although requests are received mostly from physicians. The United Kingdom Teratology Information Service does not currently routinely collect data from women, as it is their health provider who makes the initial inquiry. During the initial contact, demographics, medical and obstetric histories, and details of drug exposure, as well as concurrent exposures to other substances, were recorded by teratogen information service staff on a standardized questionnaire. Then, shortly after birth to approximately 2 to 3 months after delivery, research assistants at the teratogen information services contacted women who had taken duloxetine during pregnancy and obtained their oral and/or written consent to complete the pregnancy outcome questionnaire. The study design included 2 comparison groups of equal numbers of women unexposed to duloxetine, who were chosen randomly: (1) women who were inquiring about exposure to other antidepressants and (2) women inquiring about an exposure not considered teratogenic, such as acetaminophen, antibiotics, or hair color. These women were matched to the duloxetine group for age and alcohol and tobacco use. The main outcome of interest was the presence or absence of major malformations (genetic and cytogenetic anomalies were excluded). This study was approved by the Research Ethics Board at The Hospital for Sick Children in Toronto, Ontario, Canada, and, for centers in the other countries, by local research ethics boards. In the United Kingdom, data collection is covered by Section 251 of the NHS Act 2006. 3 Results. We completed 624 pregnancy outcomes, with 208 in each group, and rates of major malformations were similar between the 3 groups (P = .992). There were 165 live births and 3

Follow-Up of Tacrolimus Breastfed Babies

Tacrolimus is a calcineurin inhibitor immunosuppressant approved in the prevention of organ allograft rejection or in the treatment of acute graft rejection. The human experience of tacrolimus during pregnancy is reassuring with no specific pattern of neonatal complications, except possible transient hyperkalemia (1). Although the available data on human milk transfer indicate that only very limited amounts of tacrolimus are excreted into breast milk (2), clinical data on the safety of breast-feeding for the newborn of tacrolimus-treated patients are still very scarce. As a member of the European Network of Teratogen Information Services, our center provides advice on the safety and risk of medications for pregnant and lactating women. We report our experience regarding the safety of tacrolimus for newborns whose mother opted for breast-feeding after delivery. Since 2003, we have received advice queries concerning 14 women treated with tacrolimus. After individual assessment including the maternal treatment, dose, comedications, indication, characteristics of the neonate, and the expected type of breast-feeding (exclusive or not), clinical and biologic follow-up of the infant was systematically proposed if the mother decided to breast-feed. After oral consent, the clinical follow-up consisted of a standardized questionnaire filled during telephone interviews of the patient during and after the period of breast-feeding. To monitor the infant’s exposure to tacrolimus through breast-feeding, measurement of whole-blood tacrolimus concentration was also proposed within 2 to 3 weeks after starting breast-feeding to avoid any residual presence of tacrolimus in the newborn caused by transplacental passage and tacrolimus long half-life (up to 43 hr in healthy adults). No immunologic monitoring was proposed. Among these 14 patients, breast-feeding was initiated in 9, but 3 discontinued within 5 to 15 days (2 because of breast-feeding difficulties and 1 because of mycophenolate mofetil initiation), and they were not included in the follow-up. Data from Table 1 provide details on the mothers, the infant’s characteristics at birth, medication exposure, and follow-up of children for the remaining evaluable six patients. All six women (mean age, 32 years) had received tacrolimus throughout pregnancy for the prophylaxis of solid organ rejection. The mean daily dose was 9.6 mg/d (4.5–15 mg/d). Concomitant drugs included azathioprine in four women, diltiazem in one, and prednisolone and low-dose aspirin in one. The mean gestational age at delivery was 37.1 weeks, and four of six newborns were moderately premature (34–36 weeks). Breast-feeding was exclusive in four patients and partial in two. The median duration of breast-feeding was 3 months (range, 1.5–6 months), and the median duration of infant follow-up was 8.5 months (range, 2–30 months). Whole-blood tacrolimus concentration measured in four neonates between day 15 and day 27 after delivery were undetectable (lower limit of detection <1.9 μg/L, antibody-conjugated magnetic immunoassay; Siemens Healthcare Diagnostics, Tarrytown, NY). Clinical follow-up of the infants did not identify any adverse outcome that might be related to tacrolimus maternal treatment, and developmental milestones were within the expected ranges. In particular, no specific pattern of infection was observed. A longer follow-up of these infants is expected.TABLE 1: Details on mothers and child exposureOnly four previous reports have provided data on tacrolimus exposure of infants through breast-feeding. Jain et al. (2) measured tacrolimus concentrations in 10 colostrum samples from six mothers treated with tacrolimus during pregnancy. The highest tacrolimus concentration was 1.9 μg/L, corresponding to a maximal dose of 0.29 μg/kg per day delivered from milk to the neonate, that is, 0.1% of the lowest pediatric dose (based on an infant milk ingestion of 150mL/kg/d). None of these mothers had breast-fed. The very low tacrolimus exposure of infants during breast-feeding was documented by two other reports that included the measurement of tacrolimus levels in mature milk and, respectively, found a mean tacrolimus concentration of 0.6 and 1.8 μg/L in milk (3, 4). Chusney et al. (5) showed a similarly quick postpartum decrease in tacrolimus serum levels in neonates exposed throughout pregnancy, whether or not subsequently breast-fed, suggesting higher exposure in utero than through human milk. Finally, only one report included the clinical follow-up of an exclusively breast-fed neonate with normal physical and neurologic development at 2.5 months of age (3). To the best of our knowledge, the present study is the first one to provide relatively long-term follow-up in infants exposed to tacrolimus through breast-feeding. These results confirm previous analytical data suggesting that tacrolimus exposure in breast-fed babies is negligible and probably safe even in case of prematurity, therefore allowing the mother to breast-feed. Until more data are available, particularly regarding long-term safety, careful infant monitoring is required, especially in patients on a multiple immunosuppressant regimen. Aurore Gouraud Nathalie Bernard Anne Millaret Méri Bruel Nathalie Paret Jacques Descotes Thierry Vial Poison Center and Pharmacovigilance Department Lyon University Hospitals Lyon, France