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Effects of codeine on pregnancy outcome: results from a large population-based cohort study

Effects of codeine on pregnancy outcome: results from a large population-based cohort study Eur J Clin Pharmacol (2011) 67:1253–1261 DOI 10.1007/s00228-011-1069-5 PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Effects of codeine on pregnancy outcome: results from a large population-based cohort study Kateřina Nezvalová-Henriksen & Olav Spigset & Hedvig Nordeng Received: 24 January 2011 /Accepted: 23 May 2011 /Published online: 9 June 2011 The Author(s) 2011. This article is published with open access at Springerlink.com Abstract set and the Medical Birth Registry of Norway (MBRN) data Background Guidelines on codeine safety during pregnancy set. The data sets were linked via the maternal personal rely on small studies with inconsistent results, and associa- identification number. Associations between codeine therapy tions between codeine use during pregnancy and increased and pregnancy outcomes were identified using logistic risk of congenital malformations remain unsubstantiated. regression analyses. Objectives Our objective was to analyze the effect of Results No significant differences were found in the codeine on pregnancy outcome. survival rate [adjusted odds ratio (OR) 0.9, 95% confidence Methods Pregnancy outcomes of 2,666 women who used interval (CI) 0.6–1.5] or the congenital malformation rate codeine during pregnancy were compared with 65,316 (adjusted OR 0.9, 95% CI 0.8–1.1) between codeine- women who used no opioids during pregnancy. Information exposed and unexposed infants. Codeine use anytime on maternal sociodemographic and medical characteristics, during pregnancy was associated with planned Cesarean potential confounders, and pregnancy outcome was delivery (adjusted OR 1.4, 95% CI 1.2–1.7; P<0.0001). obtained from The Norwegian Mother and Child Cohort Third-trimester use was associated with acute Cesarean Study [den norske Mor & barn-undersøkelsen (MoBa)] data delivery (adjusted OR 1.5, 95% CI 1.3–1.8; P<0.0001) and postpartum hemorrhage (adjusted OR 1.3, 95% CI 1.1–1.5; P<0.0001). No significant associations with other adverse Electronic supplementary material The online version of this article (doi:10.1007/s00228-011-1069-5) contains supplementary material, pregnancy outcomes were found. which is available to authorized users. Conclusions No effects of maternal codeine intake during K. Nezvalová-Henriksen (*) H. Nordeng pregnancy were observed on infant survival or congenital Department of Social Pharmacy, School of Pharmacy, malformation rate. Our findings are reassuring; however, Faculty of Mathematics and Natural Sciences, University of Oslo, the association with acute Cesarean delivery and postpar- Sem Sælands vei 3, tum hemorrhage may justify a certain level of caution when 0316 Oslo, Norway e-mail: katerina.nezvalova-henriksen@farmasi.uio.no administering codeine toward the end of pregnancy. O. Spigset . . Keywords Codeine Delivery complications Pregnancy Department of Clinical Pharmacology, outcome St Olav’s University Hospital, 7006 Trondheim, Norway O. Spigset Introduction Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, 7491 Trondheim, Norway Few studies address the safety of codeine use during pregnancy despite its extensive use as an analgesic and H. Nordeng antitussive in the general population. The frequency of Division for Mental Health, National Institute of Health, codeine use during pregnancy has been shown to range Marcus Thranes gate 6, between 1% and 3.5% [1–3]. Studies specifically targeting 0473 Oslo, Norway 1254 Eur J Clin Pharmacol (2011) 67:1253–1261 codeine safety during pregnancy are either small case– Public Health. The overall aim of the study is to examine control studies or case reports with inherent methodological the effect of a vast number of exposures on pregnancy limitations that generally warrant cautious interpretation. outcome and maternal and fetal health during pregnancy No data from cohort studies are available to date. One case– and postpartum. Data were obtained from three self- control study of 504 children with neuroblastoma found an administered questionnaires answered by pregnant women association with in utero exposure to codeine [odds ratio who participated in the study between 1999 and 2006. (OR) 3.4, 95% confidence interval (CI) 1.4–8.4] [4]. Pregnant women received a postal invitation with an Another of 599 infants found that mothers who gave birth informed consent form and the first questionnaire prior to to infants with cleft palate or cleft lip with or without cleft their first ultrasound scan during gestational weeks 17 or palate used opioid analgesics (mainly codeine) much more 18. This first questionnaire covered the time period between frequently than the control group; the largest difference was the 6 months prior to pregnancy and the 18th gestational seen for codeine use during the first trimester (8.6% week. The second questionnaire covered the time period compared with 2.1% of infants in the control group; P< between the 19th and 29th gestational week, and the third 0.01) [5]. In a third case–control study of 1,370 infants, 12 questionnaire covered the time period from the 30th infants with major congenital malformations had been gestational week until birth. The questionnaires covered exposed to codeine during the first trimester compared sociodemographic and lifestyle data, maternal medical with seven in the control group (OR 3.7, Fisher’s one-tailed history, maternal health during the pregnancy, drug use, P value 0.004) [6]. Neonatal abstinence syndrome has been and neonatal health. The overall response rate was 43.5% described in two cases in which codeine was used by the [15]. The MBRN [16] encompasses all births in Norway mother over a period of several days close to term [7]. Two and has been prospectively collecting data on all deliveries other reports described an association between neonatal since 1967. Approximately 60,000 infants are born in abstinence syndrome and possibly cerebral infarction after Norway every year, corresponding to an annual birth rate of maternal intake of codeine close to term [8]. 1.2 infants per 100 inhabitants. Data stem from mandatory Evidently, most of studies and case reports focus either standardized forms filled out by midwives, obstetricians, on the possible teratogenicity of codeine or neonatal and/or pediatricians at each delivery and from the mother’s abstinence syndrome. The latter has mainly been shown to pregnancy medical records. The standardized forms cover be associated with other opioids [9]. Other pregnancy sociodemographic and lifestyle information on the mother outcomes, including postpartum complications, have only and medical information including maternal health prior to been studied in populations using opioid analgesics in and during pregnancy as well as delivery and postpartum general and those of addicted pregnant women [10–12] and complications and interventions. Data from the two sources not in pregnant women taking codeine in therapeutic doses. were linked via the woman’ personal identification number, It is likely that these studies were subject to bias due to which is assigned to every legal resident in Norway. The inclusion of populations with very specific sociodemo- study was approved by the Regional Committee for Ethics graphic and lifestyle characteristics, and the effects of in Medical Research, Region South, and the Norwegian codeine use as such would thus be difficult to evaluate [10– Data Inspectorate. 12]. Notwithstanding, leading literature sources on the safety of drug use during pregnancy suggest that sporadic Study population use of codeine is safe except toward the end of pregnancy [9, 13]. The original quality-assured data file released for research Using data from a large prospective cohort study, our in 2008 (version 4) consisted of data on 72,934 women. All aim was to evaluate the potential teratogenicity of codeine these women had a pregnancy outcome registered in the and investigate possible associations with other adverse MBRN. Prior to release of this data file, 3.5% of the pregnancy outcomes that have not been studied so far. women in the study did not have a pregnancy outcome registered, mainly due to spontaneous abortions that happened early on in pregnancy. Of the 72,934 women, Methods 3,005 who did not complete the first questionnaire were excluded. A total of 69,929 pregnant women with records Data for this study were retrieved from The Norwegian both in both data sets were eligible for inclusion (95.9% of Mother and Child Cohort Study [den norske Mor & barn- the original data file). In addition, women using opioids undersøkelsen (MoBa)] data set (version four) released in other than codeine (i.e., ethylmorphine, morphine, ketobe- December 2008 and from records from the Medical Birth midone, tramadol, pethidine, dextropropoxyphene, oxy- Registry of Norway(MBRN). MoBa [14] is a prospective codone, buprenorphine, and methadone) (n=1,664) and cohort study conducted by the Norwegian Institute of women using both codeine and one or several of the Eur J Clin Pharmacol (2011) 67:1253–1261 1255 aforementioned opioids (n=283) were excluded. The final current information on codeine safety during pregnancy and study population therefore consisted of 67,982 women studies on the effect of opioid analgesics on pregnancy (93.2% of the original data file). Multiple pregnancies were outcome and labor progress, with special focus on included; however, only data on the first-born infant were prolonged labor and neonatal complications. The chosen used, as only these were linked to maternal data. variables consisted of any congenital malformations detected at birth, major congenital malformations detected Explanatory variables at birth, survival (live birth, miscarriage/stillbirth, perinatal death, death during the first 12 months of life), birth weight Explanatory variables consisted of the following subsets: (i) <2,500 g, gestational age <37 weeks, Apgar scores <7 at 1 pregnant women who used codeine (alone or in a fixed and 5 min, neonatal respiratory depression, neonatal combination with paracetamol) during pregnancy (total) hypoglycemia, newborn admitted to intensive care unit, (yes/no); (ii) pregnant women who used codeine (alone or acute Cesarean delivery, planned Cesarean delivery, atonic in a fixed combination with paracetamol) during the first uterus, prolonged labor, and postpartum hemorrhage trimester (gestational weeks 0–12) (yes/no); (iii) pregnant >500 ml. All outcome variables were dichotomized into women who used codeine (alone or in a fixed combination yes or no categories. with paracetamol) during the second trimester (gestational weeks 13–28) (yes/no); (iv) pregnant women who used Statistical analysis codeine (alone or in a fixed combination with paracetamol) during the third trimester (gestational week 29 until Logistic regression analyses were performed to identify delivery) (yes/no). Drug therapy was classified and grouped significant associations between codeine therapy and according to the Anatomical Therapeutic Chemical (ATC) pregnancy outcome. Subsets of confounding factors were classification system developed by the World Health Organi- selected for each pregnancy outcome depending on clinical zation (WHO) [17]. ATC codes used were R05DA04 plausibility, statistical significance, and size of outcome (codeine alone) and N02AA59 (codeine in a fixed combi- event rates (a full list of confounding factors controlled for in nation with paracetamol). Codeine in fixed combinations each analysis is available in the ESM 1: Confounding with acetylsalicylic acid or other nonsteroidal antiinflamma- factors). Confounding factors controlled for in logistic tory drugs is not available in Norway. The explanatory regression analyses were chosen on the basis of theoretical variable subsets were created using answers to questions clinical significance and initial Pearson’s χ analyses, where regarding both codeine use and maternal illness in ques- the P value was <0.25. Preliminary logistic regression tionnaires one and two as long as the ATC code for codeine analyses enabled the subsequent removal of potential and the timing of either codeine use or the medical condition confounding variables, with a P value of >0.5, with the was specified. Subanalyses were performed to investigate exception of instances in which the coefficient change of the possible associations between the extent of codeine use exposure variable was >20%. The final logistic regression (number of days used, categorized as 1–7days, 8–14 days, models for pregnancy outcome included statistically signifi- and >14 days) and pregnancy outcome. cant variables and clinically plausible interactions only. The threshold for retaining these variables in the final logistic Confounding factors regression model was P<0.05. Potential multicollinearity among the independent variables was identified using Confounding factors included sociodemographic, lifestyle, multiple regression analysis. Tolerance values for multi- and medical characteristics (Tables 1 and 2), concomitant collinearity were set at >0.5. Hosmer and Lemeshow drug use (Table 3) (this information was derived from goodness-of-fit tests >0.5 indicated robust models and were theMoBa questionnaires), and factors related to delivery considered valid in the logistic regression analyses. All (this information was derived from the MBRN). Different statistical analyses were performed with the Statistical potential confounding factors, the majority of which are Package for Social Sciences SPSS for Windows version listed in Tables 1–4 were selected for each pregnancy 16.1 (SPSS, Chicago, IL, USA). Risk ratio estimates are outcome. (Please find the complete list of confounding given as odds ratios (OR) with 95% confidence intervals (CI). factors used in the analyses in Electronic supplementary material (ESM) 1: Confounding factors.) Results Outcome variables Of the 67,982 pregnant women in the study, 2,666 (3.9%) Outcome variables were retrieved from both MoBa and used codeine during pregnancy (exposed group), whereas MBRN. The choice of outcome variables was based on 65,316 (96.1%) did not (unexposed group). In the exposed 1256 Eur J Clin Pharmacol (2011) 67:1253–1261 Table 1 Maternal characteristics of the study population Women who used codeine during Women who did not use opioids during pregnancy; exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % Maternal age (years) < 20 32 1.2 714 1.1 20 – 29 1,194 44.8 28,840 44.1 30 – 39 1,380 51.8 34,530 52.9 ≥ 40 60 2.2 1,234 1.9 Parity 0 1,153 43.2 28,523 43.7 ≥1 1,513 56.7 36,787 56.3 Plurality 1 2,611 97.9 64,123 98.2 > 1 55 2.1 1,193 1.8 Ethnicity Of Norwegian descent 2,572 96.5 61,782 94.6 Not of Norwegian descent 94 3.5 3,534 5.4 Marital status Married/cohabiting 2,553 95.8 63,484 97.2 Other 113 4.2 1,832 2.8 Education Primary 80 3.0 1623 2.5 Secondary 1,005 37.7 20,803 31.8 Tertiary 1,525 57.2 41,607 63.4 BMI prior to pregnancy (kg/m ) < 18.5 65 2.4 2,002 3.1 18.5 – 25.0 1,479 55.5 41,930 64.2 > 25.0 1,050 39.4 19,483 29.8 Folic acid intake prior to pregnancy 596 22.3 15,041 23.0 Sick leave lasting longer than 2 weeks during pregnancy 1,023 38.4 20,505 31.4 Smoking at gestational week 30 391 14.7 6,180 9.4 a ** Alcohol intake during pregnancy 1,421 53.3 3,3512 51.3 Some data do not add up to the total due to missing values * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group, ** 2 Pearson’s χ test P<0.05 when compared with the unexposed control group Including data on sporadic intake and intake before the women were aware of their pregnancy group, 45 women used codeine alone and 2,621 used codeine infants when comparing the exposed (99.4% live births) with in a fixed combination with paracetamol. A higher proportion the unexposed (99.2% live births) groups (adjusted OR 0.9, of exposed women had attained lower levels of education, 95% CI 0.6–1.5] (Table 4). No significant difference in were not married or cohabiting with their partner, were overall congenital malformation rate was found when overweight (had a body mass index >25 kg/m )prior to comparing the exposed (4.9%) with the unexposed (5.0%) pregnancy, and smoked throughout pregnancy (Table 1). group (adjusted OR 0.9, 95% CI 0.8–1.1). No significant Moreover, these women were more likely to suffer from difference in the major congenital malformation rate was medical complications both prior to and during pregnancy found between the exposed (2.9%) and unexposed (2.9%) (Table 2). Concomitant nonsteroidal antiinflammatory drug group (adjusted OR 0.9, 95% CI 0.7–1.2) (Table 4). and psychotropic agent use was also significantly higher in Codeine use anytime during pregnancy was significantly the exposed group than in the unexposed group (Table 3). associated with an increased risk of acute Cesarean delivery No significant difference was found in the survival rate of (12.8% in the exposed group compared with 8.9% in the Eur J Clin Pharmacol (2011) 67:1253–1261 1257 Table 2 Maternal health and pregnancy complications Women who used codeine during Women who did not use opioids during pregnancy: exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % Maternal health during pregnancy Acute musculoskeletal pain 2,534 95.0 58,005 88.8 Migraine and/or headache 1,536 57.6 23,115 35.4 Proteinuria 766 28.7 13,262 20.3 Temperature>38.5°C fever associated with a rash 590 22.1 10,453 16.0 ** * Hospitalization 270 10.1 2,839 4.3 ***a Urinary tract infection and/or pyelonephritis 258 9.7% 5,371 8.2 Preeclampsia and/or eclampsia 157 5.9 2,592 4.0 Involved in an accident 122 4.7 2,003 3.1 a * High blood pressure during the first trimester 65 2.4 998 1.5 Maternal health prior to pregnancy Musculoskeletal pain (any) 1,892 71.0 34,562 52.9 Arthritis/Systemic Lupus Erythematosus/ 348 13.0 2,504 3.8 Fibromyalgia Depression 258 9.7 3,533 5.4 Asthma 190 7.1 2,885 4.4 Cardiac disease 140 5.2 2,108 3.2 **** Thyroid disorder 70 2.6 1,293 2.0 Diabetes (type I or II) 44 1.6 810 1.2 Obstetric complications Number of ultrasound examinations < 2 462 17.3 15,491 23.7 2 – 4 1,255 47.1 30,366 46.5 > 5 650 24.3 10,205 15.6 b * Vaginal bleeding during pregnancy 601 22.5 11,979 18.3 First trimester 498 18.7 10,027 15.3 Second and/or third trimesters 226 8.5 4,295 6.6 Oligohydramnios 62 2.3 1,506 2.3 **** Placenta previa 46 1.7 821 1.3 Polyhydramnios 32 1.2 556 0.8 Abruptio placentae 17 0.6 271 0.4 * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group, ** Excluding hospitalization due to vaginal bleeding and high blood pressure, *** 2 Pearson’s χ test P<0.01 when compared with the unexposed control group **** 2 Pearson’s χ test P<0.05 when compared with the unexposed control group. Defined as systolic blood pressure≥140 mmHg Vaginal bleeding lasting more than 1 day or of an amount exceeding a trace or two or more episodes of bleeding or vaginal bleeding which has led to hospitalization unexposed group) (adjusted OR 1.3, 95% CI 1.1–1.5), Upon analyzing the effects of codeine on pregnancy planned Cesarean delivery (7.4% in the exposed group outcome during the three specific trimesters, an increased compared with 5.0% in the unexposed group) (adjusted OR risk of planned Cesarean delivery was seen after exposure 1.4, 95% CI 1.2–1.7), and postpartum hemorrhage (18.3% in in the first (7.3%; adjusted OR 1.4, 95% CI 1.1–1.7), the exposed group compared with 14.5% in the unexposed second (7.5%; adjusted OR 1.5, 95% CI 1.2–1.8), and third group) (adjusted OR 1.2, 95% CI 1.1–1.4) (Table 4). (8.9%; adjusted OR 1.6, 95% CI 1.3–2.0) trimesters. Third 1258 Eur J Clin Pharmacol (2011) 67:1253–1261 Table 3 Frequency of concomitant nonsteroidal antiinflammatory drug and psychotropic agent use during pregnancy Drug Women who used codeine during Women who did not use opioids during pregnancy: exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % NSAIDs 759 28.5 8,271 12.6 Ibuprofen 470 17.6 6,269 9.6 Diclofenac 170 6.4 703 1.1 Naproxen 85 3.2 782 1.2 a * Other 185 6.9 1,323 2.0 Psychotropic agents 359 13.5 3,159 4.8 b * Antidepressants 172 6.4 1,935 3.0 c * Anxiolytics 132 4.9 788 1.2 d * Hypnotics 86 3.2 490 0.7 e * Antipsychotics 60 2.2 452 0.7 NSAIDS nonsteroidal anti-inflammatory drugs * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group Including piroxicam, meloxicam, indomethacin, acetylsalicylic acid, ketoprofen, nabumetone, and tolfenamic acid Including selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mianserin, mirtazapine, and venlafaxine Including diazepam, oxazepam, alprazolam, hydroxyzine, and buspirone Including nitrazepam, flunitrazepam, zopiclone, and zolpidem Including levomepromazine, perphenazine, prochlorperazine, flupenthixol, zuclopenthixol, olanzapine, quetiapine, and risperidone trimester use was, in addition, associated with an increased rely either on data regardng opioid analgesic use in general risk of acute Cesarean delivery (15.1%; adjusted OR 1.5, or a few case studies [9, 13], we found no increased risk of 95% CI 1.3–1.8) and postpartum hemorrhage (20.3%; congenital malformations or neonatal respiratory depres- adjusted OR 1.3, 95% CI 1.1–1.5) (Table 4). Subanalyses sion. Associations of codeine use during pregnancy and on the effect of codeine therapy duration on pregnancy neonatal abstinence syndrome were unfortunately not outcomes revealed that codeine use lasting >14 days was feasible to evaluate, as neonatal abstinence syndrome significantly associated with planned (but not acute) scores were not routinely applied. However, neither low Cesarean delivery (unadjusted OR 3.2, 95% CI 1.3–7.9). Apgar scores nor admission of the neonate to intensive care No dose–effect relationship was found for postpartum were associated with codeine use during pregnancy, and hemorrhage. these outcomes are also partly representative of neonatal abstinence syndrome. Of other adverse pregnancy outcomes, the strongest Discussion association was between codeine use during pregnancy and increased risk of planned Cesarean delivery. This associa- Information on the safety of analgesic use during pregnancy tion remained significant, even after controlling for several is an important issue for all clinicians prescribing these clinically and statistically significant potential confounders, drugs to pregnant women. It is often not feasible to including high birth weight, fetal malpresentation, plurality, prescribe the more thoroughly documented nonopioid placenta previa, and others (a full list is available in the analgesics either for safety reasons or lack of adequate ESM 1: Confounding factors). A dose–effect relationship pain relief. The safety profiles of as many different between codeine and planned Cesarean delivery was also analgesics as possible must be known before an individual detected. Nevertheless, we believe it is highly likely that the risk–benefit evaluation can be done. In this study, codeine association was due to underlying medical conditions. use during pregnancy was not found to be associated with Thirteen percent of exposed women suffered from chronic infant survival rate, congenital malformation rate, or other conditions, including arthritis, systemic lupus erythemato- adverse pregnancy outcomes, except for Cesarean delivery sus, and fibromyalgia, compared with only 3% in the and excessive postpartum hemorrhage. Unlike previous unexposed group; almost 10% had depression compared with only 5% of the unexposed women; a significantly studies [4, 5, 7, 8] and other medical literature sources that Eur J Clin Pharmacol (2011) 67:1253–1261 1259 Table 4 Adjusted Odds Ratios (OR) for pregnancy outcome in women who used codeine during pregnancy compared with the unexposed control group Pregnancy outcome Women who used codeine during pregnancy: exposed group Women who did not use opioids during pregnancy: unexposed group (n=65,316) Total pregnancy (n=2,666) First trimester (gestational Second trimester (gestational Third trimester (gestational weeks 0–12) (n=1,693) weeks 13–28) (n=1,955) week 29 until delivery) (n=1,255) No. % OR 95%CI No. % OR 95%CI No. % OR 95%CI No. % OR 95%CI No. % Congenital malformations detected at birth Any 130 4.9 0.9 0.8 – 1.1 77 4.5 0.9 0.7 – 1.1 91 4.7 0.9 0.7 – 1.1 67 5.3 1.0 0.7 – 1.3 3,247 5.0 Major 77 2.9 0.9 0.7 – 1.2 40 2.4 0.8 0.5 – 1.1 50 2.6 0.8 0.6 – 1.1 45 3.6 1.1 0.8 – 1.6 1,904 2.9 Survival (live birth) 2,649 99.4 0.9 0.6 – 1.5 1,677 99.1 0.6 0.4 – 1.0 1,939 99.2 0.7 0.4 – 1.2 1,252 99.8 2.4 0.7 – 7.5 64,797 99.2 Birth weight<2500 g 124 4.7 1.1 0.9 – 1.3 78 4.6 1.1 0.8 – 1.4 94 4.8 1.1 0.9 – 1.4 63 5.0 1.1 0.8 – 1.5 2,579 3.9 Gestational age<37 weeks 209 7.8 1.1 0.9 – 1.3 132 7.8 1.1 0.9 – 1.4 151 7.7 1.1 0.9 – 1.3 106 8.4 1.2 0.9 – 1.5 3,910 6.0 Apgar score < 7 at 1 min 183 6.9 1.2 1.0 – 1.5 118 7.0 1.3 1.0 – 1.6 131 6.7 1.2 1.0 – 1.5 83 6.6 1.2 0.9 – 1.6 3,506 5.4 < 7 at5 min 44 1.7 1.3 0.9 – 1.9 33 1.9 1.6 1.0 – 2.6 35 1.8 1.5 0.9 – 2.3 15 1.2 1.0 0.5 – 1.8 875 1.3 Neonatal respiratory depression 131 4.9 1.0 0.9 – 1.3 76 4.5 0.9 0.7 – 1.2 88 4.5 0.9 0.7 – 1.1 65 5.2 1.1 0.8 – 1.4 2,706 4.1 Hypoglycemia 72 2.7 1.1 0.8 – 1.4 45 2.7 1.0 0.7 – 1.4 50 2.6 1.0 0.7 – 1.4 41 3.3 1.2 0.9 – 1.7 1,415 2.2 Newborn admitted to intensive care unit 337 12.6 1.1 1.0 – 1.3 197 11.6 1.0 0.9 – 1.2 233 11.9 1.1 0.9 – 1.2 176 14.0 1.1 1.0 – 1.4 6,520 10.0 * * Cesarean delivery (acute) 340 12.8 1.3 1.1 – 1.5 191 11.3 1.1 0.9– 1.3 223 11.4 1.1 0.9 – 1.3 189 15.1 1.5 1.3 – 1.8 5,834 8.9 * * * * Cesarean delivery (planned) 198 7.4 1.4 1.2 – 1.7 124 7.3 1.4 1.1– 1.7 147 7.5 1.5 1.2 – 1.8 112 8.9 1.6 1.3 – 2.0 3,265 5.0 Atonic uterus 137 5.1 1.2 1.0 – 1.5 88 5.2 1.3 1.0 – 1.6 97 5.0 1.2 1.0 – 1.5 69 5.5 1.3 1.0 – 1.7 2,808 4.3 Prolonged labor 217 8.1 1.1 0.9 – 1.2 128 7.6 1.0 0.8 – 1.2 149 7.6 1.0 0.9 – 1.2 99 7.9 1.0 0.8 – 1.2 4,542 7.0 b * * * Postpartum hemorrhage 489 18.3 1.2 1.1 – 1.4 301 17.8 1.2 1.1 – 1.4 344 17.5 1.2 1.0 – 1.4 255 20.3 1.3 1.1 – 1.5 9,488 14.5 CI confidence interval Pearson’s χ2 test P<0.0001 Labor lasting >18 h Hemorrhage >500 ml 1260 Eur J Clin Pharmacol (2011) 67:1253–1261 higher number of exposed women had asthma and hand, a difference in the prevalence of drug use and cardiac disease; about 10% were hospitalized during pregnancy outcomes in the study population compared with pregnancy compared with 4% of the unexposed group; the general population may have occurred, as participant and 5.9% had preeclampsia and/or eclampsia compared response rate was only 43.5%. However, it has been shown with 4% of the unexposed group. Several of these that only minor differences (<2% in absolute differences in diseases and conditions, which were not feasible to sociodemographic variables) between MoBa participants control for in this particular analysis, are associated with and the general population of pregnant women exist, and no planned Cesarean delivery [18]. Association codeine differences in the estimates of association measures were therapy duration may also be indicative of the severity of found between participants and the general population [15, the underlying medical conditions. 24]. Despite this, the risk of false negative associations due Notwithstanding, we cannot definitively exclude a to underrepresentation of certain sociodemographic groups, direct association between codeine and acute Cesarean possible underreporting of codeine use during pregnancy, delivery and postpartum hemorrhage. A study on and the rarity of some pregnancy outcomes such as major 315,085 pregnancies concluded that preeclampsia was malformations, should be taken into account. Analyses on significantly associated with postpartum hemorrhage and specific malformations could not be undertaken due to low postulated that a deprivation of angiogenic factors statistical power. It was also not feasible to determine the resulting in the preeclamptic state may also play a role codeine dose pregnant women used and the exact point in in postpartum hemorrhage [19]. It is also known that time it was taken. opioid analgesics administered during labor in the form of In conclusion, the fact that codeine use during pregnancy epidural analgesia are implicated in uterine atony [20, 21]. hadnoeffectoninfant survivalorcongenitalmalformation Failure or weakening of myometrial contractions may rate is particularly reassuring considering the size and result in excessive postpartum hemorrhage as well as singularity of this cohort study and the accuracy of pregnancy Cesarean delivery [18]. However, atonic uterus and outcome reporting. We found an association between codeine prolonged labor, cesarean delivery, induction of labor, use anytime during pregnancy and planned Cesarean delivery epidural analgesia, third- or fourth-grade perineal tears and and between third-trimester codeine use and acute Cesarean high birth weight, preeclampsia and/or eclampsia, placenta delivery and excessive postpartum hemorrhage. Whereas the previa, and abruptio placentae, among others (a full list is increased risk of Cesarean delivery, in particular, may be available in the ESM 1: Confounding factors), were all caused by underlying medical conditions, a direct association controlled for in our analyses. It should be noted that the between codeine use toward the end of pregnancy and acute vast majority of women (98.3%) in the exposed group Cesarean delivery and postpartum hemorrhage cannot be definitively excluded. used codeine in a fixed combination with paracetamol. However, we found no evidence of a possible association between paracetamol and increased risk of acute Cesarean delivery or postpartum hemorrhage. Grants The Norwegian Mother and Child Cohort Study is Several study strengths and limitations merit specific supported by the Norwegian Ministry of Health and the Ministry of attention. Our study is the only prospective cohort study on Education and Research, NIH/NIEHS (contract no NO-ES-75558), NIH/NINDS (grant No.1 UO1 NS 047537–01), and the Norwegian codeine use during pregnancy. Information derived from Research Council/FUGE (grant no.151918/S10). We are grateful to all both MoBa and NMBR provided us with an extensive array participants and their families for taking part in this study. of medical and sociodemographic characteristics of the study population. This enabled us to control for a very large number of—but not all—important confounding factors. Conflict of interest The authors declare that they have no conflict of interest. Several validity studies concluded that the accuracy of registration of major congenital malformations is satisfac- torily high [22, 23]. The prospective collection of the Open Access This article is distributed under the terms of the Creative majority of data greatly reduced the risk of recall bias. Commons Attribution Noncommercial License which permits any Differential reporting by the pregnant women was also noncommercial use, distribution, and reproduction in any medium, avoided, as their pregnancy outcome was unknown to most provided the original author(s) and source are credited. of them at the time of data collection. In contrast to many other large studies, the chances of obtaining false positive associations due to multiple testing were reduced by References including a minimum number of cases (more than four) in the final analysis. Moreover, all associations that were 1. Andrade S, Gurwitz J, Davis R, Chan A, Finkelstein J, Fortman K et statistically significant had P values <0.0001. On the other al (2004) Prescription drug use in pregnancy. AJOG 191:398–407 Eur J Clin Pharmacol (2011) 67:1253–1261 1261 2. Rubin J, Ferencz C, Loffredo C, The Baltimore-Washington Infant 14. Norwegian Institute of Public Health (2010) The Norwegian Study Group (1993) Use of prescription and non-prescription Mother and Child Cohort Study. Oslo, Norway drugs in pregnancy. J Clin Epidemiol 46:581–589 15. Nilsen R, Vollset S, Gjessing H, Skjærven R, Melve K, Schreuder 3. Engeland A, Bramness J, Daltveit A, Rønning M, Skurtveit S, Furu K P et al (2009) Self-selection and bias in a large prospective (2008) Prescription drug use among fathers and mothers before and pregnancy cohort in Norway. Paediatr Perinat Epidemiol 23:597– during pregnancy. A population-based cohort study of 106 000 608 pregnancies in Norway 2004–2006. Br J Clin Pharmacol 65:653–660 16. Norwegian Institute of Public Health (2010) Medisinsk fødselsregister. 4. Cook M, Olshan A, Guess H, Savitz D, Poole C, Blatt J et al Oslo, Norway (2004) Maternal medication use and neuroblastoma in offspring. 17. WHO Collaborating Centre for Drug Statistics Methodology. Am J Epidemiol 159:721–731 ATC/DDD Index 2008 5. Saxen I (1975) Associations between oral clefts and drugs taken 18. Leveno KJ, Cunningham FG, Alexander JM, Bloom SL, Casey during pregnancy. Int J Epidemiol 4:37–44 BM, Dashe JS et al (2007) Williams manual of obstetrics: 6. Bracken M, Holford T (1981) Exposure to prescribed drugs in Pregnancy complications. McGraw-Hill, New York pregnancy and association with congenital malformation. Obstet 19. Eskild A, Vatten LJ (2009) Abnormal bleeding associated with Gynecol 58:336–344 preeclampsia: a population study of 315,085 pregnancies. Acta 7. Mangurten H, Benawra R (1980) Neonatal codeine withdrawal in Obstet Gynecol Scand 88:154–158 infants of nonaddicted mothers. Pediatrics 65:159–160 20. Liu EHC, Sia ATH (2004) Rates of caesarean section and 8. Reynolds E, Riel-Romero R, Bada H (2007) Neonatal abstinence instrumental vaginal delivery in nulliparous women after low syndrome and cerebral infarction following maternal codeine use concentration epidural infusions or opioid analgesia:systematic during pregnancy. Clin Pediatr 46:639–645 review. BMJ 329:293–298 9. Schaefer C, Peters P, Miller RK (2007) Drugs during pregnancy 21. Kjærgaard H, Olsen J, Ottesen B, Nyberg P, Dykes A-K (2008) and lactation. Elsevier, Amsterdam Obstetric risk indicators for labour dystocia in nulliparous 10. Mayet S, Groshkova T, Morgan L, Maccormack T, Strang J (2008) women: a multi-centre cohort study. BMC Pregnancy Child- Drugs and pregnancy - outcomes of women engaged with a birth 8:1–8 specialist perinatal outreach addictions service. Drug Alcohol Rev 22. Melve K, Lie R, Skjærven R, Van Der Hagen C, Gradek G, 27:497–503 Jonsrud C et al (2008) Registration of Down syndrome in the 11. Almario CV, Seligman NS, Dysart KC, Berghella V, Baxter JK Medical Birth Registry of Norway: validity and time trends. Acta (2009) Risk factors for preterm birth among opiate-addicted Obstet Gynecol Scand 87:824–830 gravid women in a methadone treatment program. Am J Obstet 23. Kubon C, Sivertsen A, Vindenes H, Abyholm F, Wilcox A, Lie R Gynecol 201:326.e1–6 (2007) Completeness of registration of oral clefts in a medical 12. Vucinovic M, Roje D, Vucinovic Z, Capkun V, Bucat M, Banovic birth registry: a population-based study. Acta Obstet Gynecol I (2008) Maternal and neonatal effects of substance abuse during Scand 86:1453–1457 pregnancy: our ten-year experience. Yonsei Med J 49:705–713 24. Magnus P, Irgens L, Haug K, Nystad W, Skjærven R, Stoltenberg 13. Briggs G, Freeman R, Yaffe S (2005) Drugs in pregnancy and C et al (2006) Cohort profile: The Norwegian mother and child lactation. Lippincott Williams & Wilkins, Philadelphia cohort study (MoBa). Int J Epidemiol 35:1146–1150 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Pharmacology Pubmed Central

Effects of codeine on pregnancy outcome: results from a large population-based cohort study

European Journal of Clinical Pharmacology , Volume 67 (12) – Jun 9, 2011

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Pubmed Central
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© The Author(s) 2011
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0031-6970
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1432-1041
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10.1007/s00228-011-1069-5
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Abstract

Eur J Clin Pharmacol (2011) 67:1253–1261 DOI 10.1007/s00228-011-1069-5 PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Effects of codeine on pregnancy outcome: results from a large population-based cohort study Kateřina Nezvalová-Henriksen & Olav Spigset & Hedvig Nordeng Received: 24 January 2011 /Accepted: 23 May 2011 /Published online: 9 June 2011 The Author(s) 2011. This article is published with open access at Springerlink.com Abstract set and the Medical Birth Registry of Norway (MBRN) data Background Guidelines on codeine safety during pregnancy set. The data sets were linked via the maternal personal rely on small studies with inconsistent results, and associa- identification number. Associations between codeine therapy tions between codeine use during pregnancy and increased and pregnancy outcomes were identified using logistic risk of congenital malformations remain unsubstantiated. regression analyses. Objectives Our objective was to analyze the effect of Results No significant differences were found in the codeine on pregnancy outcome. survival rate [adjusted odds ratio (OR) 0.9, 95% confidence Methods Pregnancy outcomes of 2,666 women who used interval (CI) 0.6–1.5] or the congenital malformation rate codeine during pregnancy were compared with 65,316 (adjusted OR 0.9, 95% CI 0.8–1.1) between codeine- women who used no opioids during pregnancy. Information exposed and unexposed infants. Codeine use anytime on maternal sociodemographic and medical characteristics, during pregnancy was associated with planned Cesarean potential confounders, and pregnancy outcome was delivery (adjusted OR 1.4, 95% CI 1.2–1.7; P<0.0001). obtained from The Norwegian Mother and Child Cohort Third-trimester use was associated with acute Cesarean Study [den norske Mor & barn-undersøkelsen (MoBa)] data delivery (adjusted OR 1.5, 95% CI 1.3–1.8; P<0.0001) and postpartum hemorrhage (adjusted OR 1.3, 95% CI 1.1–1.5; P<0.0001). No significant associations with other adverse Electronic supplementary material The online version of this article (doi:10.1007/s00228-011-1069-5) contains supplementary material, pregnancy outcomes were found. which is available to authorized users. Conclusions No effects of maternal codeine intake during K. Nezvalová-Henriksen (*) H. Nordeng pregnancy were observed on infant survival or congenital Department of Social Pharmacy, School of Pharmacy, malformation rate. Our findings are reassuring; however, Faculty of Mathematics and Natural Sciences, University of Oslo, the association with acute Cesarean delivery and postpar- Sem Sælands vei 3, tum hemorrhage may justify a certain level of caution when 0316 Oslo, Norway e-mail: katerina.nezvalova-henriksen@farmasi.uio.no administering codeine toward the end of pregnancy. O. Spigset . . Keywords Codeine Delivery complications Pregnancy Department of Clinical Pharmacology, outcome St Olav’s University Hospital, 7006 Trondheim, Norway O. Spigset Introduction Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, 7491 Trondheim, Norway Few studies address the safety of codeine use during pregnancy despite its extensive use as an analgesic and H. Nordeng antitussive in the general population. The frequency of Division for Mental Health, National Institute of Health, codeine use during pregnancy has been shown to range Marcus Thranes gate 6, between 1% and 3.5% [1–3]. Studies specifically targeting 0473 Oslo, Norway 1254 Eur J Clin Pharmacol (2011) 67:1253–1261 codeine safety during pregnancy are either small case– Public Health. The overall aim of the study is to examine control studies or case reports with inherent methodological the effect of a vast number of exposures on pregnancy limitations that generally warrant cautious interpretation. outcome and maternal and fetal health during pregnancy No data from cohort studies are available to date. One case– and postpartum. Data were obtained from three self- control study of 504 children with neuroblastoma found an administered questionnaires answered by pregnant women association with in utero exposure to codeine [odds ratio who participated in the study between 1999 and 2006. (OR) 3.4, 95% confidence interval (CI) 1.4–8.4] [4]. Pregnant women received a postal invitation with an Another of 599 infants found that mothers who gave birth informed consent form and the first questionnaire prior to to infants with cleft palate or cleft lip with or without cleft their first ultrasound scan during gestational weeks 17 or palate used opioid analgesics (mainly codeine) much more 18. This first questionnaire covered the time period between frequently than the control group; the largest difference was the 6 months prior to pregnancy and the 18th gestational seen for codeine use during the first trimester (8.6% week. The second questionnaire covered the time period compared with 2.1% of infants in the control group; P< between the 19th and 29th gestational week, and the third 0.01) [5]. In a third case–control study of 1,370 infants, 12 questionnaire covered the time period from the 30th infants with major congenital malformations had been gestational week until birth. The questionnaires covered exposed to codeine during the first trimester compared sociodemographic and lifestyle data, maternal medical with seven in the control group (OR 3.7, Fisher’s one-tailed history, maternal health during the pregnancy, drug use, P value 0.004) [6]. Neonatal abstinence syndrome has been and neonatal health. The overall response rate was 43.5% described in two cases in which codeine was used by the [15]. The MBRN [16] encompasses all births in Norway mother over a period of several days close to term [7]. Two and has been prospectively collecting data on all deliveries other reports described an association between neonatal since 1967. Approximately 60,000 infants are born in abstinence syndrome and possibly cerebral infarction after Norway every year, corresponding to an annual birth rate of maternal intake of codeine close to term [8]. 1.2 infants per 100 inhabitants. Data stem from mandatory Evidently, most of studies and case reports focus either standardized forms filled out by midwives, obstetricians, on the possible teratogenicity of codeine or neonatal and/or pediatricians at each delivery and from the mother’s abstinence syndrome. The latter has mainly been shown to pregnancy medical records. The standardized forms cover be associated with other opioids [9]. Other pregnancy sociodemographic and lifestyle information on the mother outcomes, including postpartum complications, have only and medical information including maternal health prior to been studied in populations using opioid analgesics in and during pregnancy as well as delivery and postpartum general and those of addicted pregnant women [10–12] and complications and interventions. Data from the two sources not in pregnant women taking codeine in therapeutic doses. were linked via the woman’ personal identification number, It is likely that these studies were subject to bias due to which is assigned to every legal resident in Norway. The inclusion of populations with very specific sociodemo- study was approved by the Regional Committee for Ethics graphic and lifestyle characteristics, and the effects of in Medical Research, Region South, and the Norwegian codeine use as such would thus be difficult to evaluate [10– Data Inspectorate. 12]. Notwithstanding, leading literature sources on the safety of drug use during pregnancy suggest that sporadic Study population use of codeine is safe except toward the end of pregnancy [9, 13]. The original quality-assured data file released for research Using data from a large prospective cohort study, our in 2008 (version 4) consisted of data on 72,934 women. All aim was to evaluate the potential teratogenicity of codeine these women had a pregnancy outcome registered in the and investigate possible associations with other adverse MBRN. Prior to release of this data file, 3.5% of the pregnancy outcomes that have not been studied so far. women in the study did not have a pregnancy outcome registered, mainly due to spontaneous abortions that happened early on in pregnancy. Of the 72,934 women, Methods 3,005 who did not complete the first questionnaire were excluded. A total of 69,929 pregnant women with records Data for this study were retrieved from The Norwegian both in both data sets were eligible for inclusion (95.9% of Mother and Child Cohort Study [den norske Mor & barn- the original data file). In addition, women using opioids undersøkelsen (MoBa)] data set (version four) released in other than codeine (i.e., ethylmorphine, morphine, ketobe- December 2008 and from records from the Medical Birth midone, tramadol, pethidine, dextropropoxyphene, oxy- Registry of Norway(MBRN). MoBa [14] is a prospective codone, buprenorphine, and methadone) (n=1,664) and cohort study conducted by the Norwegian Institute of women using both codeine and one or several of the Eur J Clin Pharmacol (2011) 67:1253–1261 1255 aforementioned opioids (n=283) were excluded. The final current information on codeine safety during pregnancy and study population therefore consisted of 67,982 women studies on the effect of opioid analgesics on pregnancy (93.2% of the original data file). Multiple pregnancies were outcome and labor progress, with special focus on included; however, only data on the first-born infant were prolonged labor and neonatal complications. The chosen used, as only these were linked to maternal data. variables consisted of any congenital malformations detected at birth, major congenital malformations detected Explanatory variables at birth, survival (live birth, miscarriage/stillbirth, perinatal death, death during the first 12 months of life), birth weight Explanatory variables consisted of the following subsets: (i) <2,500 g, gestational age <37 weeks, Apgar scores <7 at 1 pregnant women who used codeine (alone or in a fixed and 5 min, neonatal respiratory depression, neonatal combination with paracetamol) during pregnancy (total) hypoglycemia, newborn admitted to intensive care unit, (yes/no); (ii) pregnant women who used codeine (alone or acute Cesarean delivery, planned Cesarean delivery, atonic in a fixed combination with paracetamol) during the first uterus, prolonged labor, and postpartum hemorrhage trimester (gestational weeks 0–12) (yes/no); (iii) pregnant >500 ml. All outcome variables were dichotomized into women who used codeine (alone or in a fixed combination yes or no categories. with paracetamol) during the second trimester (gestational weeks 13–28) (yes/no); (iv) pregnant women who used Statistical analysis codeine (alone or in a fixed combination with paracetamol) during the third trimester (gestational week 29 until Logistic regression analyses were performed to identify delivery) (yes/no). Drug therapy was classified and grouped significant associations between codeine therapy and according to the Anatomical Therapeutic Chemical (ATC) pregnancy outcome. Subsets of confounding factors were classification system developed by the World Health Organi- selected for each pregnancy outcome depending on clinical zation (WHO) [17]. ATC codes used were R05DA04 plausibility, statistical significance, and size of outcome (codeine alone) and N02AA59 (codeine in a fixed combi- event rates (a full list of confounding factors controlled for in nation with paracetamol). Codeine in fixed combinations each analysis is available in the ESM 1: Confounding with acetylsalicylic acid or other nonsteroidal antiinflamma- factors). Confounding factors controlled for in logistic tory drugs is not available in Norway. The explanatory regression analyses were chosen on the basis of theoretical variable subsets were created using answers to questions clinical significance and initial Pearson’s χ analyses, where regarding both codeine use and maternal illness in ques- the P value was <0.25. Preliminary logistic regression tionnaires one and two as long as the ATC code for codeine analyses enabled the subsequent removal of potential and the timing of either codeine use or the medical condition confounding variables, with a P value of >0.5, with the was specified. Subanalyses were performed to investigate exception of instances in which the coefficient change of the possible associations between the extent of codeine use exposure variable was >20%. The final logistic regression (number of days used, categorized as 1–7days, 8–14 days, models for pregnancy outcome included statistically signifi- and >14 days) and pregnancy outcome. cant variables and clinically plausible interactions only. The threshold for retaining these variables in the final logistic Confounding factors regression model was P<0.05. Potential multicollinearity among the independent variables was identified using Confounding factors included sociodemographic, lifestyle, multiple regression analysis. Tolerance values for multi- and medical characteristics (Tables 1 and 2), concomitant collinearity were set at >0.5. Hosmer and Lemeshow drug use (Table 3) (this information was derived from goodness-of-fit tests >0.5 indicated robust models and were theMoBa questionnaires), and factors related to delivery considered valid in the logistic regression analyses. All (this information was derived from the MBRN). Different statistical analyses were performed with the Statistical potential confounding factors, the majority of which are Package for Social Sciences SPSS for Windows version listed in Tables 1–4 were selected for each pregnancy 16.1 (SPSS, Chicago, IL, USA). Risk ratio estimates are outcome. (Please find the complete list of confounding given as odds ratios (OR) with 95% confidence intervals (CI). factors used in the analyses in Electronic supplementary material (ESM) 1: Confounding factors.) Results Outcome variables Of the 67,982 pregnant women in the study, 2,666 (3.9%) Outcome variables were retrieved from both MoBa and used codeine during pregnancy (exposed group), whereas MBRN. The choice of outcome variables was based on 65,316 (96.1%) did not (unexposed group). In the exposed 1256 Eur J Clin Pharmacol (2011) 67:1253–1261 Table 1 Maternal characteristics of the study population Women who used codeine during Women who did not use opioids during pregnancy; exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % Maternal age (years) < 20 32 1.2 714 1.1 20 – 29 1,194 44.8 28,840 44.1 30 – 39 1,380 51.8 34,530 52.9 ≥ 40 60 2.2 1,234 1.9 Parity 0 1,153 43.2 28,523 43.7 ≥1 1,513 56.7 36,787 56.3 Plurality 1 2,611 97.9 64,123 98.2 > 1 55 2.1 1,193 1.8 Ethnicity Of Norwegian descent 2,572 96.5 61,782 94.6 Not of Norwegian descent 94 3.5 3,534 5.4 Marital status Married/cohabiting 2,553 95.8 63,484 97.2 Other 113 4.2 1,832 2.8 Education Primary 80 3.0 1623 2.5 Secondary 1,005 37.7 20,803 31.8 Tertiary 1,525 57.2 41,607 63.4 BMI prior to pregnancy (kg/m ) < 18.5 65 2.4 2,002 3.1 18.5 – 25.0 1,479 55.5 41,930 64.2 > 25.0 1,050 39.4 19,483 29.8 Folic acid intake prior to pregnancy 596 22.3 15,041 23.0 Sick leave lasting longer than 2 weeks during pregnancy 1,023 38.4 20,505 31.4 Smoking at gestational week 30 391 14.7 6,180 9.4 a ** Alcohol intake during pregnancy 1,421 53.3 3,3512 51.3 Some data do not add up to the total due to missing values * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group, ** 2 Pearson’s χ test P<0.05 when compared with the unexposed control group Including data on sporadic intake and intake before the women were aware of their pregnancy group, 45 women used codeine alone and 2,621 used codeine infants when comparing the exposed (99.4% live births) with in a fixed combination with paracetamol. A higher proportion the unexposed (99.2% live births) groups (adjusted OR 0.9, of exposed women had attained lower levels of education, 95% CI 0.6–1.5] (Table 4). No significant difference in were not married or cohabiting with their partner, were overall congenital malformation rate was found when overweight (had a body mass index >25 kg/m )prior to comparing the exposed (4.9%) with the unexposed (5.0%) pregnancy, and smoked throughout pregnancy (Table 1). group (adjusted OR 0.9, 95% CI 0.8–1.1). No significant Moreover, these women were more likely to suffer from difference in the major congenital malformation rate was medical complications both prior to and during pregnancy found between the exposed (2.9%) and unexposed (2.9%) (Table 2). Concomitant nonsteroidal antiinflammatory drug group (adjusted OR 0.9, 95% CI 0.7–1.2) (Table 4). and psychotropic agent use was also significantly higher in Codeine use anytime during pregnancy was significantly the exposed group than in the unexposed group (Table 3). associated with an increased risk of acute Cesarean delivery No significant difference was found in the survival rate of (12.8% in the exposed group compared with 8.9% in the Eur J Clin Pharmacol (2011) 67:1253–1261 1257 Table 2 Maternal health and pregnancy complications Women who used codeine during Women who did not use opioids during pregnancy: exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % Maternal health during pregnancy Acute musculoskeletal pain 2,534 95.0 58,005 88.8 Migraine and/or headache 1,536 57.6 23,115 35.4 Proteinuria 766 28.7 13,262 20.3 Temperature>38.5°C fever associated with a rash 590 22.1 10,453 16.0 ** * Hospitalization 270 10.1 2,839 4.3 ***a Urinary tract infection and/or pyelonephritis 258 9.7% 5,371 8.2 Preeclampsia and/or eclampsia 157 5.9 2,592 4.0 Involved in an accident 122 4.7 2,003 3.1 a * High blood pressure during the first trimester 65 2.4 998 1.5 Maternal health prior to pregnancy Musculoskeletal pain (any) 1,892 71.0 34,562 52.9 Arthritis/Systemic Lupus Erythematosus/ 348 13.0 2,504 3.8 Fibromyalgia Depression 258 9.7 3,533 5.4 Asthma 190 7.1 2,885 4.4 Cardiac disease 140 5.2 2,108 3.2 **** Thyroid disorder 70 2.6 1,293 2.0 Diabetes (type I or II) 44 1.6 810 1.2 Obstetric complications Number of ultrasound examinations < 2 462 17.3 15,491 23.7 2 – 4 1,255 47.1 30,366 46.5 > 5 650 24.3 10,205 15.6 b * Vaginal bleeding during pregnancy 601 22.5 11,979 18.3 First trimester 498 18.7 10,027 15.3 Second and/or third trimesters 226 8.5 4,295 6.6 Oligohydramnios 62 2.3 1,506 2.3 **** Placenta previa 46 1.7 821 1.3 Polyhydramnios 32 1.2 556 0.8 Abruptio placentae 17 0.6 271 0.4 * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group, ** Excluding hospitalization due to vaginal bleeding and high blood pressure, *** 2 Pearson’s χ test P<0.01 when compared with the unexposed control group **** 2 Pearson’s χ test P<0.05 when compared with the unexposed control group. Defined as systolic blood pressure≥140 mmHg Vaginal bleeding lasting more than 1 day or of an amount exceeding a trace or two or more episodes of bleeding or vaginal bleeding which has led to hospitalization unexposed group) (adjusted OR 1.3, 95% CI 1.1–1.5), Upon analyzing the effects of codeine on pregnancy planned Cesarean delivery (7.4% in the exposed group outcome during the three specific trimesters, an increased compared with 5.0% in the unexposed group) (adjusted OR risk of planned Cesarean delivery was seen after exposure 1.4, 95% CI 1.2–1.7), and postpartum hemorrhage (18.3% in in the first (7.3%; adjusted OR 1.4, 95% CI 1.1–1.7), the exposed group compared with 14.5% in the unexposed second (7.5%; adjusted OR 1.5, 95% CI 1.2–1.8), and third group) (adjusted OR 1.2, 95% CI 1.1–1.4) (Table 4). (8.9%; adjusted OR 1.6, 95% CI 1.3–2.0) trimesters. Third 1258 Eur J Clin Pharmacol (2011) 67:1253–1261 Table 3 Frequency of concomitant nonsteroidal antiinflammatory drug and psychotropic agent use during pregnancy Drug Women who used codeine during Women who did not use opioids during pregnancy: exposed group (n=2,666) pregnancy: unexposed group (n=65,316) No. % No. % NSAIDs 759 28.5 8,271 12.6 Ibuprofen 470 17.6 6,269 9.6 Diclofenac 170 6.4 703 1.1 Naproxen 85 3.2 782 1.2 a * Other 185 6.9 1,323 2.0 Psychotropic agents 359 13.5 3,159 4.8 b * Antidepressants 172 6.4 1,935 3.0 c * Anxiolytics 132 4.9 788 1.2 d * Hypnotics 86 3.2 490 0.7 e * Antipsychotics 60 2.2 452 0.7 NSAIDS nonsteroidal anti-inflammatory drugs * 2 Pearson’s χ test P<0.001 when compared with the unexposed control group Including piroxicam, meloxicam, indomethacin, acetylsalicylic acid, ketoprofen, nabumetone, and tolfenamic acid Including selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mianserin, mirtazapine, and venlafaxine Including diazepam, oxazepam, alprazolam, hydroxyzine, and buspirone Including nitrazepam, flunitrazepam, zopiclone, and zolpidem Including levomepromazine, perphenazine, prochlorperazine, flupenthixol, zuclopenthixol, olanzapine, quetiapine, and risperidone trimester use was, in addition, associated with an increased rely either on data regardng opioid analgesic use in general risk of acute Cesarean delivery (15.1%; adjusted OR 1.5, or a few case studies [9, 13], we found no increased risk of 95% CI 1.3–1.8) and postpartum hemorrhage (20.3%; congenital malformations or neonatal respiratory depres- adjusted OR 1.3, 95% CI 1.1–1.5) (Table 4). Subanalyses sion. Associations of codeine use during pregnancy and on the effect of codeine therapy duration on pregnancy neonatal abstinence syndrome were unfortunately not outcomes revealed that codeine use lasting >14 days was feasible to evaluate, as neonatal abstinence syndrome significantly associated with planned (but not acute) scores were not routinely applied. However, neither low Cesarean delivery (unadjusted OR 3.2, 95% CI 1.3–7.9). Apgar scores nor admission of the neonate to intensive care No dose–effect relationship was found for postpartum were associated with codeine use during pregnancy, and hemorrhage. these outcomes are also partly representative of neonatal abstinence syndrome. Of other adverse pregnancy outcomes, the strongest Discussion association was between codeine use during pregnancy and increased risk of planned Cesarean delivery. This associa- Information on the safety of analgesic use during pregnancy tion remained significant, even after controlling for several is an important issue for all clinicians prescribing these clinically and statistically significant potential confounders, drugs to pregnant women. It is often not feasible to including high birth weight, fetal malpresentation, plurality, prescribe the more thoroughly documented nonopioid placenta previa, and others (a full list is available in the analgesics either for safety reasons or lack of adequate ESM 1: Confounding factors). A dose–effect relationship pain relief. The safety profiles of as many different between codeine and planned Cesarean delivery was also analgesics as possible must be known before an individual detected. Nevertheless, we believe it is highly likely that the risk–benefit evaluation can be done. In this study, codeine association was due to underlying medical conditions. use during pregnancy was not found to be associated with Thirteen percent of exposed women suffered from chronic infant survival rate, congenital malformation rate, or other conditions, including arthritis, systemic lupus erythemato- adverse pregnancy outcomes, except for Cesarean delivery sus, and fibromyalgia, compared with only 3% in the and excessive postpartum hemorrhage. Unlike previous unexposed group; almost 10% had depression compared with only 5% of the unexposed women; a significantly studies [4, 5, 7, 8] and other medical literature sources that Eur J Clin Pharmacol (2011) 67:1253–1261 1259 Table 4 Adjusted Odds Ratios (OR) for pregnancy outcome in women who used codeine during pregnancy compared with the unexposed control group Pregnancy outcome Women who used codeine during pregnancy: exposed group Women who did not use opioids during pregnancy: unexposed group (n=65,316) Total pregnancy (n=2,666) First trimester (gestational Second trimester (gestational Third trimester (gestational weeks 0–12) (n=1,693) weeks 13–28) (n=1,955) week 29 until delivery) (n=1,255) No. % OR 95%CI No. % OR 95%CI No. % OR 95%CI No. % OR 95%CI No. % Congenital malformations detected at birth Any 130 4.9 0.9 0.8 – 1.1 77 4.5 0.9 0.7 – 1.1 91 4.7 0.9 0.7 – 1.1 67 5.3 1.0 0.7 – 1.3 3,247 5.0 Major 77 2.9 0.9 0.7 – 1.2 40 2.4 0.8 0.5 – 1.1 50 2.6 0.8 0.6 – 1.1 45 3.6 1.1 0.8 – 1.6 1,904 2.9 Survival (live birth) 2,649 99.4 0.9 0.6 – 1.5 1,677 99.1 0.6 0.4 – 1.0 1,939 99.2 0.7 0.4 – 1.2 1,252 99.8 2.4 0.7 – 7.5 64,797 99.2 Birth weight<2500 g 124 4.7 1.1 0.9 – 1.3 78 4.6 1.1 0.8 – 1.4 94 4.8 1.1 0.9 – 1.4 63 5.0 1.1 0.8 – 1.5 2,579 3.9 Gestational age<37 weeks 209 7.8 1.1 0.9 – 1.3 132 7.8 1.1 0.9 – 1.4 151 7.7 1.1 0.9 – 1.3 106 8.4 1.2 0.9 – 1.5 3,910 6.0 Apgar score < 7 at 1 min 183 6.9 1.2 1.0 – 1.5 118 7.0 1.3 1.0 – 1.6 131 6.7 1.2 1.0 – 1.5 83 6.6 1.2 0.9 – 1.6 3,506 5.4 < 7 at5 min 44 1.7 1.3 0.9 – 1.9 33 1.9 1.6 1.0 – 2.6 35 1.8 1.5 0.9 – 2.3 15 1.2 1.0 0.5 – 1.8 875 1.3 Neonatal respiratory depression 131 4.9 1.0 0.9 – 1.3 76 4.5 0.9 0.7 – 1.2 88 4.5 0.9 0.7 – 1.1 65 5.2 1.1 0.8 – 1.4 2,706 4.1 Hypoglycemia 72 2.7 1.1 0.8 – 1.4 45 2.7 1.0 0.7 – 1.4 50 2.6 1.0 0.7 – 1.4 41 3.3 1.2 0.9 – 1.7 1,415 2.2 Newborn admitted to intensive care unit 337 12.6 1.1 1.0 – 1.3 197 11.6 1.0 0.9 – 1.2 233 11.9 1.1 0.9 – 1.2 176 14.0 1.1 1.0 – 1.4 6,520 10.0 * * Cesarean delivery (acute) 340 12.8 1.3 1.1 – 1.5 191 11.3 1.1 0.9– 1.3 223 11.4 1.1 0.9 – 1.3 189 15.1 1.5 1.3 – 1.8 5,834 8.9 * * * * Cesarean delivery (planned) 198 7.4 1.4 1.2 – 1.7 124 7.3 1.4 1.1– 1.7 147 7.5 1.5 1.2 – 1.8 112 8.9 1.6 1.3 – 2.0 3,265 5.0 Atonic uterus 137 5.1 1.2 1.0 – 1.5 88 5.2 1.3 1.0 – 1.6 97 5.0 1.2 1.0 – 1.5 69 5.5 1.3 1.0 – 1.7 2,808 4.3 Prolonged labor 217 8.1 1.1 0.9 – 1.2 128 7.6 1.0 0.8 – 1.2 149 7.6 1.0 0.9 – 1.2 99 7.9 1.0 0.8 – 1.2 4,542 7.0 b * * * Postpartum hemorrhage 489 18.3 1.2 1.1 – 1.4 301 17.8 1.2 1.1 – 1.4 344 17.5 1.2 1.0 – 1.4 255 20.3 1.3 1.1 – 1.5 9,488 14.5 CI confidence interval Pearson’s χ2 test P<0.0001 Labor lasting >18 h Hemorrhage >500 ml 1260 Eur J Clin Pharmacol (2011) 67:1253–1261 higher number of exposed women had asthma and hand, a difference in the prevalence of drug use and cardiac disease; about 10% were hospitalized during pregnancy outcomes in the study population compared with pregnancy compared with 4% of the unexposed group; the general population may have occurred, as participant and 5.9% had preeclampsia and/or eclampsia compared response rate was only 43.5%. However, it has been shown with 4% of the unexposed group. Several of these that only minor differences (<2% in absolute differences in diseases and conditions, which were not feasible to sociodemographic variables) between MoBa participants control for in this particular analysis, are associated with and the general population of pregnant women exist, and no planned Cesarean delivery [18]. Association codeine differences in the estimates of association measures were therapy duration may also be indicative of the severity of found between participants and the general population [15, the underlying medical conditions. 24]. Despite this, the risk of false negative associations due Notwithstanding, we cannot definitively exclude a to underrepresentation of certain sociodemographic groups, direct association between codeine and acute Cesarean possible underreporting of codeine use during pregnancy, delivery and postpartum hemorrhage. A study on and the rarity of some pregnancy outcomes such as major 315,085 pregnancies concluded that preeclampsia was malformations, should be taken into account. Analyses on significantly associated with postpartum hemorrhage and specific malformations could not be undertaken due to low postulated that a deprivation of angiogenic factors statistical power. It was also not feasible to determine the resulting in the preeclamptic state may also play a role codeine dose pregnant women used and the exact point in in postpartum hemorrhage [19]. It is also known that time it was taken. opioid analgesics administered during labor in the form of In conclusion, the fact that codeine use during pregnancy epidural analgesia are implicated in uterine atony [20, 21]. hadnoeffectoninfant survivalorcongenitalmalformation Failure or weakening of myometrial contractions may rate is particularly reassuring considering the size and result in excessive postpartum hemorrhage as well as singularity of this cohort study and the accuracy of pregnancy Cesarean delivery [18]. However, atonic uterus and outcome reporting. We found an association between codeine prolonged labor, cesarean delivery, induction of labor, use anytime during pregnancy and planned Cesarean delivery epidural analgesia, third- or fourth-grade perineal tears and and between third-trimester codeine use and acute Cesarean high birth weight, preeclampsia and/or eclampsia, placenta delivery and excessive postpartum hemorrhage. Whereas the previa, and abruptio placentae, among others (a full list is increased risk of Cesarean delivery, in particular, may be available in the ESM 1: Confounding factors), were all caused by underlying medical conditions, a direct association controlled for in our analyses. It should be noted that the between codeine use toward the end of pregnancy and acute vast majority of women (98.3%) in the exposed group Cesarean delivery and postpartum hemorrhage cannot be definitively excluded. used codeine in a fixed combination with paracetamol. However, we found no evidence of a possible association between paracetamol and increased risk of acute Cesarean delivery or postpartum hemorrhage. Grants The Norwegian Mother and Child Cohort Study is Several study strengths and limitations merit specific supported by the Norwegian Ministry of Health and the Ministry of attention. Our study is the only prospective cohort study on Education and Research, NIH/NIEHS (contract no NO-ES-75558), NIH/NINDS (grant No.1 UO1 NS 047537–01), and the Norwegian codeine use during pregnancy. Information derived from Research Council/FUGE (grant no.151918/S10). We are grateful to all both MoBa and NMBR provided us with an extensive array participants and their families for taking part in this study. of medical and sociodemographic characteristics of the study population. This enabled us to control for a very large number of—but not all—important confounding factors. Conflict of interest The authors declare that they have no conflict of interest. Several validity studies concluded that the accuracy of registration of major congenital malformations is satisfac- torily high [22, 23]. The prospective collection of the Open Access This article is distributed under the terms of the Creative majority of data greatly reduced the risk of recall bias. 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European Journal of Clinical PharmacologyPubmed Central

Published: Jun 9, 2011

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