British Journal of Clinical Pharmacology
Br J Clin Pharmacol (2016) 82 478–486
478
DRUGS IN PREGNANCY AND LACTATION Atropinic burden of drugs during pregnancy and psychological development of children: a cohort study in the EFEMERIS database Correspondence Dr Christine Damase-Michel, Faculté de Médecine, 37 allées Jules Guesde, 31000 Toulouse, France. Tel.: +335 6114 5904; Fax: +335 6114 5642; E-mail: [email protected]
Received 30 November 2015; revised 31 March 2016; accepted 9 April 2016
Anna-Belle Beau, Jean-Louis Montastruc, Isabelle Lacroix, François Montastruc, Caroline Hurault-Delarue and Christine Damase-Michel Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, Pharmacoépidémiologie et d’Informations sur le Médicament, Pharmacopôle Midi-Pyrénées, INSERM U 1027 CHU et Faculté de Médecine de Toulouse, France
Keywords atropinic burden, drug risk, EFEMERIS cohort, pregnancy, psychological development
AIM The aim of this study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties on infant psychological development using atropinic burden (AB) scales.
METHODS Women from the EFEMERIS cohort, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, delivering between 2004 and 2010 were included (n = 43 740). Each drug was classified as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties. AB per woman was calculated by adding the atropinic scores of drugs prescribed during pregnancy. AB was categorized as exposure or no exposure. Secondary analyses were performed by dividing the exposure into four scores = [0], [1–8], [9–17] and [≥18]. Data for psychological development were extracted from children’s medical certificates completed at 9 and 24 months.
RESULTS Thirty-four% (n = 14 925) of women received at least one atropinic drug during pregnancy. Women with AB ≥1 were older and received more drugs during pregnancy than unexposed women. At 24 months, more infants of mothers with AB ≥1 had difficulties to ‘name a picture’ (ORa, 1.18, 95% CI 1.03, 1.36) and to ‘understand instructions’ (ORa, 1.61, 95% CI 1.13, , 2.30]) compared with infants of unexposed women. Analyses of four groups of exposure and analyses excluding women receiving psychotropics led to similar results.
CONCLUSIONS The study showed significant association between in utero exposure to drugs with atropinic properties and fewer infant cognitive acquisitions at 24 months. Further exploring the potential effect of simultaneous use of drugs with atropinic effects among pregnant women will bring into consideration whether such prescriptions could be inappropriate for the child.
DOI:10.1111/bcp.12978
© 2016 The British Pharmacological Society
Atropinic drugs during pregnancy and infant psychological development
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Many drugs exhibit atropinic properties and are widely prescribed. • In newborns, atropinic drugs could induce hyperexcitability, suction disorders, constipation or tachycardia when taken in late pregnancy. • It has been shown that elderly frailty, such as poorer cognitive performance, or short term memory, is associated with atropinic burden.
WHAT THIS STUDY ADDS • The study reports that one third of the women are exposed to at least one drug with atropinic properties during pregnancy. • The study highlighted a significant association between in utero exposure to drugs with atropinic properties and fewer cognitive acquisitions of infants aged 24 months.
Introduction Drugs with atropinic properties are widely prescribed in the general population and pregnant women are not an exception. Their indications are various. The main properties of atropinics are used to treat symptoms of urinary incontinence, asthma, allergy, Parkinson’s disease and emesis. Several drugs used for sleep disorders, depression or psychosis are also competitive antagonists of muscarinic receptors (mAChR) and can cause atropinic side effects. Taking several drugs exhibiting atropinic properties can expose patients to central, as well as peripheral adverse drug reactions, especially in case of vulnerable subjects [1–3] (for example confusion or delirium in elderly patients or impaired gastrointestinal motility in neonates). During in utero life, muscarinic responses to acetylcholine (ACh) in the heart can be detected from 4 weeks post-conception [4]. Foetal brain mAChR can be quantified at 16 weeks of gestation and gradually increases thereafter [5, 6]. We hypothesized that exposure to atropinic drugs during pregnancy may affect the development of the foetal central nervous system resulting in psychological development alterations. The aim of the study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties (main or side effects) on the psychological development of the infant during the first 2 years.
Methods Data sources We conducted an observational comparative study among children, using data from the EFEMERIS database (Evaluation chez les Femmes Enceintes des MEdicaments et de leurs RISques). Detailed information about EFEMERIS has been described previously [7, 8]. Briefly, EFEMERIS is a French database of prescription drugs in the general population constructed to evaluate risks associated with drugs during pregnancy. At the time of the study, this database includes 55 035 pregnant women who delivered from 1 July 2004 until 31 December 2010. Data come from four different sources. First, the French Health Insurance System (Caisse Primaire d’Assurance Maladie; CPAM) of Haute-Garonne (south-western France) records all the reimbursed drugs (name, ATC code, date of dispensation, prescriber) prescribed and dispensed to patients under general state coverage. Drugs are
classified according to the World Health Organization’s Anatomical Therapeutic Chemical classification (ATC classification). Second, the Mother and Child Protection Centre (Protection Maternelle et Infantile; PMI) records data from children’s certificates filled out during the compulsory medical examinations at birth, 9 and 24 months (according to the French law). These health certificates contain data about the health of the mother (maternal characteristics, some pathologies during pregnancy) and the child (weight, size, Apgar score, neonatal pathologies, psychomotor development, congenital malformations). The examinations are performed by a general practitioner or a paediatrician, using the standardized questionnaire forming the certificates. Third, the Prenatal Diagnosis Centre (Centre Pluridisciplinaire de Diagnostic Prénatal; CPDPN) centralizes data corresponding to all occurrences of major and minor malformations in the maternities of the region where therapeutic termination has been considered (cause and date of termination). Fourth, the French hospital medical information system (Programme de médicalisation des systèmes d’information; PMSI) provides the nature and date of termination (legal termination, stillbirth and spontaneous abortion) from the Toulouse University Hospital centre. Data for both the mother and her outcome (live birth or pregnancy loss) are linked with an anonymous irreversible code. Setting up the EFEMERIS database was approved by the French Data Protection Agency on 7 April 2005 (authorization number 05–1140).
Population Our study was restricted to all live-births from 1 July 2004 to 31 December 2010 recorded in EFEMERIS. Two-year-old children with at least one record of a health certificate at 9 or 24 months were selected for the analyses (Figure S1 in Supplement).
Exposure Each prescribed and dispensed drug during pregnancy was classified according to its atropinic activity based on the Duran [9], Laroche [10] and Agence Nationale de Sécurité du Médicament et des produits de santé [11] lists. Drugs were defined as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties (Table S1 in Supplement). Atropinic burden per woman was calculated by adding the atropinic scores of each prescribed drug at each date of prescription during the whole pregnancy. In the main analysis, women were categorized into two atropinic burden exposure Br J Clin Pharmacol (2016) 82 478–486
479
A.-B. Beau et al. categories: no exposure (score = 0) and exposure (score ≥ 1). Then, secondary analysis was performed categorizing the subjects into four atropinic burden exposure categories: [0], [1–8], [9–17], [≥18].
Outcomes Mandatory child medical certificates completed at 9 and 24 months include 14 items designed to detect children at risk of psychomotor development abnormalities [12, 13]. Some of them are relevant to motor development, and others to psychological development. In this study, we focused on psychological development items at ages 9 and 24 months. Seven items were studied separately: ’reacts to own name’, ‘points with finger’, ‘repeats a syllable’, ‘plays peek-a-boo’, ‘understands a simple instruction’, ‘is able to name at least one image’, ‘associates two words’. All items were assessed by the child’s general practitioner or the paediatrician using the standardized questionnaires in the certificates at the time of the medical consultation.
Potential confounders Covariates being taken into account in the adjustment for confounding were maternal, obstetrical and child characteristics. Maternal characteristics included maternal age at delivery, occupation, smoking during pregnancy, presence of a long term adverse health condition and number of drugs prescribed during pregnancy. Obstetrical characteristics were multiparty, multiple births, presence of pathology during pregnancy such as pre-eclampsia, diabetes and hypertension. Child data studied were prematurity (a birth before 37 completed weeks), breastfeeding status, gender, pathology during the first week of life, an Apgar score at 5 min fewer than 7 and diagnosis of major congenital anomaly.
Statistical analysis Continuous variables are expressed as means (± SD) and categorical variables as percentages. We described the characteristics of the study population by exposure categories. Quantitative variables or proportions were described in four exposure groups (score = [0], [1–8], [9–17], [≥18]) using multinomial logistic regression. Associations between atropinic burden and child psychological development were evaluated using multivariable logistic regressions. Adjusted odds ratios (ORs) and their 95% confidence intervals (95% CIs) were used to describe strength of associations. For rare outcomes, a Firth biascorrection was used. In primary analyses, exposure was categorized into two groups (score = 0, score ≥ 1). Secondary analyses were performed dividing exposure into four groups: [0], [1–8], [9–17] and [≥18], in order to analyze the dose– response relationship between atropinic burden and each outcome. Women receiving no atropinic drug during pregnancy (score = 0) were used as the reference group for comparison. We assessed confounding by variables previously found to be associated with either exposure or outcome. Only the variables meeting the Greenland entry criteria (P < 0.20) and that were clinically relevant were selected for inclusion in the multivariable models [14]. 480
Br J Clin Pharmacol (2016) 82 478–486
For all models including covariates, missing values were addressed using multivariate imputation by chained equation (fully conditional specification) assuming that the data were missing at random [15]. We generated 30 imputed data sets for each outcome of interest. The multiple imputation models included respective outcome and the covariates. Results were then combined using Robin’s rule [16].
Sensitivity analyses Maternal psychiatric pathology was previously identified as a significant risk factor for psychomotor development problems of infants [17–19]. Several psychotropics exhibit atropinic properties (imipraminic antidepressants, phenothiazines). In order to exclude confounding due to a psychiatric pathology, we performed sensitivity analyses by excluding the women exposed to any psychotropic drug during pregnancy. Sensitivity analyses were made similarly to the primary analyses. As mAChR can be quantified in human foetal brain from 16 weeks of gestation and increases up until 20 weeks, considering this period as a vulnerability period, we performed a complementary analysis taking only into account women exposed during the second and the third trimester of pregnancy. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). All statistical tests were two-sided. Values of P < 0.05 were considered statistically significant.
Results Overall, 43 740 women who gave birth between 1 July 2004 and 31 December 2010 were included in the study. Among them, 14 925 (34%) received at least one atropinic drug during pregnancy. Around 33% (n = 14 349) of the women had an atropinic burden score between 1 and 8, 1% (n = 473) between 9 and 17 and 0.2% (n = 103) a score greater than 18. More than 23% (n = 10 211) of the women received at least one atropinic drug during the first trimester of pregnancy, 11.2% (n = 4910) during the second and 8.8% (n = 3829) during the third. Among the women exposed to atropinic drugs during pregnancy, the mean atropinic burden score was 2.8 ± 3.1 during the first trimester of pregnancy, 1.6 ± 2.0 during the second and 0.7 ± 1.5 during the third. Characteristics of women according to atropinic burden exposure categories are reported in Table 1. Atropinic burden during pregnancy was associated with a high mean maternal age. Women with a high atropinic burden were more frequently unemployed, smokers during pregnancy, diabetic, with more long term adverse health conditions and receiving more different active substances during pregnancy than unexposed women (P < 0.05). Among almost 2000 drugs prescribed to our population of pregnant women, 8% (n = 143) had an atropinic property. The most prescribed substances with atropinic properties were domperidone (47% of the exposed women), metopimazine (25%), cetirizine (11%), oxomemazine (7%) and
Atropinic drugs during pregnancy and infant psychological development
Table 1 Characteristics of pregnant women by atropinic burden categories
score = 0 (n = 28 815)
score [1–8] (n = 14 349)
score [9–17] (n = 473)
score ≥ 18 (n = 103)
P value
30.3 ± 4.9
30.5 ± 5.0
31.1 ± 5.0
33.0 ± 5.1
Br J Clin Pharmacol (2016) 82 478–486
478
DRUGS IN PREGNANCY AND LACTATION Atropinic burden of drugs during pregnancy and psychological development of children: a cohort study in the EFEMERIS database Correspondence Dr Christine Damase-Michel, Faculté de Médecine, 37 allées Jules Guesde, 31000 Toulouse, France. Tel.: +335 6114 5904; Fax: +335 6114 5642; E-mail: [email protected]
Received 30 November 2015; revised 31 March 2016; accepted 9 April 2016
Anna-Belle Beau, Jean-Louis Montastruc, Isabelle Lacroix, François Montastruc, Caroline Hurault-Delarue and Christine Damase-Michel Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, Pharmacoépidémiologie et d’Informations sur le Médicament, Pharmacopôle Midi-Pyrénées, INSERM U 1027 CHU et Faculté de Médecine de Toulouse, France
Keywords atropinic burden, drug risk, EFEMERIS cohort, pregnancy, psychological development
AIM The aim of this study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties on infant psychological development using atropinic burden (AB) scales.
METHODS Women from the EFEMERIS cohort, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, delivering between 2004 and 2010 were included (n = 43 740). Each drug was classified as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties. AB per woman was calculated by adding the atropinic scores of drugs prescribed during pregnancy. AB was categorized as exposure or no exposure. Secondary analyses were performed by dividing the exposure into four scores = [0], [1–8], [9–17] and [≥18]. Data for psychological development were extracted from children’s medical certificates completed at 9 and 24 months.
RESULTS Thirty-four% (n = 14 925) of women received at least one atropinic drug during pregnancy. Women with AB ≥1 were older and received more drugs during pregnancy than unexposed women. At 24 months, more infants of mothers with AB ≥1 had difficulties to ‘name a picture’ (ORa, 1.18, 95% CI 1.03, 1.36) and to ‘understand instructions’ (ORa, 1.61, 95% CI 1.13, , 2.30]) compared with infants of unexposed women. Analyses of four groups of exposure and analyses excluding women receiving psychotropics led to similar results.
CONCLUSIONS The study showed significant association between in utero exposure to drugs with atropinic properties and fewer infant cognitive acquisitions at 24 months. Further exploring the potential effect of simultaneous use of drugs with atropinic effects among pregnant women will bring into consideration whether such prescriptions could be inappropriate for the child.
DOI:10.1111/bcp.12978
© 2016 The British Pharmacological Society
Atropinic drugs during pregnancy and infant psychological development
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Many drugs exhibit atropinic properties and are widely prescribed. • In newborns, atropinic drugs could induce hyperexcitability, suction disorders, constipation or tachycardia when taken in late pregnancy. • It has been shown that elderly frailty, such as poorer cognitive performance, or short term memory, is associated with atropinic burden.
WHAT THIS STUDY ADDS • The study reports that one third of the women are exposed to at least one drug with atropinic properties during pregnancy. • The study highlighted a significant association between in utero exposure to drugs with atropinic properties and fewer cognitive acquisitions of infants aged 24 months.
Introduction Drugs with atropinic properties are widely prescribed in the general population and pregnant women are not an exception. Their indications are various. The main properties of atropinics are used to treat symptoms of urinary incontinence, asthma, allergy, Parkinson’s disease and emesis. Several drugs used for sleep disorders, depression or psychosis are also competitive antagonists of muscarinic receptors (mAChR) and can cause atropinic side effects. Taking several drugs exhibiting atropinic properties can expose patients to central, as well as peripheral adverse drug reactions, especially in case of vulnerable subjects [1–3] (for example confusion or delirium in elderly patients or impaired gastrointestinal motility in neonates). During in utero life, muscarinic responses to acetylcholine (ACh) in the heart can be detected from 4 weeks post-conception [4]. Foetal brain mAChR can be quantified at 16 weeks of gestation and gradually increases thereafter [5, 6]. We hypothesized that exposure to atropinic drugs during pregnancy may affect the development of the foetal central nervous system resulting in psychological development alterations. The aim of the study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties (main or side effects) on the psychological development of the infant during the first 2 years.
Methods Data sources We conducted an observational comparative study among children, using data from the EFEMERIS database (Evaluation chez les Femmes Enceintes des MEdicaments et de leurs RISques). Detailed information about EFEMERIS has been described previously [7, 8]. Briefly, EFEMERIS is a French database of prescription drugs in the general population constructed to evaluate risks associated with drugs during pregnancy. At the time of the study, this database includes 55 035 pregnant women who delivered from 1 July 2004 until 31 December 2010. Data come from four different sources. First, the French Health Insurance System (Caisse Primaire d’Assurance Maladie; CPAM) of Haute-Garonne (south-western France) records all the reimbursed drugs (name, ATC code, date of dispensation, prescriber) prescribed and dispensed to patients under general state coverage. Drugs are
classified according to the World Health Organization’s Anatomical Therapeutic Chemical classification (ATC classification). Second, the Mother and Child Protection Centre (Protection Maternelle et Infantile; PMI) records data from children’s certificates filled out during the compulsory medical examinations at birth, 9 and 24 months (according to the French law). These health certificates contain data about the health of the mother (maternal characteristics, some pathologies during pregnancy) and the child (weight, size, Apgar score, neonatal pathologies, psychomotor development, congenital malformations). The examinations are performed by a general practitioner or a paediatrician, using the standardized questionnaire forming the certificates. Third, the Prenatal Diagnosis Centre (Centre Pluridisciplinaire de Diagnostic Prénatal; CPDPN) centralizes data corresponding to all occurrences of major and minor malformations in the maternities of the region where therapeutic termination has been considered (cause and date of termination). Fourth, the French hospital medical information system (Programme de médicalisation des systèmes d’information; PMSI) provides the nature and date of termination (legal termination, stillbirth and spontaneous abortion) from the Toulouse University Hospital centre. Data for both the mother and her outcome (live birth or pregnancy loss) are linked with an anonymous irreversible code. Setting up the EFEMERIS database was approved by the French Data Protection Agency on 7 April 2005 (authorization number 05–1140).
Population Our study was restricted to all live-births from 1 July 2004 to 31 December 2010 recorded in EFEMERIS. Two-year-old children with at least one record of a health certificate at 9 or 24 months were selected for the analyses (Figure S1 in Supplement).
Exposure Each prescribed and dispensed drug during pregnancy was classified according to its atropinic activity based on the Duran [9], Laroche [10] and Agence Nationale de Sécurité du Médicament et des produits de santé [11] lists. Drugs were defined as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties (Table S1 in Supplement). Atropinic burden per woman was calculated by adding the atropinic scores of each prescribed drug at each date of prescription during the whole pregnancy. In the main analysis, women were categorized into two atropinic burden exposure Br J Clin Pharmacol (2016) 82 478–486
479
A.-B. Beau et al. categories: no exposure (score = 0) and exposure (score ≥ 1). Then, secondary analysis was performed categorizing the subjects into four atropinic burden exposure categories: [0], [1–8], [9–17], [≥18].
Outcomes Mandatory child medical certificates completed at 9 and 24 months include 14 items designed to detect children at risk of psychomotor development abnormalities [12, 13]. Some of them are relevant to motor development, and others to psychological development. In this study, we focused on psychological development items at ages 9 and 24 months. Seven items were studied separately: ’reacts to own name’, ‘points with finger’, ‘repeats a syllable’, ‘plays peek-a-boo’, ‘understands a simple instruction’, ‘is able to name at least one image’, ‘associates two words’. All items were assessed by the child’s general practitioner or the paediatrician using the standardized questionnaires in the certificates at the time of the medical consultation.
Potential confounders Covariates being taken into account in the adjustment for confounding were maternal, obstetrical and child characteristics. Maternal characteristics included maternal age at delivery, occupation, smoking during pregnancy, presence of a long term adverse health condition and number of drugs prescribed during pregnancy. Obstetrical characteristics were multiparty, multiple births, presence of pathology during pregnancy such as pre-eclampsia, diabetes and hypertension. Child data studied were prematurity (a birth before 37 completed weeks), breastfeeding status, gender, pathology during the first week of life, an Apgar score at 5 min fewer than 7 and diagnosis of major congenital anomaly.
Statistical analysis Continuous variables are expressed as means (± SD) and categorical variables as percentages. We described the characteristics of the study population by exposure categories. Quantitative variables or proportions were described in four exposure groups (score = [0], [1–8], [9–17], [≥18]) using multinomial logistic regression. Associations between atropinic burden and child psychological development were evaluated using multivariable logistic regressions. Adjusted odds ratios (ORs) and their 95% confidence intervals (95% CIs) were used to describe strength of associations. For rare outcomes, a Firth biascorrection was used. In primary analyses, exposure was categorized into two groups (score = 0, score ≥ 1). Secondary analyses were performed dividing exposure into four groups: [0], [1–8], [9–17] and [≥18], in order to analyze the dose– response relationship between atropinic burden and each outcome. Women receiving no atropinic drug during pregnancy (score = 0) were used as the reference group for comparison. We assessed confounding by variables previously found to be associated with either exposure or outcome. Only the variables meeting the Greenland entry criteria (P < 0.20) and that were clinically relevant were selected for inclusion in the multivariable models [14]. 480
Br J Clin Pharmacol (2016) 82 478–486
For all models including covariates, missing values were addressed using multivariate imputation by chained equation (fully conditional specification) assuming that the data were missing at random [15]. We generated 30 imputed data sets for each outcome of interest. The multiple imputation models included respective outcome and the covariates. Results were then combined using Robin’s rule [16].
Sensitivity analyses Maternal psychiatric pathology was previously identified as a significant risk factor for psychomotor development problems of infants [17–19]. Several psychotropics exhibit atropinic properties (imipraminic antidepressants, phenothiazines). In order to exclude confounding due to a psychiatric pathology, we performed sensitivity analyses by excluding the women exposed to any psychotropic drug during pregnancy. Sensitivity analyses were made similarly to the primary analyses. As mAChR can be quantified in human foetal brain from 16 weeks of gestation and increases up until 20 weeks, considering this period as a vulnerability period, we performed a complementary analysis taking only into account women exposed during the second and the third trimester of pregnancy. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). All statistical tests were two-sided. Values of P < 0.05 were considered statistically significant.
Results Overall, 43 740 women who gave birth between 1 July 2004 and 31 December 2010 were included in the study. Among them, 14 925 (34%) received at least one atropinic drug during pregnancy. Around 33% (n = 14 349) of the women had an atropinic burden score between 1 and 8, 1% (n = 473) between 9 and 17 and 0.2% (n = 103) a score greater than 18. More than 23% (n = 10 211) of the women received at least one atropinic drug during the first trimester of pregnancy, 11.2% (n = 4910) during the second and 8.8% (n = 3829) during the third. Among the women exposed to atropinic drugs during pregnancy, the mean atropinic burden score was 2.8 ± 3.1 during the first trimester of pregnancy, 1.6 ± 2.0 during the second and 0.7 ± 1.5 during the third. Characteristics of women according to atropinic burden exposure categories are reported in Table 1. Atropinic burden during pregnancy was associated with a high mean maternal age. Women with a high atropinic burden were more frequently unemployed, smokers during pregnancy, diabetic, with more long term adverse health conditions and receiving more different active substances during pregnancy than unexposed women (P < 0.05). Among almost 2000 drugs prescribed to our population of pregnant women, 8% (n = 143) had an atropinic property. The most prescribed substances with atropinic properties were domperidone (47% of the exposed women), metopimazine (25%), cetirizine (11%), oxomemazine (7%) and
Atropinic drugs during pregnancy and infant psychological development
Table 1 Characteristics of pregnant women by atropinic burden categories
score = 0 (n = 28 815)
score [1–8] (n = 14 349)
score [9–17] (n = 473)
score ≥ 18 (n = 103)
P value
30.3 ± 4.9
30.5 ± 5.0
31.1 ± 5.0
33.0 ± 5.1
