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Try out PMC Labs and tell us what you think. Learn More. Guidelines on codeine safety during pregnancy rely on small studies with inconsistentand associations between codeine use during pregnancy and increased risk of congenital malformations remain unsubstantiated. Our objective was to analyze the effect of codeine on pregnancy outcome. Pregnancy outcomes of 2, women who used codeine during pregnancy were compared with 65, women who used no opioids during pregnancy. The data sets were linked via the maternal personal identification.
Associations between codeine therapy and pregnancy outcomes were identified using logistic regression analyses. No ificant differences were found in the survival rate [adjusted odds ratio OR 0. Codeine use anytime during pregnancy was associated with planned Cesarean delivery adjusted OR 1. Third-trimester use was associated with acute Cesarean delivery adjusted OR 1. No ificant associations with other adverse pregnancy outcomes were found. No effects of maternal codeine intake during pregnancy were observed on infant survival or congenital malformation rate. Our findings are reassuring; however, the association with acute Cesarean delivery and postpartum hemorrhage may justify a certain level of caution when administering codeine toward the end of pregnancy.
The online version of this article doi Few studies address the safety of codeine use during pregnancy despite its extensive use as an analgesic and antitussive in the general population. Studies specifically targeting codeine safety during pregnancy are either small case—control studies or case reports with inherent methodological limitations that generally warrant cautious interpretation.
No data from cohort studies are available to date. One case—control study of children with neuroblastoma found an association with in utero exposure to codeine [odds ratio OR 3. Another of infants found that mothers who gave birth to infants with cleft palate or cleft lip with or without cleft palate used opioid analgesics mainly codeine much more frequently than the control group; the largest difference was seen for codeine use during the first trimester 8.
In a third case—control study of 1, infants, 12 infants with major congenital malformations had been exposed to codeine during the first trimester compared with seven in the control group OR 3. Neonatal abstinence syndrome has been described in two cases in which codeine was used by the mother over a period of several days close to term [ 7 ].
Two other reports described an association between neonatal abstinence syndrome and possibly cerebral infarction after maternal intake of codeine close to term [ 8 ]. Evidently, most of studies and case reports focus either on the possible teratogenicity of codeine or neonatal abstinence syndrome. The latter has mainly been shown to be associated with other opioids [ 9 ]. Other pregnancy Taking co codamol when pregnant, including postpartum complications, have only been studied in populations using opioid analgesics in general and those of addicted pregnant women [ 10 — 12 ] and not in pregnant women taking codeine in therapeutic doses.
It is likely that these studies were subject to bias due to inclusion of populations with very specific sociodemographic and lifestyle characteristics, and the effects of codeine use as such would thus be difficult to evaluate [ 10 — 12 ]. Notwithstanding, leading literature sources on the safety of drug use during pregnancy suggest that sporadic use of codeine is safe except toward the end of pregnancy [ 913 ].
Using data from a large prospective cohort study, our aim was to evaluate the potential teratogenicity of codeine and investigate possible associations with other adverse pregnancy outcomes that have not been studied so far. The overall aim of the study is to examine the effect of a vast of exposures on pregnancy outcome and maternal and fetal health during pregnancy and postpartum. Data were obtained from three self-administered questionnaires answered by pregnant women who participated in the study between and Pregnant women received a postal invitation with an informed consent form and the first questionnaire prior to their first ultrasound scan during gestational weeks 17 or This first questionnaire covered the time period between the 6 months prior to pregnancy and the 18th gestational week.
The second questionnaire covered the time period between the 19th and 29th gestational week, and the third questionnaire covered the time period from the 30th gestational week until birth. The questionnaires covered sociodemographic and lifestyle data, maternal Taking co codamol when pregnant history, maternal health during the pregnancy, drug use, and neonatal health. The overall response rate was The MBRN [ 16 ] encompasses all births in Norway and has been prospectively collecting data on all deliveries since Approximately 60, infants are born in Norway every year, corresponding to an annual birth rate of 1.
The standardized forms cover sociodemographic and lifestyle information on the mother and medical information including maternal health prior to and during pregnancy as well as delivery and postpartum complications and interventions. The original quality-assured data file released for research in version 4 consisted of data on 72, women. All these women had a pregnancy outcome registered in the MBRN.
Prior to release of this data file, 3.
Of the 72, women, 3, who did not complete the first questionnaire were excluded. A total of 69, pregnant women with records both in both data sets were eligible for inclusion In addition, women using opioids other than codeine i. The final study population therefore consisted of 67, women Multiple pregnancies were included; however, only data on the first-born infant were used, as only these were linked to maternal data.
Codeine in fixed combinations with acetylsalicylic acid or other nonsteroidal antiinflammatory drugs is not available in Norway. The explanatory variable subsets were created using answers to questions regarding both codeine use and maternal illness in questionnaires one and two as long as Taking co codamol when pregnant ATC code for codeine and the timing of either codeine use or the medical condition was specified.
Different potential confounding factors, the majority of which are listed in Tables 1 — 4 were selected for each pregnancy outcome. Please find the complete list of confounding factors used in the analyses in Electronic supplementary material ESM 1 : Confounding factors. Frequency of concomitant nonsteroidal antiinflammatory drug and psychotropic agent use during pregnancy.
Adjusted Odds Ratios OR for pregnancy outcome in women who used codeine during pregnancy compared with the unexposed control group. The choice of outcome variables was based on current information on codeine safety during pregnancy and studies on the effect of opioid analgesics on pregnancy outcome and labor progress, with special focus on prolonged labor and neonatal complications. All outcome variables were dichotomized into yes or no.
Logistic regression analyses were performed to identify ificant associations between codeine therapy and pregnancy outcome.
Subsets of confounding factors were selected for each pregnancy outcome depending on clinical plausibility, statistical ificance, and size of outcome event rates a full list of confounding factors controlled for in each analysis is available in the ESM 1: Confounding factors.
The final logistic regression models for pregnancy outcome included statistically ificant variables and clinically plausible interactions only. Potential multicollinearity among the independent variables was identified using multiple regression analysis. Of the 67, pregnant women in the study, 2, 3. In Taking co codamol when pregnant exposed group, 45 women used codeine alone and 2, used codeine in a fixed combination with paracetamol.
Moreover, these women were more likely to suffer from medical complications both prior to and during pregnancy Table 2. Concomitant nonsteroidal antiinflammatory drug and psychotropic agent use was also ificantly higher in the exposed group than in the unexposed group Table 3. No ificant difference was found in the survival rate of infants when comparing the exposed No ificant difference in overall congenital malformation rate was found when comparing the exposed 4.
No ificant difference in the major congenital malformation rate was found between the exposed 2. Codeine use anytime during pregnancy was ificantly associated with an increased risk of acute Cesarean delivery Upon analyzing the effects of codeine on pregnancy outcome during the three specific trimesters, an increased risk of planned Cesarean delivery was seen after exposure in the first 7.
Third trimester use was, in addition, associated with an increased risk of acute Cesarean delivery No dose—effect relationship was found for postpartum hemorrhage. Information on the safety of analgesic use during pregnancy is an important issue for all clinicians prescribing these drugs to pregnant women. It is often Taking co codamol when pregnant feasible to prescribe the more thoroughly documented nonopioid analgesics either for safety reasons or lack of adequate pain relief.
The safety profiles of as many different analgesics as possible must be known before an individual risk—benefit evaluation can be done. In this study, codeine use during pregnancy was not found to be associated with infant survival rate, congenital malformation rate, or other adverse pregnancy outcomes, except for Cesarean delivery and excessive postpartum hemorrhage. Unlike studies [ 4578 ] and other medical literature sources that rely either on data regardng opioid analgesic use in general or a few case studies [ 913 ], we found no increased risk of congenital malformations or neonatal respiratory depression.
Associations of codeine use during pregnancy and neonatal abstinence syndrome were unfortunately not feasible to evaluate, as neonatal abstinence syndrome scores were not routinely applied. However, neither low Apgar scores nor admission of the neonate to intensive care were associated with codeine use during pregnancy, and these outcomes are also partly representative of neonatal abstinence syndrome.
Of other adverse pregnancy outcomes, the strongest association was between codeine use during pregnancy and increased risk of planned Cesarean delivery. This association remained ificant, even after controlling for several clinically and statistically ificant potential confounders, including high birth weight, fetal malpresentation, plurality, placenta previa, and others a full list is available in the ESM 1: Confounding factors.
A dose—effect relationship between codeine and planned Cesarean delivery was also detected. Nevertheless, we believe it is highly likely that the association was due to underlying medical conditions. Several of these diseases and conditions, which were not feasible to control for in this particular analysis, are associated with planned Cesarean delivery [ 18 ].
Association codeine therapy duration may also be indicative of the severity of the underlying medical conditions. Notwithstanding, we cannot definitively exclude a direct association between codeine and acute Cesarean delivery and postpartum hemorrhage. A study onpregnancies concluded that preeclampsia was ificantly associated with postpartum hemorrhage and postulated that a deprivation of angiogenic factors resulting in the preeclamptic state may also play a role in postpartum hemorrhage [ 19 ].
It is also known that opioid analgesics administered during labor Taking co codamol when pregnant the form of epidural analgesia are implicated in uterine atony [ 2021 ]. Failure or weakening of myometrial contractions may result in excessive postpartum hemorrhage as well as Cesarean delivery [ 18 ].
It should be noted that the vast majority of women However, we found no evidence of a possible association between paracetamol and increased risk of acute Cesarean delivery or postpartum hemorrhage. Several study strengths and limitations merit specific attention. Our study is the only prospective cohort study on codeine use during pregnancy. Information derived from both MoBa and NMBR provided us with an extensive array of medical and sociodemographic characteristics of the study population. This enabled us to control for a very large of—but not all—important confounding factors.
Several validity studies concluded that the accuracy of registration of major congenital malformations is satisfactorily high [ 2223 ]. The prospective collection of the majority of data greatly reduced the risk of recall bias. Differential reporting by the pregnant women was also avoided, as their pregnancy outcome was unknown to most 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 including a minimum of cases more than four in the final analysis. On the other hand, a difference in the prevalence of drug use and pregnancy outcomes in the study population compared with the general population may have occurred, as participant response rate was only Despite this, the risk of false negative associations due to underrepresentation of certain sociodemographic groups, possible underreporting of codeine use during pregnancy, and the rarity of some pregnancy outcomes such as major malformations, should be taken into.
Analyses on specific malformations could not be undertaken due to low statistical power. It was also not feasible to determine the codeine dose pregnant women used and the exact point in time it was taken. In conclusion, the fact that codeine use during pregnancy had no effect on infant survival or congenital malformation rate is particularly reassuring considering the size and singularity of this cohort study and the accuracy of pregnancy outcome reporting.
We found an association between codeine use anytime during pregnancy and planned Cesarean delivery and between third-trimester codeine use and acute Cesarean delivery and excessive postpartum hemorrhage. Whereas the increased risk of Cesarean delivery, in particular, may be caused by underlying medical conditions, a direct association between codeine use toward the end of pregnancy and acute Cesarean delivery and postpartum hemorrhage cannot be definitively excluded.Taking co codamol when pregnant
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