Antiemetic treatment of hyperemesis gravidarum in 1,064 Norwegian women and the impact of European warning on metoclopramide: a retrospective cohort study 2002–2019

Background: Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and fetal complications. There is increasing and reassuring knowledge about safety of antiemetics in pregnancy. In 2013, the European Medical Agency (EMA) issued a warning on metoclopramide limiting treatment to maximum five days. Metoclopramide was the most used antiemetic in pregnancy at the time the warning was implemented in the Norwegian hyperemesis guidelines (2014). We aimed at describing changes in the treatment of hyperemesis over time, including changes associated with the EMA warning. Methods: Retrospective chart review of all women hospitalized for hyperemesis gravidarum with metabolic disturbances between 01/Jan/2002 and 31/Dec/2019 at a university hospital serving nearly 10% of the pregnant population in Norway. Time-series analysis described changes over time and interrupted time series analysis quantified changes in treatment and clinical outcomes related to the EMA warning. Results: In total, 1,064 women (1.2% of the birthing population) were included. The use of meclizine, prochlorperazine, and ondansetron increased during 2002–2019. This led to a yearly increase in the percentage of women using any antiemetic of 1.5% (95%CI 0.6; 2.4) pre-hospital, 0.6% (95%CI 0.2; 1.1) during hospitalization, and 2.6% (95%CI 1.3; 3.8) at discharge. Overall, only 50% of the women received antiemetics pre-hospital. Following the EMA warning, prehospital use of metoclopramide dropped by 30% (95%CI 25; 36), while use of any antiemetic pre-hospital dropped by 20% (95%CI 5.7; 34). In timely association, we observed a decrease in gestational age (-3.8 days, 98.75%CI 0.6; 7.1) at first admission, as well as indication of increased rate of termination of pregnancy with an absolute increase of 4.8% (98.75%CI 0.9; 8.7) in 2014. Conclusion: During 2002–2019, the overall use of antiemetics in treatment of hyperemesis increased. The EMA-warning on metoclopramide in 2013 temporarily limited pre-hospital antiemetic provision associated with hospitalization at lower gestational length and indication of an increase in termination of pregnancy.publishedVersio

The burden of nausea and vomiting during pregnancy: severe impacts on quality of life, daily life functioning and willingness to become pregnant again – results from a cross-sectional study

Background: Though nausea and vomiting is very common during pregnancy, no studies have investigated the impact of this condition on the women’s daily lives in a Scandinavian population. The aim of this study was to describe the burden of nausea and vomiting during pregnancy (NVP) on global quality of life, daily life functioning and willingness to become pregnant again according to the severity of NVP symptoms. Methods: This study is a cross-sectional population-based study conducted in Norway. Pregnant women and mothers with children <1 year of age with current or prior NVP were eligible to participate. Data were collected through an anonymous on-line questionnaire accessible from November 10th, 2014 to January 31st, 2015. Severity of NVP was measured using the 24-h Pregnancy Unique Quantification of Emesis Scale (PUQE). Associations between severity of NVP, daily life functioning and willingness to become pregnant again were tested using chisquare tests. Associations with global quality of life measured in terms of the Quality of Life Scale (QOLS) were estimated using generalized linear models and reported as unstandardized regression coefficients (β) with 95% confidence intervals (CI). Results: 712 women with NVP were included in the study. NVP was significantly associated with several characteristics, including daily life functioning, quality of life and willingness to become pregnant again. The negative impact was greater the more severe the symptoms were, although considerable adverse effects were also seen among women with mild and moderate NVP symptoms. Over one fourth of the women with severe NVP considered terminating the pregnancy due to NVP, and three in four considered not to get pregnant again. Severity of NVP remained significantly associated with reduced global quality of life when adjusting for maternal characteristics and illnesses with β (95% CI) = −10.9 (−16.9, −4.9) for severe versus mild NVP. Conclusions: NVP as measured by PUQE had a major impact on various aspects of the women’s lives, including global quality of life and willingness to become pregnant again.publishedVersio

Breastfeeding women in need of information about antiemetics for nausea and vomiting during pregnancy: a review of inquiries to a medicines information service

Introduction: The medicines information service, SafeMotherMedicine, regularly receives inquiries from breastfeeding women asking about antiemetics for nausea and vomiting during pregnancy (NVP) or hyperemesis gravidarum (HG). However, treatment guidelines for NVP or HG do not address the use of antiemetics in women who are breastfeeding while becoming pregnant again. Our objective was to characterize inquiries to describe the need for lactation risk information among women with NVP or HG and also to raise awareness of this topic.Method: We conducted a review of inquiries to the Norwegian web-based medicines information service, SafeMotherMedicine.Results: In total, 97 inquiries addressing the use of antiemetics for NVP or HG during breastfeeding were identified. The following medications were addressed in the inquiries (n = 97): meclizine (51%), metoclopramide (33%), promethazine (16%), ondansetron (9%), and others (6%). The breastfed child was older than 6 months and 1 year in 96% and 71% of the inquiries, respectively. There was a preponderance of general inquiries (unclear motivation/double checking) (64%); however, one-third of the inquiries were generated by restrictive information from sources such as product information.Conclusion: Based on our small review of spontaneous inquiries, there seems to be an information need about the use of antiemetics during lactation among women breastfeeding an older infant whilst suffering from NVP or HG. Addressing such use in guidelines for NVP and HG and/or other easily available information sources may be considered in order to balance out the restrictive information provided by the manufacturers. This could avoid potential unnecessary weaning of breastfeeding in an otherwise challenging situation

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Betydning av CYP3A4/5- og POR-genotype for individuell variasjon i nivå av 4β-hydroksykolesterol

Problemstilling: Enzymer tilhørende cytokrom P450 3A (CYP3A)-subfamilen representerer de viktigste i metabolisme av legemidler. Det er stor individuell variasjon i CYP3A-fenotype, og 4β-hydroksykolesterol (4β-OH-K) er en aktuell biomarkør for denne variasjonen. Hensikten med dette masterprosjektet var å undersøke betydningen av CYP3A4/5- og P450 oksidoreduktase (POR)-genotype for individuell variasjon i CYP3A-fenotype, målt som nivå av 4β-OH-K. Metode: Prosjektet tok utgangspunkt i biobankede serum- og blodprøver fra 400 pasienter, ved Senter for Psykofarmakologi (SFP), Diakonhjemmet Sykehus. Serumkonsentrasjon av 4β-OH-K ble analysert med en tidligere etablert UPLC-APCI-MS/MS-metode ved SFP, mens aktuelle mutasjoner i kandidatgenene, henholdsvis CYP3A4*22 (15389C>T), CYP3A5*3 (6986A>G) og POR*28 (1508C>T), ble analysert ved Avdeling for Biomedisinsk Biokjemi, Rikshospitalet. Rekvisisjoner tilknyttet de inkluderte serumprøvene ble gjennomgått, og informasjon om evt. komedikasjon med CYP3A-indusere eller -hemmere registrert. Serum fra pasienter med 4β-OH-K konsentrasjoner over 250 nmol/L ble i tillegg systematisk analysert for evt. tilstedeværelse av enzyminduserende antiepileptika (fenobarbital, fenytoin og karbamazepin). Personer med kjent bruk av CYP3A-indusere eller –hemmere ble ekskludert fra statistiske analyser. Studiegruppen ble videre delt i ulike CYP3A-genotypekombinasjonene for å undersøke betydning av POR-genotype i de ulike genotypekombinasjonene for nivået av 4β-OH-K. Statistiske sammenligninger av 4β-OH-K-nivåer mellom subgrupper i studien ble gjort ved ikke-parametriske av Mann-Whitney tester. Resultater: Serumkonsentrasjonen av 4β-OH-K varierte fra 13.1 til 1370 nmol/L, og i alt fem pasienter ble bekreftet komedisinert med CYP3A-induseren karbamazepin. Disse hadde alle høye serumkonsentrasjoner av 4β-OH-K (245-1370 nmol/L). For bærere av CYP3A4*1/*22 ble det målt en om lag 20 % lavere median 4β-OH-K serumkonsentrasjon sammenlignet med CYP3A4*1/*1-bærere, hhv. 43.6 og 57.8 nmol/L (p=0.0145). Tilsvarende var mediankonsentrasjon av 4β-OH-K signifikant høyere hos bærere av funksjonell vs. Ikke-funksjonell CYP3A5-genotype, hhv. 62.8 vs. 52.2 nmol/L (p=0,004). POR*28/*28 hadde størst betydning for genotypekombinasjonen CYP3A4*1/*1 + CYP3A5*1-bærere, hvor median serumkonsentrasjon var 102.7 nmol/L. Konklusjon: Denne studien viser at CYP3A4/5- og POR-genotyper har signifikant betydning for individuell variasjon i CYP3A-fenotype. Personer med ikke-funksjonell CYP3A5-genotype i kombinasjon med CYP3A4*22 kan tenkes å representere en gruppe med generelt nedsatt CYP3A-fenotype, men effekten på farmakokinetisk variasjon kan variere mellom ulike CYP3A-substrater. Videre tyder studien på at effekten av genvarianten POR*28 varierer mye avhengig av den enkelte persons CYP3A4/5-genotype, og mister trolig påvirkningsevne ved nedsatt CYP3A4-metabolisme

Kartlegging av holdninger til og bruk av urtemedisin i svangerskapet - En intervjuundersøkelse blant 142 barselkvinner ved Haukeland Universitetssjukehus

Bakgrunn: Mange kvinner opplever en eller flere plager under graviditet. Få konvensjonelle legemidler er godkjente til bruk i svangerskapet, og flere vestlige studier rapporterer at en stor andel av gravide kvinner bruker urtemedisin. To studier utført tidligere i Norge indikerer at urtemedisin brukes av mange gravide også her i landet. Vi vet svært lite om effekt og sikkerhet ved bruk av urtemedisin i svangerskapet. Hensikt: Hensikten med studien var å studere forekomst og konsekvenser ved bruk av urtemedisin under svangerskapet, og i tillegg holdninger til og kunnskap om urtemedisin blant barselkvinner ved Haukeland Universitetssjukehus. Metode: Totalt 142 kvinner i barselseng på Barselloftet, Kvinneklinikken, Haukeland Universitetssjukehus, Bergen, ble intervjuet en til to dager etter fødsel. Et strukturert spørreskjema ble brukt. Intervjuene fant sted i perioden fra og med november -08 til og med mars -09. Det ble også samlet inn data fra skjema som sendes Medisinsk fødselsregister. Resultater: I alt 53 % av kvinnene hadde brukt urtemedisin i svangerskapet. De hyppigst brukte urtene var bringebærblad for å "sette i gang fødsel, stimulere livmor og for å forhindre rifter under fødsel" (40 %), ingefær "mot kvalme" (37 %), kamille "mot søvnvansker" (28 %) og tranebær "mot urinveisinfeksjon" (13 %). Den mest sannsynlige bruker var førstegangsfødende, hadde brukt urtemedisin før og ville bruke urtemedisin igjen. Blant de kvinnene som hadde barn fra før, hadde 39 % brukt ammete eller tilsvarende urter ved tidligere ammeperioder. De fleste av kvinnene som hadde brukt urtemedisin, hadde brukt det på eget initiativ eller fått det anbefalt av familie eller venner. Internett og helsekost var de stedene flest kvinner ville oppsøkt for å få informasjon om urtemedisin. Apotek var den delen av helsevesenet flest kvinner ville oppsøkt for å få tak i informasjon. Det ble funnet en signifikant positiv sammenheng mellom kunnskap om og bruk av urtemedisin. Totalt 63 % av kvinnene ble klassifiserte som positive til urtemedisin. På bakgrunn av at urtemedisin er naturlig, trakk mange av kvinnene slutningen at urtemedisin har mindre bivirkninger enn legemidler, og er ufarlig å bruke også i svangerskapet. I alt 63 % av kvinnene sa seg uenig i påstanden: "Gravide bør ikke bruke noe urtemedisin uten at legen har sagt at det er greit." Av de som hadde brukt urtemedisin under svangerskapet sa 79 % seg ikke enig i denne påstanden. Konklusjon: Selv om denne studien baseres på et lite, begrenset utvalg, ser det ut til at det er en høy forekomst av bruk av urtemedisiner blant gravide. Det er derfor behov for mer dokumentasjon angående effekt og sikkerhet ved bruk av urtemedisiner under graviditet. Tiltak for å øke brukernes kunnskaper om at naturlig ikke nødvendigvis betyr ufarlig, er etterlengtet. Leger, farmasøyter, jordmødre og annet helsepersonell må ha kunnskap om urtemedisin slik at de kan gi råd og veiledning vedrørende bruk av disse preparatene. Det er viktig med en god dialog mellom helsepersonell og pasient slik at bruk av urtemedisin blir avdekket, og uheldig bruk og eventuelle interaksjoner med legemidler unngås. Farmasøyter på apotek står i en ideell posisjon til å komme med balansert informasjon om urtemedisin til brukere, da de er lett tilgjengelige og både utvalget og omsetning av urtemedisin

Treatment of nausea and vomiting during pregnancy - with special focus on attitudes to and use of pharmacological treatment

Background: Nausea and vomiting during pregnancy (NVP) is one of the most commonly experienced pregnancy complaints and has been associated with decreased quality of life and occupational and daily life functioning, as well as negative socioeconomic consequences. Though several treatment guidelines exist for NVP, including recommendations for medicines that are safe to use during pregnancy, we know little about how this condition is managed, both internationally and nationally in Norway. We also know little about attitudes to treatment of this complaint. Ginger is included in most guidelines. However, only one study exists that was designed to investigate the safety of its use during pregnancy. Objectives: The main aim of this doctorial work was to explore various aspects of treatment of NVP. The specific objectives were: 1) to investigate whether exposure to ginger, a common NVP herbal drug, was associated with an increased risk of congenital malformations or other selected negative pregnancy outcomes; 2) to explore patterns of and factors related to NVP and its treatment across countries in Europe, North America, and Australia; 3) to explore thoughts and attitudes among Norwegian pregnant women and GPs about the treatment of NVP, and to identify potential barriers to optimal care for women with NVP; 4) to investigate the treatments used for NVP according to NVP severity among women in Norway, and to assess whether maternal characteristics and attitudes were related to the use of pharmacological treatment of NVP. Methods: In order to address the above objectives, several methods and data sources were used. 1) The large population-based Norwegian Mother and Child Cohort study, which provides information on the use of ginger and several potential confounders, was linked to the Medical Birth Registry of Norway from which information on pregnancy outcomes was retrieved (Paper I). 2) The Multinational Medication Use in Pregnancy Study, a web-based cross-sectional study carried out among women and new mothers in 18 countries (Paper II). 3) Focus group discussions were used to explore thoughts about and attitudes to the treatment of NVP among pregnant women and general practitioners (Paper III). 4) A web-based cross-sectional study was conducted among pregnant women and new mothers in Norway with NVP (Paper IV). Results: The study in Paper I showed that the use of ginger during pregnancy was neither associated with any increased risk of congenital malformations nor with any increased risk of stillbirth/perinatal death, preterm birth, low birth weight, or low Apgar score. In the study in Paper II, nausea during pregnancy was reported by 73.5% of women, 17.9% of whom used conventional medicines and 8.3% herbal medicines. The prevalence of self-reported nausea and its treatment varied across countries. Education, working status and folic acid use were significantly associated with the use of conventional medicines against nausea. Respondents who suffered from nausea also had a high burden of comorbidity. In the focus group study in Paper III, the GPs thought it was important to normalise NVP symptoms. However, the women felt that their distress due to NVP was trivialised by the GPs. The women were sceptical about using medicines while pregnant, and avoidance was sought despite being ill. The GPs, who appeared to be uncertain and rather restrictive with respect to medical treatment of NVP, seemed to regard sick leave as an important part of the treatment regime. The women had good experience of graded sick leave. The Norwegian study described in Paper IV showed that, of the 712 women who were included in the study, 8.7%, 61.7% and 29.5% had mild, moderate and severe NVP, respectively. A total of 38.9% women had used one or more antiemetics, of which meclizine was the most commonly used, closely followed by metoclopramide. Different drug utilisation patterns were found between the groups of women with mild, moderate and severe NVP, and many women with moderate and severe NVP had not used medicines for NVP (70.2% and 32.9%, respectively). Sick leave was prescribed without initiating medical treatment in the case of 62.1% of the women who had been on sick leave. The women’s beliefs about medicines had an important impact on their use of medicines for NVP. Conclusion and implications: The findings of this doctorial work show that there are potential areas for improvement with respect to the management of NVP. The findings indicate 1) a need to increase awareness among healthcare personnel of the great distress women suffering from NVP may experience, and 2) that it is necessary to educate them about the recommendations in guidelines for the treatment of NVP. Due to the pregnant women’s fear of teratogenic effects of medicines, balanced evidence-based information about the maternal and foetal risks of medicines for NVP and tailored risk communication are necessary in order to reassure pregnant women in need of NVP medication