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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

A Scandinavian cohort of pregnant women in opioid maintenance treatment during pregnancy: long term consequences for the child

Alternative title: Legemiddelassistert rehabilitering av opioidavhengigige gravide; en skandinavisk studie av langtidseffekter på barnet

Awarded: NOK 5.2 mill.

Opioid maintenance treatment (OMT) compared to continued illicit opioid use during pregnancy, has been shown to have positive effects for both the pregnant woman and the offspring. However, it has also been shown that maternal OMT is not without risk to the fetus. Earlier studies have mainly been performed on small, selected groups of women in countries with large socioeconomic differences, and the quality of the studies have been rated as low. Therefore, more knowledge about the impact of OMT during pregnancy is needed. We are conducting a large registry linkage study on all pregnant women who receive OMT in Norway, Sweden and Denmark and will focus on long-term effects of such treatment in the offspring. A register linkage study is well suited to investigate the effects of OMT, because of large study samples and the possibility to include all pregnant women who receive OMT drugs (methadone and buprenorphine) in all the countries. Socioeconomic differences are considered small in Scandinavian countries. We will focus on long-term effects of maternal OMT during pregnancy for the child's health, such as whether they are at increased risk for epilepsy, ADHD, anxiety, or sleep disorders. Data on pregnant women in OMT treatment, as well as all other pregnant women, from central health registers and other registers in Norway, Sweden, and Denmark will form the basis for the analyzes. From previous studies, we know that women in OMT have more comorbidity and use more prescription drugs than other pregnant women use. This will be taken into account. We will study whether there are differences between the different OMT drugs, and whether the doses used are of importance with respect to possible long-term effects in the offspring. It has taken time to establish the Scandinavian register linkage, and in the meantime, we have used Norwegian and Czech registry data to study some of the aims in the project. Based on these data, there were no statistical differences in neonatal outcomes between children prenatally exposed to buprenorphine compared to methadone, although buprenorphine children tended to have better birth parameters. We did not find improved neonatal outcomes in OMT exposed newborns compared to neonates of women who continued opioid misuse during pregnancy. An exception was longer gestational age in OMT exposed children in the Norwegian cohort. This finding might indicate that socio-economic factors are of great importance for neonatal outcomes. With regard to long-term outcomes associated with OMT treatment, we have studied hospital admissions in childhood. We compared OMT exposed children with children of mothers who had stopped OMT treatment before pregnancy and with children of mothers with ongoing opioid drug misuse during pregnancy in the Czech Republic. In short, we found that the morbidity of the children in each of these three groups was similar, but higher than that of children in the general population. This supports the fact that background variables related to the pregnant woman's health, lifestyle and socioeconomic status, and not the use of the OMT drugs in pregnancy, were the most important for the child's morbidity since one of the three groups of pregnant women had only used opioids before, but not during pregnancy. We have also studied the differences of background variables such as health, lifestyle and socioeconomic variables in women who used different types of drugs during pregnancy in a Czech registry linkage study. This study showed that pregnant women who used drugs had a more unfavorable profile in terms of health, lifestyle and socioeconomic variables than women from the general population did, and that those who used illicit drugs (including opioids) had the most unfavorable profile compared to women who drank alcohol or abused prescription drugs (sedatives/hypnotics). In this study we also compared the proportion of children born "small for gestational age (SGA)" in the groups of children with different prenatal exposure. Compared to the children of the general population, only children of mothers who had consumed alcohol during pregnancy had an increased risk of SGA after adjusting for background variables. This study again emphasized the great importance of other factors in maternal health, lifestyle and socioeconomics not only for pregnant women using opioids, but also for pregnant women who use all types of drugs. We are still working with the Scandinavian data, and we will publish manuscripts on the remaining research questions in the near future. We have established new and advanced methods for causal inference analysis and preliminary results from these data support the results from the Norwegian/Czech Republic data that the maternal background characteristics are of great importance.

Den Skandinaviske registerkoblingen som er etablert i prosjektet er enestående i verdenssammenheng, og vil benyttes videre i forskning. Det er etablert nye metoder i prosjektet. Resultatene i prosjektet til nå har vært betryggende med hensyn på sikkerheten for fostret av bruk av LAR legemidler i svangerskapet. Vi forventer å publiserer flere resultatene som vil kunne gi mer informasjon om sikkerheten på lang sikt for barna. Våre resultater viser at kvinner som er i LAR behandling eller bruker rusmidler under svangerskapet har mange fellestrekk når det gjelder helse, livsstil og sosioøkonomisk status. Vi har også vist at disse faktorene har stor betydning for hvordan det går med barna. Det er derfor viktig å fokusere på å hjelpe kvinnene med å få god og helhetlig helsehjelp og at de får gode livsstilsråd og at man legger til rette for bedring av sosioøkpnomiske forhold hvis mulig i behandling av denne pasientgruppen.

Limited knowledge exists on long term outcomes in children born to opioid dependent mothers treated with methadone or buprenorphine during pregnancy as part of their Opioid Maintenance Treatment (OMT),but some studies suggest that e.g.asthma and ADHD are more frequent. Due to high prevalence of somatic and psychiatric problems, co-medication with other prescription drugs is common among pregnant women in OMT. Knowledge on risks from such co-medication is scarce and based on interviews and questionnaires which may be incomplete and biased. Reports indicate that co-medication contributes to adverse neonatal outcomes indicating that such medication has negative effects on the developing fetus and therefore may reinforce undesirable long-term effects of OMT drugs. More knowledge is needed to study if children exposed to OMT with or without co-medication are more prone to diseases than children born to mothers not in OMT. The main objective of the proposed study is therefore to study long term outcomes in children exposed to OMT during fetal life in a large pregnancy cohort in a Scandinavian setting. The role of prescription drugs common in pregnant women in OMT is a primary focus. In addition to studying OMT as one treatment we will also focus on potential differences in safety between methadone and buprenorphine, and dose administered. We will use a cohort design and link data form the unique health registries (Birth Registries, Prescription databases, Patient registries, KUHR and Databases for socio-economic data) in Norway, Sweden and Denmark. The study population will be the largest OMT pregnant population studied in observation studies to date and the cohort has necessary power to answer questions that offer invaluable knowledge for involved women and medical doctors working with this patient group and could form the basis for developing clinical guidelines for co-medication in pregnant women in OMT.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering