Medication use in pregnancy: a cross-sectional, multinational web-based study.

OBJECTIVES: Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. DESIGN: Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. SETTING: Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. PARTICIPANTS: Pregnant women and new mothers with children less than 1 year of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. RESULTS: The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. CONCLUSIONS: In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

Preliminary results of venlafaxine exposure in pregnancy, a multicenter prospective cohort ENTIS study

Introduction: Venlafaxine (Efexor®) is a serotonin and noradrenaline reuptake inhibitor (SNRI) used for the treatment of depression and anxiety disorders. The limited data on the use of venlafaxine in human pregnancy do not indicate an increased risk of congenital malformations. The main purpose of the study is to assess the rate of major malformations after first trimester exposure to venlafaxine. Methods: This multicenter, prospective cohort study was performed using data from nine centers who are member of the European Network of Teratology Information Services (ENTIS). Data on pregnancy and pregnancy outcome of women who used venlafaxine in pregnancy were collected during individual risk counseling. Standardized procedures for data collection and followup were used by each center. Results: Follow up data were collected on 744 pregnancies of womenwhoused venlafaxine during gestation. In 583 (78.4%) cases the exposure had occurred at least in the first trimester. In total, there were 600 live births (5 twins), 85 spontaneous abortions, 57 elective terminations of pregnancy, 5 fetal deaths, and 2 ectopic pregnancies. The overall rate of major malformations after first trimester exposure and excluding chromosomal and genetic disorders was 3.2% (16/500) in all pregnancies ending in delivery, pregnancy terminations or fetal deaths with fetal-pathological examination. Among live births the malformation rate was 2.7% (13/490). We observed no increased risk for organ specific malformations. Conclusions: The present study indicates that venlafaxine is not a major human teratogen.

Expositions médicamenteuses pendant la grossesse: une approche différenciée [Drug exposure during pregnancy: a differentiated approach].

Numerous drug exposures do occur unintentionally at the beginning of pregnancy. On the other hand, pursuing drug treatment may be necessary in women who wish to be pregnant. In these situations risk evaluation has to be done in a precise and differentiated manner, taking into account at the same time the risk for the fetus and maternal health. Teratovigilance services are able to give a thorough information enabling to avoid unwarranted drug arrests or pregnancy terminations. In return, physician's catamnesis about the outcome of the pregnancy exposed to one or several therapeutic agents will increase the bulk of knowledge health professionals and pregnant women have at their disposal.

Paroxetine use in pregnancy and cardiovascular defects

Background: Paroxetine (Paxil,) is an SSRI, used for thetreatment of depression, obsessive compulsive disorder,anxiety disorders and premenstrual dysphoria. Untilrecently, no studies had associated SSRIs as a group withan increased risk for major malformations above the 1%-3% baseline rate. However, in the past year, several studiesnoted specifically, an increase risk of cardiovascular defectsassociated with paroxetine, compared to other antidepressantswithin its class.Objectives: To determine whether paroxetine increases therisk of cardiovascular defects in infants of women exposedduring the first trimester of pregnancy.Methods: We collected prospectively ascertained cases ofinfants from Teratogen Information Services throughout theworld, exposed to paroxetine in the first trimester of pregnancyand compared them to a non-exposed Motheriskcohort.We also contacted the authors of data base studies thathad been published on antidepressants as a class, to determinehow many of these women had been exposed to paroxetineand the rates of cardiovascular defects in their infants.Results: We were able to ascertain the outcomes of 1177infants from 9 services. The rate of heart defects in the paroxetineparoxetinegroup was 0.8% versus 0.7% non-exposed group.The combined rate in the data base studies was 1.5%.Conclusions: Paroxetine does not appear to be associated withan increase risk for cardiovascular defects following use inpregnancy, as the incidence in more than 3000 infants was wellwithin the population incidence of approximately 1%.

Patterns and factors associated with low adherence to psychotropic medications during pregnancy-a cross-sectional, multinational web-based study.

BACKGROUND: No previous studies have explored how closely women follow their psychotropic drug regimens during pregnancy. This study aimed to explore patterns of and factors associated with low adherence to psychotropic medication during pregnancy. METHODS: Multinational web-based study was performed in 18 countries in Europe, North America, and Australia. Uniform data collection was ensured via an electronic questionnaire. Pregnant women were eligible to participate. Adherence was measured via the 8-item Morisky Medication Adherence Scale (MMAS-8). The Beliefs about Prescribed Medicines Questionnaire (BMQ-specific), the Edinburgh Postnatal Depression Scale (EPDS), and a numeric rating scale were utilized to measure women's beliefs, depressive symptoms, and antidepressant risk perception, respectively. Participants reporting use of psychotropic medication during pregnancy (n = 160) were included in the analysis. RESULTS: On the basis of the MMAS-8, 78 of 160 women (48.8%, 95% CI: 41.1-56.4%) demonstrated low adherence during pregnancy. The rates of low adherence were 51.3% for medication for anxiety, 47.2% for depression, and 42.9% for other psychiatric disorders. Smoking during pregnancy, elevated antidepressant risk perception (risk≥6), and depressive symptoms were associated with a significant 3.9-, 2.3-, and 2.5-fold increased likelihood of low medication adherence, respectively. Women on psychotropic polytherapy were less likely to demonstrate low adherence. The belief that the benefit of pharmacotherapy outweighed the risks positively correlated (r = .282) with higher medication adherence. CONCLUSIONS: Approximately one of two pregnant women using psychotropic medication demonstrated low adherence in pregnancy. Life-style factors, risk perception, depressive symptoms, and individual beliefs are important factors related to adherence to psychotropic medication in pregnancy.

Changes in motor behavior during pregnancy in rats: the basis for a possible animal model of restless legs syndrome

PURPOSE:Pregnant women have a 2-3 fold higher probability of developing restless legs syndrome (RLS – sleep-related movement disorders) than general population. This study aims to evaluate the behavior and locomotion of rats during pregnancy in order to verify if part of these animals exhibit some RLS-like features.METHODS:We used 14 female 80-day-old Wistar rats that weighed between 200 and 250 g. The rats were distributed into control (CTRL) and pregnant (PN) groups. After a baseline evaluation of their behavior and locomotor activity in an open-field environment, the PN group was inducted into pregnancy, and their behavior and locomotor activity were evaluated on days 3, 10 and 19 of pregnancy and in the post-lactation period in parallel with the CTRL group. The serum iron and transferrin levels in the CTRL and PN groups were analyzed in blood collected after euthanasia by decapitation.RESULTS:There were no significant differences in the total ambulation, grooming events, fecal boli or urine pools between the CTRL and PN groups. However, the PN group exhibited fewer rearing events, increased grooming time and reduced immobilization time than the CTRL group (ANOVA, p<0.05).CONCLUSION:These results suggest that pregnant rats show behavioral and locomotor alterations similar to those observed in animal models of RLS, demonstrating to be a possible animal model of this sleep disorder.

Fetal alcohol spectrum disorders in Finnish children and adolescents : diagnosis, cognition, behavior, adaptation and brain metabolic alterations

Alcohol consumption during pregnancy can potentially affect the developing fetus in devastating ways, leading to a range of physical, neurological, and behavioral alterations most accurately termed Fetal Alcohol Spectrum Disorders (FASD). Despite the fact that it is a preventable disorder, prenatal alcohol exposure today constitutes a leading cause of intellectual disability in the Western world. In Western countries where prevalence studies have been performed the rates of FASD exceed, for example, autism spectrum disorders, Down’s syndrome and cerebral palsy. In addition to the direct effects of alcohol, children and adolescents with FASD are often exposed to a double burden in life, as their neurological sequelae are accompanied by adverse living surroundings exposing them to further environmental risk. However, children with FASD today remain remarkably underdiagnosed by the health care system. This thesis forms part of a larger multinational research project, The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (the CIFASD), initiated by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in the U.S.A. The general aim of the present thesis was to examine a cohort of children and adolescents growing up with fetal alcohol-related damage in Finland. The thesis consists of five studies with a broad focus on diagnosis, cognition, behavior, adaptation and brain metabolic alterations in children and adolescents with FASD. The participants consisted of four different groups: one group with histories of prenatal exposure to alcohol, the FASD group; one IQ matched contrast group mostly consisting of children with specific learning disorder (SLD); and two typically-developing control groups (CON1 and CON2). Participants were identified through medical records, random sampling from the Finnish national population registry and email alerts to students. Importantly, the participants in the present studies comprise a group of very carefully clinically characterized children with FASD as the studies were performed in close collaboration with leading experts in the field (Prof. Edward Riley and Prof. Sarah Mattson, Center for Behavioral Teratology, San Diego State University, U.S.A; Prof. Eugene Hoyme, Sanford School of Medicine, University of South Dakota, U.S.A.). In the present thesis, the revised Institute of Medicine diagnostic criteria for FASD were tested on a Finnish population and found to be a reliable tool for differentiating among the subgroups of FASD. A weighted dysmorphology scoring system proved to be a valuable additional adjunct in quantification of growth deficits and dysmorphic features in children with FASD (Study 1). The purpose of Study 2 was to clarify the relationship between alcohol-related dysmorphic features and general cognitive capacity. Results showed a significant correlation between dysmorphic features and cognitive capacity, suggesting that children with more severe growth deficiency and dysmorphic features have more cognitive limitations. This association was, however, only moderate, indicating that physical markers and cognitive capacity not always go hand in hand in individuals with FASD. Behavioral problems in the FASD group proved substantial compared to the typically developing control group. In Study 3 risk and protective factors associated with behavioral problems in the FASD group were explored further focusing on diagnostic and environmental factors. Two groups with elevated risks for behavioral problems emerged: length of time spent in residential care and a low dysmorphology score proved to be the most pervasive risk factor for behavioral problems. The results underscore the clinical importance of appropriate services and care for less visibly alcohol affected children and highlight the need to attend to children with FASD being raised in institutions. With their background of early biological and psychological impairment compounded with less opportunity for a close and continuous caregiver relationship, such children seem to run an especially great risk of adverse life outcomes. Study 4 focused on adaptive abilities such as communication, daily living skills and social skills, in other words skills that are important for gradually enabling an independent life, maintain social relationships and allow the individual to become integrated into society. The results showed that adaptive abilities of children and adolescents growing up with FASD were significantly compromised compared to both typically-developing peers and IQ-matched children with SLD. Clearly different adaptive profiles were revealed where the FASD group performed worse than the SLD group, who in turn performed worse than the CON1 group. Importantly, the SLD group outperformed the FASD group on adaptive behavior in spite of comparable cognitive levels. This is the first study to compare adaptive abilities in a group of children and adolescents with FASD relative to both a contrast group of IQ-matched children with SLD and to a group of typically-developing peers. Finally, in Study 5, through magnetic resonance spectroscopic imaging (MRS) evidence of longstanding neurochemical alterations were observed in adolescents and young adults with FASD related to alcohol exposure in utero 14-20 years earlier. Neurochemical alterations were seen in several brain areas: in frontal and parietal cortices, corpus callosum, thalamus and frontal white matter areas as well as in the cerebellar dentate nucleus. The findings are compatible with neuropsychological findings in FASD. Glial cells seemed to be more affected than neurons. In conclusion, more societal efforts and resources should be focused on recognizing and diagnosing FASD, and supporting subgroups with elevated risk of poor outcome. Without adequate intervention children and adolescents with FASD run a great risk of marginalization and social maladjustment, costly not only to society but also to the lives of the many young people with FASD.

Enhanced expression of Ang-(1-7) during pregnancy

Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.

Are birth weight and maternal smoking during pregnancy associated with malnutrition and excess weight among school age children?

In the late 1980's child malnutrition was still prevalent in Brazil, and child obesity was beginning to rise in the richest regions of the country. To assess the extent of the nutritional transition during the period and the influence of birth weight and maternal smoking on the nutritional condition of schoolchildren, we estimated the prevalence of excess weight and malnutrition in a cohort of Brazilian schoolchildren from 1987 to 1989. We calculated the body mass index (BMI) of 8- to 10-year-old schoolchildren born in Ribeirão Preto in 1978/79. We considered children with a BMI <5th percentile (P5) to be malnourished, children with P5³BMIdisorders with birth factors (infant weight, sex, preterm delivery, number of pregnancies, maternal smoking during pregnancy, marital status, and schooling) and type of school using nominal logistic regression. A total of 2797 schoolchildren were evaluated. There was a significant prevalence of malnutrition (9.5%) and excess weight already tended to increase (15.7%), while 6.4% of the children were obese. Excess weight was more prevalent among children attending private schools (odds ratio, OR = 2.27) and firstborn children (OR = 1.69). Maternal smoking during pregnancy protected against malnutrition (OR = 0.56), while children with lower birth weight were at higher risk for malnutrition (OR = 4.23). We conclude that a nutritional transition was under way while malnutrition was still present, but excess weight and related factors were already emerging.

The longitudinal development of emotion regulation capacities in children at risk for externalizing disorders

The development of emotional regulation capacities in children at high versus low risk for externalizing disorder was examined in a longitudinal study investigating: a) whether disturbances in emotion regulation precede and predict the emergence of externalizing symptoms; and b) whether sensitive maternal behavior is a significant influence on the development of child emotion regulation. Families experiencing high (n=58) and low (n=63) levels of psychosocial adversity were recruited to the study during pregnancy. Direct observational assessments of child emotion regulation capacities and maternal sensitivity were completed in early infancy, at 12 and 18-months, and at 5-years. Key findings were as follows. First, high risk children showed poorer emotion regulation capacities than their low risk counterparts at every stage of assessment. Second, from 12-months onwards, emotion regulation capacities showed a degree of stability, and were associated with behavioral problems, both concurrently and prospectively. Third, maternal sensitivity was related to child emotion regulation capacities throughout development, with poorer emotion regulation in the high risk group being associated with lower maternal sensitivity. The results are consistent with a causal role for problems in the regulation of negative emotions in the etiology of externalizing psychopathology, and highlight insensitive parenting as a potentially key developmental influence.

Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks

The low activity variant of the monoamine oxidase A (MAOA) functional promoter polymorphism, MAOA-LPR, in interaction with adverse environments (G × E) is associated with child and adult antisocial behaviour disorders. MAOA is expressed during foetal development so in utero G × E may influence early neurodevelopment. We tested the hypothesis that MAOA G × E during pregnancy predicts infant negative emotionality soon after birth. In an epidemiological longitudinal study starting in pregnancy, using a two stage stratified design, we ascertained MAOA-LPR status (low vs. high activity variants) from the saliva of 209 infants (104 boys and 105 girls), and examined predictions to observed infant negative emotionality at 5 weeks post-partum from life events during pregnancy. In analyses weighted to provide estimates for the general population, and including possible confounders for life events, there was an MAOA status by life events interaction (P = 0.017). There was also an interaction between MAOA status and neighbourhood deprivation (P = 0.028). Both interactions arose from a greater effect of increasing life events on negative emotionality in the MAOA-LPR low activity, compared with MAOA-LPR high activity infants. The study provides the first evidence of moderation by MAOA-LPR of the effect of the social environment in pregnancy on negative emotionality in infancy, an early risk for the development of child and adult antisocial behaviour disorders.

Association Between Insulin Resistance, Glucose Intolerance, and Hypertension in Pregnancy

There is an association between insulin resistance, glucose intolerance, and essential hypertension, but the relation between insulin resistance, glucose intolerance, and hypertension diagnosed during pregnancy is not well understood. Transient hypertension of pregnancy, the new-onset nonproteinuric hypertension of late pregnancy, is associated with a high risk of later essential hypertension and glucose intolerance; thus, these conditions may have a similar pathophysiology. To assess the association between insulin resistance, glucose intolerance, essential hypertension, and subsequent development of proteinuric and nonproteinuric hypertension in pregnancy in women without underlying essential hypertension, we performed a prospective study comparing glucose (fasting, I and 2 hours postglucose load), insulin, glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and triglycerides levels on routine screening for gestational diabetes mellitus. Women who developed hypertension in pregnancy (n = 37) had higher glycemic levels (fasting, 1 and 2 hours postglucose load) on a 100-gram oral glucose loading test, although only the fasting values showed a statistical significance (p < 0.05), and a significantly higher frequency of abnormal glucose loading tests, two hours after glucose load (>= 140 mg/dL) (p < 0.05) than women who remained normotensive (n = 180). Glucose intolerance was common in women who developed both subtypes of hypertension, particularly preeclampsia. Women who developed hypertension had greater prepregnancy body mass index (p < 0.0001), higher frequency and intensity of acanthosis nigricans (p < 0.0001), and higher baseline systolic and diastolic blood pressures (p <= 0.0001 for both), although all subjects were normotensive at baseline by study design; they also presented lower levels of HDL-C (p < 0.05). However, after adjustment for these and other potential confounders, an abnormal glucose loading test remained a significant predictor of development of hypertension (p < 0.05) and, specifically, preeclampsia (p < 0.01). There was a trend toward higher insulin and homeostasis model assessment-insulin resistance (HOMA-IR) levels in women developing any type of hypertension. When comparing women that remained normotensive to term with those with transient hypertension and preeclampsia, the preeclamptic women were born with lower weight (p < 0.05) and shorter length (p < 0.005); at screening they were older (p < 0.005), showed higher frequency and intensity of acanthosis nigricans (p < 0.0001), had higher prepregnancy BMI (p < 0.0005), as well as higher baseline systolic and diastolic blood pressures (p <= 0.0001 for both). They also showed higher HOMA-IR levels that did not show a statistical significance. When glucose tolerance status was taken in account, an association was found between increasing indexes of hypertension (p < 0.05) and of HOMA-IR (p < 0.05) with the worsening of glucose tolerance. These results suggest that insulin resistance and relative glucose intolerance are associated with an increased risk of new-onset hypertension in pregnancy, particularly preeclampsia, and support the hypothesis that insulin resistance may play a role in the pathogenesis of this disorder.

Microscopic evaluation of proliferative disorders in the gerbil female prostate: Evidence of aging and the influence of multiple pregnancies

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

A comparative-analysis of glycosaminoglycans from human umbilical arteries in normal subjects and in pathological conditions affecting pregnancy

BACKGROUND: Vascular cells express different phenotypes in adult and fetal vessels, and the extracellular matrix they synthesize should reflect these differences. Alterations of vascular proteoglycan/glycosaminoglycan is verified in disorders such as hypertension and diabetes, and when occurring during pregnancy, they bring about structural changes to fetal vessels that often lead to impaired fetus growth. Yet there is little data about the extracellular matrix of an important human fetal vessel, the umbilical artery.EXPERIMENTAL DESIGN: This study involved the biochemical characterization of the extracellular matrix of normal umbilical arteries, umbilical arteries from complicated pregnancies (maternal hypertension and diabetes and intrauterine growth retardation syndrome), and, for purpose of comparison, normal adult arteries (aorta and iliac and pulmonary arteries). Although the collagen types I:III ratio was determined in some cases, emphasis was placed on analysis of glycosaminoglycans.RESULTS: Normal umbilical arteries differ from normal adult arteries in that they contain greater concentrations of hyaluronic acid and lesser concentrations of heparan sulfate and chondroitin 4-and 6-sulfate. The umbilical artery also differs from adult arteries in the disaccharide composition of its chondroitin and heparan sulfates and in the molecular weight of this latter glycosaminoglycan. The glycosaminoglycan distribution in umbilical arteries derived from complicated pregnancies is roughly similar to that of controls. However, total glycosaminoglycan and collagen were significantly reduced, and the collagen I:III ratio was increased in the umbilical arteries from hypertension-complicated pregnancies.CONCLUSIONS: the glycosaminoglycan composition of the normal umbilical artery, a fully differentiated tissue, differs in many aspects from that of normal adult arteries. of the cases of complicated pregnancies studied, the extracellular matrix of umbilical arteries was altered only in maternal hypertension. The changes, notably a mild fibrosis, were not very pronounced and should not impair hemodynamic properties of the vessel.

Hypertensive disorders in pregnant women with diabetes mellitus

The present study was performed to assess the rate of hypertensive complications in diabetic pregnant patients and the influence of White's classification and the quality of the diabetic control. This study included 169 diabetic pregnant women who had delivered at the University Hospital of Botucatu Brazil from 1980 to 1981. The hypertensive disorders occurred in 29.8% of the cases. The incidence of the hypertensive process was the same in all classes of diabetic patients, and it was independent of the glycemic control. In patients with gestational diabetes (classes A and AB), chronic hypertension was the commnest type found; in patients with short-term diabetes (classes B and C) pregnancy-induced hypertension (PIH) and chronic hypertension with superimposed PIH was the most frequent type, and diabetic patients with vasculopathies (classes D-R) had preeclampsia and chronic hypertension with superimposed preeclampsia as the commonest type found.