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Medicatiegebruik bij inflammatoire reumatische aandoeningen rondom de zwangerschap

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Medicatiegebruik tijdens de zwangerschap

Beoordeeld: 27-05-2024

Uitgangsvraag

Welke medicatie kan worden gebruikt tijdens de verschillende trimesters van de zwangerschap door vrouwen met een inflammatoire reumatische aandoening?

Deze uitgangsvraag omvat de volgende deelvragen:

  1. Wat is het effect van antireumatische medicatie, wanneer gebruikt tijdens conceptie en/of zwangerschap, op het risico op aangeboren afwijkingen en miskramen?
  2. Is er een verhoogd risico op infecties bij moeder en/of kind (tot 12 maanden postpartum), wanneer bDMARDs gebruikt zijn door de moeder tijdens de conceptie en/of zwangerschap?

Aanbeveling

Continueer behandeling met azathioprine, chloroquine, ciclosporine, colchicine, hydroxychloroquine, IVIG, sulfasalazine en tacrolimus gedurende de gehele zwangerschapsperiode wanneer nodig om onderliggende reumatische ziekte in remissie te houden of om opvlamming te behandelen.

 

Continueer niet-selectieve COX-remmers (klassieke NSAIDs) uitsluitend indien strikt nodig en bij voorkeur zo kort mogelijk tijdens de eerste twee trimesters van de zwangerschap; gebruik in het derde trimester is gecontra-indiceerd.

 

Overweeg om de TNF blokkers adalimumab en infliximab te stoppen bij 20 weken zwangerschap, en etanercept bij 30-32 weken zwangerschap. Continueer wanneer nodig certolizumab gedurende de gehele zwangerschap. Over golimumab zijn onvoldoende gegevens bekend en dit middel heeft daarom niet de voorkeur voor gebruik tijdens de zwangerschap.

 

Vermijd behandeling met cyclofosfamide, methotrexaat en mycofenolaat mofetil tijdens de zwangerschap gezien het verhoogde risico op miskramen en aangeboren afwijkingen. Staak de behandeling onmiddellijk indien er toch een zwangerschap is en verwijs patiënte naar de gynaecoloog voor een geavanceerd ultrageluidsonderzoek (GUO-1).

 

Behandel met glucocorticoïden (prednison of prednisolon) gedurende de zwangerschap als dit nodig is om de onderliggende reumatische ziekte in remissie te houden of om een flare te behandelen. Behandel met een zo laag mogelijke dosis en een zo kort mogelijke duur.

 

Staak de behandeling met abatacept, anakinra, belimumab, canakinumab, selectieve COX II remmers, golimumab, leflunomide, rituximab, tocilizumab, sarilumab, tofacitinib en ustekinumab als dit mogelijk is (na zorgvuldige afweging in overleg met patiënte en behandelaars), gezien onvoldoende gegevens over miskramen en over aangeboren afwijkingen of andere nadelige effecten op foetus en neonaat beschikbaar zijn.

 

Houd rekening met de mogelijkheid van een infectie, waarbij ook sprake kan zijn van een ernstig beloop en/of een opportunistische infectie, bij behandeling met een bDMARD tijdens de zwangerschap. Wees alert op het mogelijk maskerend effect op ernstige symptomen. Start laagdrempelig vervolgonderzoek en behandeling met antibiotica.

 

Welke medicatie kan worden gebruikt tijdens de verschillende trimesters van de zwangerschap door vrouwen met een inflammatoire reumatische aandoening?

Staak de behandeling met abatacept, anakinra, belimumab, canakinumab, selectieve COX II remmers, golimumab, leflunomide, rituximab, tocilizumab, sarilumab, ustekinumab en targeted synthetic DMARDS (inclusief nieuw beschikbare JAK-remmers) als dit mogelijk is (na zorgvuldige afweging in overleg met patiënte en behandelaars), gezien onvoldoende gegevens over miskramen en over aangeboren afwijkingen of andere nadelige effecten op foetus en neonaat beschikbaar zijn.

Overwegingen

Op basis van de huidige literatuur wordt geconcludeerd dat het gebruik van niet-selectieve COX remmers (aceclofenac, dexketoprofen, diclofenac, fenylbutazon, ibuprofen, indometacine, meloxicam, nabumeton, naproxen, piroxicam en tiaprofeenzuur), chloroquine, hydroxychloroquine, sulfasalazine, azathioprine, ciclosporine, tacrolimus, colchicine, IVIG, infliximab, adalimumab, etanercept en certolizumab pegol tijdens de zwangerschap geen verhoogd risico geeft op miskramen of aangeboren afwijkingen. Wel dient opgemerkt te worden dat gebruik van azathioprine tijdens de zwangerschap “de hielprik” een vals positieve uitslag kan geven voor severe combined immunodeficiency (SCID) (Blom et al 2021).

 

Voor niet-selectieve COX remmers geldt dat deze veilig kunnen worden gebruikt in de eerste twee trimesters van de zwangerschap. Echter, in het derde trimester van de zwangerschap is het gebruik van niet-selectieve COX remmers gecontra-indiceerd vanwege het risico op vervroegd sluiten van de ductus arteriosus (ductus Botalli) en persisterende pulmonale hypertensie bij de neonaat, verminderde foetale urineproductie waardoor oligohydramnion en irreversibele neonatale oligo- en anurie optreedt. Daarnaast is er een verhoogd risico op verminderde weeënactiviteit en versterkt bloedverlies tijdens de baring.

 

Bij gebruik van sulfasalazine tijdens de zwangerschap is voorschrijven van een hogere dosis foliumzuur dan 0,4 - 0,5 mg/dag (de normale dosering voor alle zwangeren in Nederland) niet nodig (er zijn geen data bekend die het voorschrijven van een hogere dosis onderschrijft); wel dient foliumzuur gedurende de gehele zwangerschap gebruikt te worden.

 

Wat betreft TNF-blokkerende middelen wordt geconcludeerd dat infliximab, adalimumab, etanercept en certolizumab pegol geen verhoogd risico geven op aangeboren afwijkingen wanneer gebruikt tijdens de zwangerschap. Over golimumab zijn onvoldoende gegevens beschikbaar om hierover een conclusie te trekken. Op basis van theoretische gronden is de verwachting dat  het gebruik van TNF blokkers tijdens het eerste trimester geen verhoogd risico geeft op miskramen of congenitale afwijkingen, omdat TNF blokkers in het eerste trimester nauwelijks de placenta passeren (Mariette et al, 2018). Overwegingen bij het gebruik tijdens de zwangerschap zijn met name ook ten aanzien van infectierisico bij het kind. 

 

Op basis van de huidige literatuur wordt geconcludeerd dat het gebruik van methotrexaat, cyclofosfamide en mycofenolaat mofetil tijdens de zwangerschap  een verhoogd risico geeft op miskramen of aangeboren afwijkingen. Het bewijs is gegradeerd als lage kwaliteit bewijs, omdat er beperkingen zijn in de onderzoeksopzet. Dergelijk onderzoek kan niet in een experimentele setting plaatsvinden. Onder de betrokken beroepsgroepen wordt echter niet getwijfeld aan het gevonden effect. Het gebruik van mycofenolaat mofetil, methotrexaat en cyclofosfamide wordt dan ook sterk afgeraden tijdens de zwangerschap. Wanneer er toch methotrexaat, cyclofosfamide of mycofenolaat mofetil is gebruikt tijdens de zwangerschap, dient te worden verwezen naar de gynaecoloog voor een geavanceerd ultrageluid onderzoek (GUO1)(NVOG, 2019 en LAREB).

 

Voor een groot aantal geneesmiddelen zijn de data niet eenduidig of zijn er onvoldoende data om een conclusie te trekken ten aanzien van het risico op miskramen en aangeboren afwijkingen. Dit geldt voor abatacept, anakinra, belimumab, canakinumab, selectieve COX II remmers (celecoxib en etoricoxib), golimumab, leflunomide, rituximab, tocilizumab, sarilumab, tofacitinib en ustekinumab. Overweging bij het gebruik van deze middelen tijdens de zwangerschap is ook in deze periode te streven naar lage ziekteactiviteit. Mocht dit niet lukken met middelen die veilig zijn gebleken tijdens de zwangerschap dan kan eventueel worden uitgeweken naar een middel in de categorie middelen waar de data niet eenduidig zijn of er onvoldoende data zijn.

 

tsDMARDs

De ontwikkelingen van nieuwe targeted synthetic DMARDS (tsDMARDs) staat niet stil en er zullen ook de komende periode nieuwe middelen beschikbaar komen, met name JAK-remmers. Zo zijn naast tofacitinib inmiddels ook andere JAK-remmers als baricitinib, deucravacitinib, filgotinib en upadacitinib beschikbaar.

Eind 2023 heeft de British Society of Rheumatology een update van de richtlijn over het voorschrijven van onder andere tsDMARDs tijdens zwangerschap en borstvoeding gepubliceerd. Voor deze update is de literatuur bekeken tot januari 2021. Een geïncludeerde review naar onder andere tsDMARDs beschrijft twee studies over tofacitinib en een case report over baricitinib. Ondanks het laag aantal zwangerschappen (n < 60) en uitkomsten (onder andere miskraam, misvorming, vroeggeboorte, n < 20) concludeerden de schrijvers dat er geen aanwijzingen gevonden zijn voor nadelige effecten van deze genoemde middelen tijdens de zwangerschap of tijdens borstvoeding (Nguyen, 2021). Daarnaast geeft de Britse richtlijn nog extra informatie over tofacitinib, baricitinib en upadacitinib (zie de Britse richtlijn: Russell, 2023). In totaal wordt gerapporteerd over minder dan 120 zwangerschappen bij tofacitinib-gebruikers met een laag aantal uitkomsten (onder andere miskraam, misvorming, vroeggeboorte, n < 20). Ook in de Britse richtlijn wordt naar hetzelfde case report over baricitinib gerefereerd. Over het gebruik van upadacitinib zijn geen gegevens gevonden.

Het blijft lastig om op basis van deze gegevens een conclusie te trekken vanwege het lage aantal events en beperkte informatie die beschikbaar is over blootstelling tijdens zwangerschap of borstvoeding. JAK-remmers zijn kleine moleculen met een laag moleculairgewicht die in theorie de placenta kunnen passeren en ook in moedermelk terecht kunnen komen (Russell, 2023). Dit, tezamen met het beperkte bewijs, maakt dat vooralsnog het gebruik van deze middelen tijdens conceptie, tijdens zwangerschap en tijdens borstvoeding wordt afgeraden.

 

Niet gefluorideerde glucocorticoiden (prednison, prednisolon) kunnen  tijdens de zwangerschap gebruikt worden voor behandeling van de moeder. Niet gefluorideerde glucocorticoiden worden geïnactiveerd in de placenta en bereiken slechts in beperkte mate de foetus. De foetale serumconcentraties zijn bij prednisolon ongeveer 10% van de maternale concentratie. Doseer predniso(lo)n zo kort en zo laag mogelijk. Tegen een stootkuur met prednison of prednisolon is geen bezwaar.

Indien het er tijdens de zwangerschap een indicatie is om de foetus te behandelen (induceren van foetale longrijping, behandeling foetaal hartblok) worden gefluorideerde glucocorticoiden voorgeschreven (betamethason, dexamethason), omdat deze niet door de placenta geïnactiveerd worden. Bij betamethason zijn de foetale serumconcentraties ongeveer 30% van de maternale concentratie, bij dexamethason bijna 100%.

Voor intra-articulaire en intramusculaire injecties tijdens de zwangerschap heeft methylprednisolon (Depo-Medrol R) de voorkeur boven triamcinolonacetonide (KenacortR), omdat methylprednisolon in tegenstelling tot triamcinolonacetonide niet gefluorideerd is.

 

Bij gebruik van glucocorticoïden tijdens de zwangerschap kan er bij de neonaat bijnierschorsinsufficiëntie ontstaan. Het is belangrijk dat in een ziekenhuis eenduidig beleid wordt gemaakt tussen kinderartsen, gynaecologen en reumatologen voor kinderen van moeders die tijdens de zwangerschap glucocorticoïden hebben gebruikt.

 

Wanneer leflunomide is gebruikt tijdens de zwangerschap dient zo snel mogelijk een washout procedure gevolgd te worden. De washout-procedure bestaat uit driemaal daags 8 gram colestyramine gedurende 11 dagen. Als alternatief kan geactiveerde kool worden gebruikt. Direct na het uitwassen dient een spiegelbepaling gedaan te worden, en 2 weken later nogmaals. Galzuurbindende harsen verstoren de opname van voedingsstoffen, waaronder de vetoplosbare vitaminen A, D, E en K. Daardoor bestaat de kans op maternale deficiëntie van vetoplosbare vitaminen, vooral van vitamine K. Dit kan in theorie negatieve gevolgen hebben voor de foetus en de neonaat. Suppletie van vetoplosbare vitaminen wordt daarom aangeraden.

Er is geen literatuur bekend over wanneer hervat kan worden met een DMARD na de partus (vaginaal of sectio). De werkgroep adviseert dat behandeling met DMARDs na 1 a 2 weken  hervat kan worden, mits er geen infectie aanwezig is.

 

Overwegingen infectierisico bij bDMARD gebruik:
Zoals beschreven in de literatuursamenvattingen zijn slechts 4 observationele studies gepubliceerd waarin het risico op maternale infecties tijdens de zwangerschap bij gebruik van bDMARDs door de moeder tijdens de zwangerschap wordt gerapporteerd. Deze studies gebruiken verschillende uitkomstmaten en het totaal aantal events is klein (<200 events totaal). De meeste data betreffen het gebruik van TNF blokkers, over de overige bDMARDs zijn nauwelijks gegevens bekend. Verschillende TNF blokkers zijn onderzocht, maar er zijn te weinig gegevens om een verschil tussen deze middelen aan te tonen. Daarnaast betreffen het heterogene data wat betreft timing van het geven van de bDMARD: bijvoorbeeld tot aan bevestigde zwangerschap, gedurende eerste periode van de zwangerschap of gedurende de gehele zwangerschap. Op basis van deze literatuur wordt geconcludeerd dat er zeer lage kwaliteit bewijs is, dat behandeling van de moeder met een bDMARD tijdens de zwangerschap niet leidt tot een verhoogd risico op maternale infectie tijdens zwangerschap of de post-partum periode. Overwegingen voor het gebruik van een bDMARD en risico op infecties bij de moeder zijn daarnaast de activiteit van de onderliggende ziekte en gebruik van comedicatie, zoals glucocorticoïden om de ziekte rustig te houden tijdens de zwangerschap. Deze kunnen beide ook bijdragen aan een verhoogd risico op infecties.

 

Zoals beschreven in de literatuursamenvattingen zijn slechts 3 observationele studies gepubliceerd waarin het risico op infecties van het kind in het eerste jaar post-partum bij gebruik van bDMARDs door de moeder tijdens de zwangerschap wordt gerapporteerd. Het totaal aantal events in deze studies is klein (<200 events totaal). De meeste data betreffen het gebruik van TNF blokkers, over de overige bDMARDs zijn nauwelijks gegevens bekend. Verschillende TNF blokkers zijn onderzocht, maar er zijn te weinig gegevens om een verschil tussen deze middelen aan te tonen. Daarnaast betreffen het heterogene data wat betreft timing van het geven van de bDMARD: bijvoorbeeld tot aan bevestigde zwangerschap, gedurende eerste periode van de zwangerschap of gedurende de gehele zwangerschap. Op basis van deze literatuur wordt geconcludeerd dat er zeer lage kwaliteit bewijs is, dat behandeling van de moeder met een bDMARD tijdens de zwangerschap niet leidt tot een verhoogd risico op infecties van het kind tijdens de post-partum periode tot 12 maanden. Overwegingen voor het gebruik van een bDMARD en risico op infecties bij het kind zijn de timing van blootstelling tijdens de zwangerschap en welk bDMARD gegeven wordt. Bij blootstelling later in de zwangerschap is het risico mogelijk hoger dan bij blootstelling alleen vroeg in de zwangerschap, aangezien de hoeveelheid medicatie die in het bloed van het kind aanwezig is, bij gebruik later in de zwangerschap hoger is en de medicatie bij gebruik in het derde trimester in de neonatale periode nog bij het kind aanwezig is. Daarnaast is het risico waarschijnlijk met name aanwezig bij bDMARDs die over de placenta worden getransporteerd en waarschijnlijk niet voor certolizumab pegol, dat de placenta nauwelijks passeert, en mogelijk ook niet voor etanercept, dat de placenta in geringe mate passeert.

Onderbouwing

De effectiviteit van disease modifying antirheumatic drugs (DMARDs) voor reductie van ziekteactiviteit en preventie van orgaanschade bij diverse inflammatoire reumatische aandoeningen (inclusief bindweefsel- en systeemziekten) is ruimschoots aangetoond. Het gaat hierbij om conventional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), targeted synthetic DMARDs (tsDMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoiden en andere anti-reumatische middelen. In deze module zal het effect van het gebruik van deze middelen tijdens de zwangerschap op moeder en kind worden beschreven, zowel vanuit de literatuur als met overwegingen voor de Nederlandse praktijk. Daarnaast wordt aandacht besteed aan het mogelijke infectierisico voor moeder en/of kind bij gebruik van bDMARDs tijdens de zwangerschap.



zeer laag GRADE


There is very low quality evidence that the use of the following medications during pregnancy is not associated with an increased risk of miscarriages or congenital malformations:

Non-selective COX inhibitors, antimalarials (chloroquine and hydroxychloroquine), sulfasalazine, azathioprine, ciclosporin, colchicine, IVIG, infliximab, tacrolimus, adalimumab, etanercept, certolizumab pegol

 

zeer laag GRADE


There is very low quality evidence that the use of the following medications during pregnancy leads to an increased risk of miscarriages or congenital malformations:

Methotrexate, cyclophosphamide, and mycophenolate mofetil

 

geen GRADE


The evidence is unclear about the use of the following medications during pregnancy with regard to risk of miscarriages or congenital malformations: Leflunomide, tofacitinib, selective COX II inhibitors, glucocorticoids, golimumab, rituximab, anakinra, abatacept, tocilizumab, ustekinumab, belimumab, and canakinumab

 

 

zeer laag GRADE

 

There is very low quality evidence that bDMARD use during pregnancy does not lead to an elevated risk of maternal infection during pregnancy and the postpartum period.

 

Sources: Carman 2017, Hoxha 2017, Desai 2017 and Tsao 2019

 

 

zeer laag GRADE

 

There is very low quality evidence that maternal bDMARD use during pregnancy does not lead to an elevated risk of infant infections during the first year of life.

 

Sources: Tsao 2019, Vinet 2018, Hoxha 2017

Description of studies

The 2016 EULAR recommendations on anti-rheumatic medication during pregnancy
The 2016 EULAR recommendations investigated the effect of antirheumatic medication on maternal and fetal outcomes in women with inflammatory rheumatic diseases through pregnancy (EULAR, 2016). Two electronic searches, one for biologic drugs and a separate search for non-biologic drugs were performed in the databases Embase, Medline and the Cochrane library from January 1st, 2008 until April 1st, 2015. This search period was chosen because of the consensus paper on immunosuppressive drugs that was updated in 2008. The medications included in the systematic literature review were: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional synthetic DMARDs (methotrexate, sulfasalazine, leflunomide, azathioprine, mycophenolate mofetil), targeted synthetic DMARDs (tofacitinib), biological DMARDs (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, abatacept, rituximab, belimumab, tocilizumab and anakinra), and other antirheumatic medication (cyclophosphamide, antimalarials, intravenous immunoglobulin, colchicine, ciclosporin, tacrolimus). Predefined primary outcomes were miscarriages among included pregnancies and major congenital malformations among live-born children. The included study population was not limited to rheumatic disease but to all indications for a given drug. The included study designs were prospective and retrospective cohort studies or registries, case-control studies and case series/reports. The literature search also included studies of which only abstracts were available, including abstracts from major international congresses. A total of 319 publications, of which 45 cohort studies, 24 case control studies and 250 case series/case reports were included (Gotestam, 2016).

 

The updated literature
The updated literature consisted of 45 publications, of which 33 cohort studies, one case control study and 11 case series/case reports. Of the 33 cohort studies, 9 had a comparative design and more than 100 patients. Here is a description of the 9 comparative studies:

  • A retrospective single center cohort study by Barsalou (2017) investigated the effect of antimalarial use during pregnancy on children born to women with positive anti-Ro and/or anti-La antibodies. Of the 268 pregnancies, 73 were exposed to antimalarials (hydroxychloroquine (HCQ) or chloroquine) and 195 unexposed. The outcomes cardiac and non-cardiac neonatal lupus were assessed.
  • A retrospective  single center registry by Kroese (2017) investigated the effect of HCQ use during pregnancy in women with systemic lupus erythematosus (SLE). Of the 110 pregnancies, 30 were exposed to HCQ and 80 unexposed. Pregnancy outcomes such as miscarriages and preterm birth were assessed.
  • A retrospective single center cohort study by Leroux (2015) investigated the effect of HCQ during pregnancy. A total of 118 pregnancies (41 exposed to HCQ and 77 unexposed) were analyzed with regards to pregnancy outcomes, such as miscarriages, intrauterine growth restriction, preterm birth and congenital malformations.
  • A retrospective single center cohort study by Sciascia (2016) investigated the effect of HCQ treatment during pregnancy in women with antiphospholipid syndrome. Of the 170 pregnancies, 51 were exposed to HCQ and 119 unexposed. Main outcomes were the amount of live births and pregnancy complications.
  • A retrospective single center cohort study by Saavedra (2015) evaluated the risk of an adverse pregnancy outcome in women with SLE exposed to azathioprine during pregnancy. A total of 178 pregnancies were included of which 87 were exposed to azathioprine and 91 unexposed. Main outcomes were miscarriages, preterm birth and congenital malformations.
  • A prospective multiple center cohort study by Chambers (2019) assessed birth outcomes in pregnant women exposed to adalimumab. Both women with rheumatoid arthritis (RA) as well as Crohn’s disease were included, however for the purpose of this review only women with RA were assessed. A total of 143 women with RA were included, of whom 69 were exposed to adalimumab and 74 unexposed. Main outcomes were major/minor birth defects, miscarriages and preterm birth.
  • A large retrospective multicenter registry by Carman (2017) in 4883 patients (3048 chronic inflammatory arthritis (cIA) and 1835 psoriasis(PsO)) assessed the effect of etanercept (ETN). The cIA cohort consisted of 256 ETN exposed patients and 1512 unexposed patients. The PsO cohort consisted of 810 ETN exposed patients and 1349 unexposed patients. The study also included people from the general population as a third comparison group in both cohorts, however for the purpose of this review only the exposed versus unexposed cohorts are examined. Pregnancy and birth outcomes such as live births and major congenital malformations were assessed.
  • A large nationwide (Denmark and Sweden) health register by Bröms (2016) investigated use of TNF inhibitors during pregnancy in 22.232 women with a chronic inflammatory disease. In this large cohort, 683 were exposed to TNF inhibitors and compared with 21.549 unexposed patients with a chronic inflammatory disease. The study also included the general population as a third comparison group, however for the purpose of this review only the exposed versus unexposed cohorts are reported. The prevalence of birth defects in infants was the main outcome.
  • A retrospective population based registry by Tsao (2019) investigated the influence of bDMARD use during pregnancy in 8607 women with an autoimmune disease. In this large registry, 100 infants were exposed to bDMARDs and 8507 were unexposed. The association between bDMARD exposure during pregnancy and the occurrence of serious infections in mothers and children was the main outcome.


Results

The EULAR recommendations
The results of the EULAR search, including the references of the cohort studies and case control studies, are summarized in the data sheet (shaded light green, Table 1).

 

The updated literature
The results of the updated literature (45 studies) were added to the EULAR data sheet in Table 1, using a new row for each new found study. As described in the methods section, information about the exposed versus unexposed was given (if available), the disease indications were added and the quality of evidence was not given for the updated studies. Here is a descriptive overview of the 9 comparative studies with more than 100 patients:

  • Barsalou (2017) reported 1/73 (1.4%) developed cardiac Neonatal Lupus Erythematosus (NLE) in the hydroxychloroquine (HCQ)/chloroquine exposed children versus 12/195 (6.2%) of the unexposed children. The odds ratio (OR) for developing cardiac NLA was 0.21 (95% CI 0.03-1.66), which was not significant.
  • Leroux (2015) reported a miscarriage rate of 3/41 (7.3%) among HCQ exposed foetuses versus 3/77 (13.0%) among non HCQ exposed foetuses. Among live born children, no congenital malformations were found in the HCQ exposed group: 0/38, while 4/74 (5.4%) congenital malformations were reported in the non HCQ exposed children. No children were born with a congenital heart block due to congenital NLE in the HCQ exposed group, while one child was born with a congenital heart block in the HCQ unexposed group. None of the reported differences were significant.
  • Kroese (2017) reported an early miscarriage rate (<10 weeks pregnant) of 9/30 (30.0%) in the HCQ exposed foetuses compared with 10/80 (12.5%) of the non HCQ exposed foetuses. The OR for early miscarriage 1.5 (95% CI 0.3 to 9.0). No congenital malformations appeared in the HCQ exposed live born children (0/20) while 4/68 (5.9%) in the HCQ exposed live born children. This included one case of congenital cardiac neonatal lupus and three other diagnoses. None of the reported differences were significant.
  • Sciascia (2016) reported a significantly lower miscarriage rate in the HCQ exposed foetuses versus no HCQ exposed foetuses: 17/51 (33.3) HCQ exposed, 59/119 (49.6) non HCQ exposed. However, this study is confounded by disease indication. SLE prevalence was 64.5% in HCQ exposed women versus 7.7% in non HCQ exposed women (P < 0.001), and APS syndrome was prevalent in 16.1% in HCQ exposed women vs 9.2% in HCQ unexposed women (P < .001).
  • Saavedra (2015) reported a miscarriage rate of 7/87 (8.0%) in the azathioprine (AZA) exposed foetuses, versus 6/91 (6.6%) in the non AZA exposed foetuses, which was non-significant. In both groups no congenital malformations were detected.
  • Chambers (2019) reported a major birth defect rate of 6/69 (8.7%) in the adalimumab exposed group of live born children, versus 5/74 (6.8%) in the adalimumab unexposed group. The risk ratio (RR) was 1.29 (95% CI 0.41 to 4.03), which was not significant.
  • Among women with chronic inflammatory arthritis, Carman (2017) reported a miscarriage rate of 56/256 (21.9%) in etanercept (ETN) exposed foetuses, versus 287/1512 (19.0%) in ETN unexposed foetuses. Among women with psoriasis, the authors reported a miscarriage rate of 13/81 (16.0%) in ETN exposed foetuses versus 211/1349 (16.0%) in ETN unexposed foetuses. Among women with chronic inflammatory arthritis a major congenital malformation rate of 10/165 (6.1%) was reported for ETN exposed live born children versus 54/990 (5.5%) in ETN unexposed children. Among women with psoriasis the major congenital malformation rate was 1/51 (2.0%) in ETN exposed children versus 40/942 (4.2%) ETN unexposed children. None of the reported differences were significant.
  • Bröms (2016) reported a major birth defect rate of 43/683 (6.3%) in anti-TNF exposed children versus 1019/21547 (4.7%) in unexposed children. An OR of 1.32 (95% CI 0.93 to 1.82) was reported, which was not significant.
  • Tsao (2019) reported a miscarriage rate of 28/100 (28.0%) in the bDMARD exposed foetuses versus 2230/8507 (26.2%) in bDMARD unexposed foetuses. In the exposed group no congenital anomalies were reported, while 74/6277 (1.0%) was reported in the unexposed group. Both differences were not significant.

 

Level of evidence of the literature
A GRADE analysis per outcome measure could not be performed because there were insufficient data from the EULAR 2016 recommendations to perform a systematic analysis of the literature. Hence, overarching conclusions were formulated.

 

Description of studies
Carman (2017) performed a retrospective database study in the US (1995 to 2012) evaluating the outcome of women with chronic inflammatory arthritis (cIA) or psoriasis (PsO) and their infants, exposed or unexposed to etanercept during pregnancy. In the cIA cohort, 212 etanercept exposed and 1512 unexposed were included. In the PsO cohort, 81 exposed and 1349 unexposed were included. The authors also used a matching comparator cohort from the general population as a second control group, however this group did not match our PICO and is therefore not reported. The main outcome was major congenital malformations among infants. Infection was not a predefined outcome, but maternal infections were reported under pregnancy characteristics in the baseline table. No definition was given for maternal infections, however from the baseline characteristics table we can deduce “any infection during pregnancy”. Rude odds ratios were recalculated. Infant infections were not reported.

 

Desai (2017) performed a retrospective cohort study of a health insurance database in the US (2000-2010) evaluating the risk of infections due to immunologic medication (e.g. bDMARDs, corticosteroids and non-bDMARDs) in pregnant woman with autoimmune inflammatory conditions. Patient diagnoses were systemic lupus erythematosus (37%), rheumatoid arthritis (36%), inflammatory bowel disease (23%), ankylosing spondylitis (12%) and psoriatic arthritis (3%). In the cohort, 776 pregnant women were exposed to bDMARDs and 816 were not exposed to bDMARDs. The study also included a “corticosteroid” group however for the purpose of this analysis this group is not reported. In the bDMARDs group as well as the non-bDMARDs group, the use of corticosteroids was allowed, to reflect routine clinical practice. Hazard ratios were given, adjusted for maternal age, geographic region, insurance program, underlying systemic disorders (diagnosis), additional immunosuppressive drugs used during pregnancy and three months before pregnancy, and healthcare utilization recorded three months before the index date. Maternal infection was defined as a serious infection during pregnancy after the first prescription of an immunosuppressive drug was taken, as composite of a bacterial infection (meningitis, encephalitis, cellulitis, endocarditis, pneumonia, pyelonephritis, septic arthritis, osteomyelitis, and bacteraemia) or an opportunistic infection (tuberculosis, systemic candidiasis, cryptococcosis, aspergillosis) and identified using discharge diagnosis codes from hospital admission records.

 

Hoxha (2017) performed a prospective cohort study in Italy (2008-2016) studying adverse pregnancy and infant outcomes in pregnant women using bDMARDs. Patient diagnoses consisted of rheumatoid arthritis (69%), ankylosing spondylitis (23%) and psoriatic arthritis (9%). Two groups were formed: 27 bDMARD-exposed pregnancies (at conception or first semester) and 9 bDMARD preconception exposed (withdrawn to bDMARDs 1-6 months prior to conception). No definition of maternal or infant infection was given.

 

Tsao (2019) performed a retrospective population based database study in Canada (2002 to 2012) evaluating the risk of maternal and infant infections after bDMARD use during pregnancy. In the cohort, bDMARDs were prescribed in 100 pregnancies and 8507 were unexposed. The bDMARD exposed group consisted of e.g. inflammatory bowel disease (50%), rheumatoid arthritis (44%), psoriasis/psoriatic arthritis (16%), juvenile idiopathic arthritis (8%), systemic autoimmune rheumatic diseases (5%), ankylosing spondylitis (5%), which was in percentage significantly different from the control group that consisted of inflammatory bowel disease (29%), rheumatoid arthritis (21%), psoriasis/psoriatic arthritis (40%), systemic autoimmune diseases (12%), ankylosing spondylitis (5%) and juvenile idiopathic arthritis (1%). Absolute numbers were not provided, however odds ratios for maternal and infant infections were reported, adjusted for maternal characteristics including factors of the current pregnancy (including BMI, antenatal visits, hospitalisation at baseline, delivery by caesarean section), prior obstetrical history (including previous pregnancies (if applicable): premature delivery, miscarriages, neonatal death, stillbirth, low birth weight and congenital anomalies), comorbidities and concomitant medication use (including DMARDs or immunosuppressants, glucocorticoids, antidepressants, anxiolytics, traditional and COX-2 non-steroidal anti-inflammatory drugs (NSAIDs)) and infant characteristics including sex and Apgar score. Maternal infection was defined as a serious postpartum infection requiring an episode of hospitalisation including the delivery episode, with one or more ICD-9/10 codes for an infection anytime from the date of delivery until 42 days post-partum. Infant infection was defined as an episode of hospitalisation with one or more ICD-9/10 codes for an infection anytime during the first year of life—due to the lengthy accumulation of biologics in infant circulation—or until death, whichever occurred first.

 

Vinet (2018) performed a prospective population-based cohort study, based on a commercial database in the US with over 230 million subjects with employer-provided health care insurance from 2011 to 2015. The PAROUS cohort was used to assess the risk on infections in the offspring of woman with rheumatoid arthritis. In the PAROUS cohort 380 bDMARD exposed during pregnancy and 2476 unexposed women were included. Besides this, the authors also used a matching “non rheumatoid arthritis” group as a second control group, however this group also didn’t match our PICO and was not reported in this review. The authors were interested in infant infections, and no data about maternal infections were available. The “TNF inhibitors exposure group” was described as having ≥1 fulfilled prescription or subcutaneous injection/infusion of adalimumab, certolizumab, etanercept, golimumab or infliximab during pregnancy. The “no TNF inhibitors exposure group” was described as having fulfilled no bDMARD prescription or subcutaneous injection/infusion during pregnancy or in the 12 weeks preceding pregnancy. Infections were defined as a hospitalization period any time during the first year of the infant with an infection as the primary reason for hospital admission. Odds ratios were provided for infant infections, adjusted for maternal age, pregestational diabetes mellitus, gestational diabetes mellitus, preterm birth, and medications (i.e., corticosteroids

and nonbiologic and bDMARDs). Maternal infections were not reported. Infant infection was defined as a serious infection occurring in the offspring based on ≥1 hospitalization with infection within the first 12 months of life, with a relevant diagnostic code, as primary reason for admission (i.e., hospitalization where the primary diagnosis was an infection, including ICD-9/10 coding by organism and/or organ involvement).

 

Results
The 5 included studies used different effect measures (adjusted odds ratios, unadjusted odds ratios and hazard ratios), therefore pooling of the results was not possible. A descriptive overview over the results per outcome measure will be provided.

 

1. Maternal infections

Four studies reported the outcome maternal infections (Carman 2017, Tsao 2019, Desai 2017, Hoxha 2017). The outcome maternal infection was defined as “a serious infection during pregnancy requiring hospital admission for bacterial or opportunistic infection” by Desai (2017), “a serious infection requiring hospitalisation during the postpartum period in women” by Tsao (2019), “any infection during pregnancy” by Carman (2017), and not defined by Hoxha (2017).

 

Carman (2017) reported in the cIA cohort 24/256 (9.4%) infections during pregnancy in etanercept exposed mothers, while 162/1512 (10.7%) infections were reported in the unexposed group (Unadjusted OR 0.86 (95%CI 0.55 to 1.35). In the PsO cohort, the authors reported 8/81 (9.9%) infections during pregnancy in the etanercept exposed mothers, versus 132/1349 (9.7%) infections during pregnancy in unexposed mothers (Unadjusted OR 1.01 (95% CI 0.48 to 2.14)). The number of infections did not differ between etanercept exposed women during pregnancy, and etanercept unexposed women during pregnancy.

 

Desai (2017) did not report absolute infection numbers in the bDMARD exposed group, however the percentages were reported: 2.3% in the bDMARD exposed mothers and 1.3% in the bDMARD unexposed mothers. The adjusted hazard ratio was 1.36 (95%CI 0.47 to 3.93). The number of maternal infections during pregnancy did not differ between women treated with bDMARD or without bDMARDs.

Hoxha (2017) reported one maternal infection in the bDMARD exposed group (1/24), while in the unexposed group no infections were reported (0/11). Group sizes were too small to calculate effect measures.

 

Tsao (2019) reported an infection rate during pregnancy and the postpartum period between 0-5% (absolute numbers not provided and percentage was depending on concomitant exposures to csDMARDs or glucocorticoids) of 100 bDMARD exposed mothers and 3-4% of 8507 bDMARD unexposed mothers (adjusted OR 0.79 (95%CI 0.24 to 2.54). The number of maternal postpartum infections did not differ between women exposed and unexposed to bDMARDs during pregnancy.

 

2. Infant infections

3 studies reported the outcome infant infections (Hoxha 2017, Tsao 2019, Vinet, 2018). The outcome was not defined by Hoxha (2017). Tsao (2019) and Vinet (2018) both defined infant infections as “a serious infection requiring hospitalization anytime during the first year of infants”.

 

Hoxha (2017) reported no infant infections in the 34 live-born infants during the mean follow up of 20 months (ranging 3-82 months). Group sizes (and the numbers of reported infections) were too small to draw conclusions.

 

Tsao (2019) reported an infant infection rate during the first year of life of 0-6% in the 100 exposed infants (absolute numbers not provided and percentage was depending on concomitant exposures to csDMARDs or glucocorticoids) versus 5-7% in the 8507 unexposed children (adjusted OR 0.56 (95%CI 0.17 to 1.81). The number of infant infections did not differ between bDMARD exposed and unexposed infants.

 

Vinet (2018) reported 12/380 (3.2%) infant infections during the first year of life among exposed children, versus 49/2476 (2.0%) in the unexposed children (adjusted 1.4 (95%CI 0.7 to 2.8).The risk of a serious infection during the first year of life was similar among exposed and unexposed children.

 

Level of evidence of the literature
Observational studies start a GRADE low.

 

The level of evidence regarding the outcome measure maternal infections was downgraded by 1 level to a very low GRADE, because of indirectness (different definitions of maternal infections (e.g. serious infection during pregnancy or serious infection during the postpartum period) made it not possible to pool data) and imprecision (4 studies, event rate <200 for all included studies).

 

The level of evidence regarding the outcome measure infant infections was downgraded by 1 level to a very low GRADE because of imprecision (3 trials, event rate <200 for all included studies).

Clinical question 1:

In 2016, the EULAR performed a systematic literature review (SLR) on the use of antirheumatic drugs during pregnancy, of all literature published from January 1st 2008, until April 1st 2015 (Gotestam, 2016). The outcomes of interest were miscarriages and congenital malformations. For clinical question 1, the working group decided to update this SLR with literature until July 10th, 2019, to answer the following question:

 

What is the effect of antirheumatic medication, taken during conception and/or pregnancy on the risk of congenital malformations and miscarriages?

P:           Females with inflammatory rheumatic diseases (connective tissue diseases and

Systemic autoimmune diseases included), defined as rheumatoid arthritis, (axial and peripheral) spondylo-arthritis, reactive arthritis, juvenile idiopathic arthritis(JIA)/juvenile arthritis, uveitis in JIA, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, mixed connective tissue disease, vasculitis, polymyalgia rheumatica, polymyositis, dermatomyositis, ANCA-associated vasculitis, polyarteritis nodosa, Behçet’s disease, gout and adult-onset Still’s disease;

I:            Disease-modifying antirheumatic drugs (DMARDs) and Non-steroidal anti-inflammatory drugs  (NSAIDs) including: classical NSAIDs, COX-2 selective NSAIDs, glucocorticoids, conventional synthetic DMARDs (methotrexate, sulfasalazine, leflunomide, azathioprine, mycophenolate mofetil), targeted synthetic DMARDs (tofacitinib, baricitinib), biological DMARDs (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, rituximab, belimumab, tocilizumab, anakinra, canakinumab, ustekinumab, secukinumab and ixekizumab) and other antirheumatic medication (cyclophosphamide, antimalarials, intravenous immunoglobulin, colchicine, ciclosporin, tacrolimus);

C:           No or other use of antirheumatic medication;

O:          Miscarriage and congenital malformations.

 

Relevant outcome measures
The working group considered miscarriages and congenital malformations as critical outcome measures for decision making.

 

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

 

Search and select (Methods)
For the update of the EULAR 2016 recommendations (Gotestam, 2016), the databases Medline (via OVID), Embase (via Embase.com) and the Cochrane Library were searched with relevant search terms from 1 April 2015 until 10 July 2019. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 452 hits. Studies were selected based on the following criteria:

  • A separate description of at least one woman with an inflammatory rheumatic disease;
  • Intake of antirheumatic medication as defined in PICO, during conception and/or pregnancy;
  • Description of at least one outcome measure, e.g. miscarriage and/or congenital malformations;
  • It involves the original study data.

Research into safety of drugs during pregnancy in women with rheumatic diseases cannot be conducted in an experimental design due to ethical/safety concerns. The working group decided to include studies of all designs, because even a small amount of information on safety of rheumatic medication during pregnancy could be important. 69 studies were initially selected based on title and abstract screening. After reading the full text, 22 studies were excluded (see the exclusion table with reasons for exclusion) and 45 studies were included.


Clinical question 2:
A systematic review of the literature was performed to answer the following question:

 

What is the risk of infection in mother and child during pregnancy and postpartum in women with an inflammatory rheumatic disease treated with a bDMARD compared to no treatment with a bDMARD?

P:           Women with an inflammatory rheumatic disease, that could be treated with a bDMARD

I:            At least one prescription of a bDMARD during conception or pregnancy

C:           No or other use of a bDMARD during conception or pregnancy

O:          Any maternal infection during pregnancy or the postpartum period and any infant infection during the first year postpartum

 

Relevant outcome measures
The working group considered maternal infection and infant infection as both important outcomes for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

 

Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until the 28th of June, 2019. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 439 hits. Studies were selected based on the following criteria:

P:           Women with inflammatory rheumatic diseases (connective tissue diseases and systemic autoimmune diseases included), defined as rheumatoid arthritis, (axial and peripheral) spondylo-arthritis, reactive arthritis, juvenile idiopathic arthritis(JIA)/juvenile arthritis, uveitis in JIA, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, mixed connective tissue disease, vasculitis, polymyalgia rheumatica, polymyositis, dermatomyositis, ANCA-associated vasculitis, polyarteritis nodosa, Behçet’s disease, gout and adult-onset Still’s disease;

I:            Treatment with a bDMARD during pregnancy, or during the year before conception, including biosimilar DMARDs;

C:           No exposure to the specific bDMARD of interest during pregnancy or during the year before conception;

O:          Infection during pregnancy, or <12 months post-partum.

 

31 studies were initially selected based on title and abstract screening. After reading the full text, 5 studies were identified with a comparative design. These 5 studies are included in the systematic summary of the literature. 15 studies were found with a non-comparative design, which are described in the evidence table, in order to give a complete overview of available data. Finally, 11 studies were excluded (see the table with reasons for exclusion under the tab Methods).


Results
Clinical question 1:
The evidence table of the EULAR recommendations on anti-rheumatic medication during pregnancy was taken and updated with 45 studies that were published since the publication of EULAR (Gotestam, 2016).

 

The evidence table of the 2016 EULAR recommendations contains information on the type of drug, the type of publication, the total number of pregnancies, the number of miscarriages of eligible pregnancies, the number of congenital malformations of live births, comments on miscarriages/congenital malformations compared with control groups or background data and the strength of evidence according.

 

The EULAR 2016 recommendations has used a pragmatic approach to synthesize the large amount of study data: in total 319 publications of which 45 cohort studies, 24 case-control studies and 250 case series/reports. The EULAR 2016 evidence table summarizes all data per  medication/medication group, regardless of study design. For this update of the literature, it was not possible to extract information on individual studies from the EULAR 2016 recommendations that fulfil the PICO criteria for inclusion in the systematic literature analysis according to GRADE.

In addition, the EULAR 2016 recommendations graded the evidence based on group discussions, expert opinions and consensus papers. A ranking was based on two scales (a simplified GRADE and Oxford scale) (Gotestam, 2016). For this update of the literature, this method of quality assessment by the EULAR 2016 recommendations is not fully transparent nor reproducible, and should therefore be interpreted with caution. Hence, it was also not possible to perform a GRADE assessment based on both the EULAR recommendations, and the updated literature. Literature conclusions were formulated, and when comparative study designs were included for a specific medication, a GRADE very low was assigned.

 

The working group decided on the following approach to best meet the need for information on the effects of antirheumatic medication in pregnant women with rheumatic disease.

 

In the evidence table:

  • A new row for each new study was added, to provide an overview of all new added studies and the different designs of the added studies.
  • For observational studies, information about a comparison (exposed versus unexposed cohort) was added, if available. This information was added within the columns “number of miscarriages” and “number of congenital malformations”.
  • The “comments on miscarriages and congenital malformation” are based on the study authors’ conclusions, not on the expert opinions of the working group.
  • One extra column was added with information about the indication for which the medication was prescribed, which was provided for the newly added literature.

Furthermore, a descriptive overview of the studies with a comparative design (using a control group) and investigating at least 100 patients was provided in the results section.

 

Results
Clinical question 2:
5 comparative studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence table. The assessment of the risk of bias is summarized in the risk of bias table.

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  50. Zhan Z, Yang Y, Zhan Y, Chen D, Liang L, Yang X. Fetal outcomes and associated factors of adverse outcomes of pregnancy in southern Chinese women with systemic lupus erythematosus. PloS one. 2017;12(4):e0176457.
  51. Al Arfaj AS, Khalil N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus. 2010 Dec;19(14):1665-73.
  52. Alami Z, Agier MS, Ahid S, Vial T, Dautriche A, Lagarce L, Toutain A, Cherrah Y, Jonville-Bera AP. Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study. Therapie. 2018 May -Jun;73(3):199-207.
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  58. Casanova MJ, Chaparro M, Domènech E, Barreiro-de Acosta M, Bermejo F, Iglesias E, Gomollón F, Rodrigo L, Calvet X, Esteve M, García-Planella E, García-López S, Taxonera C, Calvo M, López M, Ginard D, Gómez-García M, Garrido E, Pérez-Calle JL, Beltrán B, Piqueras M, Saro C, Botella B, Dueñas C, Ponferrada A, Mañosa M, García-Sánchez V, Maté J, Gisbert JP. Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol. 2013 Mar;108(3):433-40.
  59. Chambers C, Johnson D, Jones K; Pregnancy outcomes in women exposed to adalimumab: The OTIS autoimmune diseases in pregnancy project. Journal of American Academy of Dermatology. 2007 Feb; 56(2):AB10.
  60. Chambers CD, Johnson DL, Robinson LK, Braddock SR, Xu R, Lopez-Jimenez J, Mirrasoul N, Salas E, Luo YJ, Jin S, Jones KL; Organization of Teratology Information Specialists Collaborative Research Group. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum. 2010 May;62(5):1494-503.
  61. Cleary BJ, Källén B. Early pregnancy azathioprine use and pregnancy outcomes. Birth Defects Res A Clin Mol Teratol. 2009 Jul;85(7):647-54.
  62. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006 Nov;54(11):3640-7.
  63. Coelho J, Beaugerie L, Colombel JF, Hébuterne X, Lerebours E, Lémann M, Baumer P, Cosnes J, Bourreille A, Gendre JP, Seksik P, Blain A, Metman EH, Nisard A, Cadiot G, Veyrac M, Coffin B, Dray X, Carrat F, Marteau P; CESAME Pregnancy Study Group (France). Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut. 2011 Feb;60(2):198-203.
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  70. Diav-Citrin O, Otcheretianski-Volodarsky A, Shechtman S, Ornoy A. Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study. Reprod Toxicol. 2014 Jan;43:78-84.
  71. Diav-Citrin O, Shechtman S, Schwartz V, Avgil-Tsadok M, Finkel-Pekarsky V, Wajnberg R, Arnon J, Berkovitch M, Ornoy A. Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol. 2010 Aug;203(2):144.e1-6.
  72. Edwards DR, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol. 2012 Jul;120(1):113-22.
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  74. Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014 Oct;290(4):757-62.
  75. Heilmann L, Schorch M, Hahn T, Adasz G, Schilberz K, Adiguzel C, Fareed J. Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study. Semin Thromb Hemost. 2008 Nov;34(8):794-802.
  76. Hoeltzenbein M, Elefant E, Vial T, Finkel-Pekarsky V, Stephens S, Clementi M, Allignol A, Weber-Schoendorfer C, Schaefer C. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A. 2012 Mar;158A(3):588-96.
  77. Hviid A, Mølgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ. 2011 Apr 19;183(7):796-804.
  78. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, Friedman D, Llanos C, Piette JC, Buyon JP. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012 Jul 3;126(1):76-82.
  79. Johnson, D. L., Y. ; Jones K.L. (2011). Pregnancy outcomes in women exposed to adalimumab: an update on the autoimmune diseases in pregnancy project. Arthritis Rheum, 1, 1874.
  80. Julsgaard M, Nørgaard M, Hvas CL, Grosen A, Hasseriis S, Christensen LA. Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn's disease. Scand J Gastroenterol. 2014 Mar;49(3):302-8.
  81. Kalari S, Granath F, Guo CY, Harrison DD, Bröms G, Geldhof A, Nissinen R, Sanders M, Gissler M, Pedersen L, Sorensen HT, Kieler H. Pregnancy Outcomes In Women With Rheumatologic Conditions Exposed To Infliximab. American College of Rheumatology. 2013;Annual Meeting.
  82. Karadag O, Kilic L, Erbil AA, Yilmaz N, Akdogan A, Kalyoncu U, Bilgen SA, Kiraz S. Pregnancy outcomes of rheumatic patients with pre/peri gestational leflunomide exposure. BMJ Journals. Annals of Rheumatic Diseases. 2013;72(3):A896-A897.
  83. Kelly O, Hartery K., Boland K, Cullen G, Keegan D, Patchett S, Doherty G (2014). P336 TNF alpha inhibitor use in pregnancy: experience in a European cohort. Journal of Crohn's and Colitis, 8(Supplement_1), S204-S205.
    Koh JH, Ko HS, Kwok SK, Ju JH, Park SH. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus. 2015 Feb;24(2):210-7.
  84. Langagergaard V, Pedersen L, Gislum M, Nørgard B, Sørensen HT. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy: A Danish nationwide cohort study. Aliment Pharmacol Ther. 2007 Jan 1;25(1):73-81.
  85. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, Ullman T, Glover S, Valentine JF, Rubin DT, Miller J, Abreu MT. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013 Mar;11(3):286-92; quiz e24.
  86. Martín MC, Barbero P, Groisman B, Aguirre MÁ, Koren G. Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol. 2014 Jan;43:26-9.
  87. Mohamed-Ahmed O, Nelson-Piercy C, Bramham K, Gao H, Kurinczuk JJ, Brocklehurst P, Knight M. Pregnancy outcomes in liver and cardiothoracic transplant recipients: a UK national cohort study. PLoS One. 2014 Feb 19;9(2):e89151.
  88. Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011 Oct 18;183(15):1713-20. Nezvalová-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen,
    diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study. BJOG. 2013 Jul;120(8):948-59.
  89. Nørgård B, Pedersen L, Christensen LA, Sørensen HT. Therapeutic drug use in women with Crohn's disease and birth outcomes: a Danish nationwide cohort study. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
  90. Nulman I, Sgro M, Barrera M, Chitayat D, Cairney J, Koren G. Long-term neurodevelopment of children exposed in utero to ciclosporin after maternal renal transplant. Paediatr Drugs. 2010 Apr 1;12(2):113-22.
  91. Perales-Puchalt A, Vila Vives JM, López Montes J, Diago Almela VJ, Perales A. Pregnancy outcomes after kidney transplantation-immunosuppressive therapy comparison. J Matern Fetal Neonatal Med. 2012 Aug;25(8):1363-6.
  92. Perricone R, De Carolis C, Kröegler B, Greco E, Giacomelli R, Cipriani P, Fontana L, Perricone C. Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology (Oxford). 2008 May;47(5):646-51.
  93. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. Reprod Toxicol. 2008 Feb;25(2):271-5.
  94. Reddy D, Murphy SJ, Kane SV, Present DH, Kornbluth AA. Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes. Am J Gastroenterol. 2008 May;103(5):1203-9.
  95. Schnitzler F, Fidder H, Ferrante M, Ballet V, Noman M, Van Assche G, Spitz B, Hoffman I, Van Steen K, Vermeire S, Rutgeerts P. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy. Inflamm Bowel Dis. 2011 Sep;17(9):1846-54.
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  97. Shim L, Eslick GD, Simring AA, Murray H, Weltman MD. The effects of azathioprine on birth outcomes in women with inflammatory bowel disease (IBD). J Crohns Colitis. 2011 Jun;5(3):234-8.
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N.B. the original EULAR data sheet is shaded green and for each new included study a new row is added to the original table.

 

Drug

Prescribed for?

Type of publication in numbers

Author (year)

Total pregnancies (prospective/ retrospective)

Number of miscarriages of eligible pregnancies‡ (%)

Number of congenital malformations of live births§ (%)

Comments on miscarriages (MC) and/or congenital malformations (CM) compared with control groups and/or background data§

Non-selective COX inhibitors (classical NSAIDs)

-

3 cohorts, 3 case controls

Daniel (2014); Daniel (2012); Edwards (2012); Nezvalova-Henriksen (2013); van Gelder (2011); Viktil (2012)

17 992 (7684/10 308)

530/5609 (9.4)

457/ 12 354 (3.7)

No difference MC or CM

Selective COX II inhibitors (rofecoxib, celecoxib,etoricoxib)

-

3 case controls

Daniel (2014); Daniel (2012); Nakhai-Pour (2011)

215 (0/215)

11/71 (15.5)

9/114 (7.9)

Significance for slightly increased rate MC and CM questionable due to confounders

NSAIDs/COX II update

SLE, RA, MS  and rare autoimmune diseases

cohort

Berard (2018)

155,755 (771 autoimmune diseases) (771/0)

NR

NR

MC and CM not reported. Only 7 pregnancies were exposed during late pregnancy.

Glucocorticoids (any route/formulation)

-

2 cohorts, 5 case controls, 17 case reports/series (1 abstract)

Al Arfaj (2010); Bay Bjorn (2014); Gomaa (2014); Hviid  (2011); Reddy (2008); Tang  (2013); Viktil  (2012)

3500¶ (94/3406)

70/331 (21.1)

34/3180 (1.1)

MC slightly increased confounded by disease indication, no difference CM compared with control

Glucocorticoids (prednisone): update

RA

cohort

Palmsten (2018)

254 (254/0)

NR

NR

MC or CM not reported.

Antimalarials

-

2 cohorts, 4 case controls

Clowse (2006); Cooper (2014); Diav-Citrin (2013); Izmirly (2012); Koh (2015); Viktil (2012)

492 (170/322)

20/170 (11.8)

23/492 (4.7)

No difference MC or CM

Antimalarials (hydroxychloroquine and chloroquine): update

Women with Ro/La antibodies: SLE (89%), cutaneous lupus, SS, RA

cohort

Barsalou (2017)

268 (0/268)

NR

1/73 (1.4) developed cardiac NLE in exposed group, vs. 12/195 (6.2) unexposed

Congenital NLE slightly decreased for AM exposed vs. unexposed (non significant)

Antimalarials (hydroxychloroquine): update

SLE

cohort (registry)

Zhan (2017)

263 (0/263)

18/263 (6.8) N.B.: percentage medication users not reported

6/188 (3.2) N.B.: percentage medication users not reported

Antimalarial medication was associated with lower adverse pregnancy outcomes. Risk CM/MC with/without medication not reported.

Antimalarials (hydroxychloroquine): update

SLE

cohort

Leroux (2015)

118 (0/118)

3/41 (7.3) HCQ users, 3/77 (3.9) non HCQ users

0/38 HCQ users, 4/74 (5.4) non HCQ users

No difference on MC or CM

Antimalarials (hydroxychloroquine): update

SLE

cohort (registry)

Kroese (2017)

110 (0/110)

9/30 (30.0) in HCQ users, 10/80 (12.5) in non HCQ

0/20 HCQ, 4/68 (5.9) in non-HCQ

No difference MC or CM

Antimalarials (hydroxychloroquine): update

SLE

cohort

Liu (2018)

78 (78/0)

NR

NR

MC or CM not reported

Antimalarials (hydroxychloroquine): update

SLE (59%), primary or secondary SS (37%), RA or JIA (3%), dermatomyositis (0.1%) 

case control

Barsalou (2018)

73 (0/73)

NR

NR

Cutaneous neonatal lupus decreased in HCQ treated mothers with SLE

Antimalarials (hydroxychloroquine): update

Women with Ro/La antibodies: SLE, SS, Mixed connective tissue disease, RA, Scleroderma, Polychondritis, Unknown maternal diagnosis.

cohort (registry)

Mollerach (2019)

62 (0/62)

0/14 HCQ users, 1/48 (2.1) non HCQ users

NR

No difference in MC, HCQ tends to decrease atrioventricular block

Antimalarials (hydroxychloroquine): update

Women with Ro/La antibodies: SLE (56%), RA, JIA, undifferentiated CD and other

cohort

Balevic (2019)

50 (50/0)

2/46 (4.3)

0/46

No difference MC or CM

Antimalarials (hydroxychloroquine): update

SLE/APS

cohort

Sciascia (2016)

170 (0/170)

17/51 (33.3) HCQ users, 59/119 (49.6) No HCQ users

NR

Reduced MC. However confounding by indication (more SLE and less APS in treatment group).

Antimalarials (hydroxychloroquine): update

APS

cohort (registry)

Mekinian (2015)

20 (0/20)

4/20 (20.0)

NR

MC decrease in refractory APS

Antimalarials (hydroxychloroquine): update

APS (obstetrical)

case report

De Carolis (2015)

1 (1/0)

0/1

0/1

-

Sulfasalazine

-

2 cohorts, 2 case controls

de Man (2009); Norgard (2007); Rahimi (2008); Viktil (2012)

525 (227/298)

12/186 (6.5)

16/339 (4.7)

No difference MC or CM

Leflunomide

-

2 cohorts (1 abstract), 1 case control, 4 case reports/series

Chambers (2010); Karadag(2013); Viktil (2012)

129 (80/49)

12/122 (9.8)

5/129 (3.9)

No difference MC or CM

Leflunomide: update

RA (83%), PsA (9%) and, other diseases (6%)

cohort (registry)

Weber-Schoendorfer (2017)

65 (65/0)

10/65 (15.3)

1/39 (2.5)

No difference MC or CM

Azathioprine

-

4 cohorts (1 abstract), 7 case controls

Alami (2013); Ban (2014); Casanova (2013); Cleary (2009); Coelho (2011); Goldstein (2007); Julsgaard (2014); Langagergaard (2007); Norgard (2007); Shim (2011); Viktil (2012)

1327 (434/893)

40/559 (7.2)

65/1327 (4.9)

No significant difference MC or CM compared with disease-matched controls

Azathioprine: update

ANCA-associated AAV

cohort

Saavedra (2015)

178 (0/178)

7/87 (8.0) in AZA users, 6/91 (6.6) in NO AZA users

0/72 AZA users, 0/79 No AZA users

No increased MC or CM

Azathioprine: update

ANCA-associated AAV

case series

Croft (2015)

15 (0/15)

0/15

0/15

No difference MC or CM

Methotrexate

-

2 cohorts, 2 case controls, 8 case reports/series

Cooper (2014); Martin (2014); Viktil (2012); Weber-Schoendorfer (2014)

372 (332/40)

140/329 (42.6)

15/143 (10.5)

Increased rate MC
Increased rate CM with specific
pattern

Methotrexate: update

RA

cohort

Brouwer (2015)

162 (162/0)

28/162

NR

Increased MC

Cyclophosphamide

-

2 cohorts, 28 case reports/series (2 abstracts)

Cardonick (2010); Silva (2008)

276 (160/116)

No separate studies on MC published

23/86 (26.7)

High rate CM No studies with control group available

Ciclosporin

-

2 cohorts, 1 case control, 11 case reports/series (1 abstract)

Mohamed-Ahmed (2014); Nulman (2010); Perales-Puchalt (2012)

1126 (1010/116)

137/953 (14.4)

9/261 (3.4)

No difference MC or CM

Ciclosporin: update

RA, SLE, PsA and SS

cohort

Reggia (2016)

29 (0/29)

3/29 (10.3)

0/25

No increased MC or CM

Tacrolimus

-

1 cohort, 1 case control, 10 case reports/series

Mohamed-Ahmed (2014); Perales-Puchalt (2012)

505 (482/23)

91/344 (26.5)

3/107 (2.8)

MC increase confounded by disease indication. No difference CM

Tacrolimus: update

SLE

cohort

Ichinose (2018)

54 (0/54)

0/15

0/15

No increased MC or CM

Tacrolimus: update

SLE

cohort

Hiramatsu (2018)

25 (25/0)

2/25 (8.0)

NR

No increased MC

Mycophenolate mofetil

-

2 cohorts, 1 register data, 20 case reports/series (2 abstracts)

Hoeltzenbein (2012); Mohamed-Ahmed (2014)

333 (199/134)

119/318 (37.4)

48/174** (27.6)

In studies without control group high rate MC and CM with specific pattern

Colchicine

 

1 cohort, 1 case control, 1 case series

Ben-Chetrit (2010); Diav-Citrin (2010)

460 (238/222)

30/417 (7.2)

11/460 (2.4)

No difference MC or CM

Colchicine: update

BD

cohort (registry)

Orgul (2018)

66 (0/66): 6 colchicine users

0/6

0/6

No increased MC or CM reported

IVIG

-

3 cohorts, 3 case reports/series

Dendrinos (2009); Heilmann (2008); Perricone (2008)

96 (93/3)

24/93 (25.8)

0/96

No increase of MC or CM compared with disease-matched controls

Tofacitinib

-

1 case series (abstract)

-

27 (27/0)

7/2027 (25.9)

1/15

In case series and with concomitant MTX exposure high rate MC, no indication of an increased rate CM

Tofacitinib: update

UC

cohort (registry/safety database)

Mahadevan (2018)

11(0/11)

2/11 (18.2)

0/11

No difference MC or CM

Tofacitinib: update

RA, PsA

cohort (registry)

Clowse (2016)

47 (0/47)

3/18 (16.7)

1/18 (5.56)

No difference MC or CM

Infliximab

-

9 cohorts (1 abstract), 4 case controls (1 abstract), 2 register data (1 abstract), 16 case reports/series (3 abstracts)

Bortlik (2013); Casanova (2013); Cooper (2014); Diav-Citrin (2014); Giacuzzo (2014); Kalari (2014); Mahadevan (2013); Schnitzler (2011); Seirafi (2014); Verstappen (2011); Weber-Schoendorfer (2015); Zelinkova (2013)

1161 (968/ 193)

64/676 (9.5)

20/756††(2.6)

No difference MC or CM

Adalimumab

-

10 cohorts (2 abstracts), 5 case controls (1 abstract), 2 register data (1 abstract), 6 case reports/series (1 abstract)

Bortlik (2013); Casanova (2013); Chambers (2014); Diav-Citrin (2014); Giacuzzo (2014); Johnson (2011); Kelly (2014); Mahadevan (2013); Schnitzler (2011); Seirafi (2014); Verstappen (2011); Viktil (2012); Weber-Schoendorfer (2015); Zelinkova (2013)

524 (266/258)

23/191 (12.0)

24/350†† (6.9)

No significant difference MC. Increased rate CM in one study, no increase compared with disease-matched controls

Adalimumab: update

RA (only RA cohort included)

cohort

Chambers (2019)

143 (143/0) (only RA cohort included)

NR

6/69 (8.7) adalimumab exposed & 5/74 (6.8) nonexposed

No difference on CM

Etanercept

-

3 cohorts, 3 case controls (1 abstract), 2 register data (1 abstract), 11 case reports/series (3 abstracts)

Cooper (2014); Diav-Citrin (2014); Giacuzzo (2014); Verstappen (2011); Viktil (2012); Weber-Schoendorfer (2015)

332 (213/119)

12/74 (16.2)

9/251†† (3.6)

No difference MC or CM

Etanercept: update

Chronic Inflammatory Arthritis (n = 3048), PsA (n = 1835)

cohort

Carman (2017)

4883 (0/4883)

56/256 (21.9) ETN exposes in chronic inflammatory arthritis vs. 287/1512 (19.0) ETN unexposed. 13/81 (16.0) in ETN exposed psoriasis vs.   211/1349 ETN unexposed (16.0)

10/165 (6.1) ETN exposed chronic inflammatory arthritis vs. 54/990 (5.5) ETN unexposed. 1/51 (2.0%) ETN exposed psoriasis vs. 40/942 ETN unexposed (4.2) ETN unexposed.

No difference on MC or CM

Certolizumab

 

2 cohorts, 1 case control, 2 case reports/series

Mahadevan (2013); Seirafi (2014); Weber-Schoendorfer (2015)

362 (243/119)

52/339 (15.3)

12/267†† (4.5)

No increased rate MC or CM. No studies with control group available

Certolizumab: update

Reumatic disease (only rheumatic disease selected). Unknown diagnosis.

cohort

Clowse (2018)

301/(301/0)

29/305 (4 twins)

4/252 (1.6)

No difference on MC or CM

Certolizumab: update

RA (n=11), CD (n=3), PsA (n=1), AS (n=1)

cohort

Mariette (2018)

16 (16/0)

0/16

0/16

No difference on MC or CM

Certolizumab: update

RA (n=5) and SA (n=8)

case series

Förger (2016)

13(13/0)

0/13

1/13

No difference on MC or CM

Certolizumab: update

Obstetric APS

case series

Alijotas-Reig (2019)*

18 (18/0): 2 certolizumab

0/2  certolizumab users

0/2 certolizumab users

-

Golimumab

-

1 cohort, 1 case series (abstract)

Weber-Schoendorfer (2015)

50 (38/12)

13/47 (27.7)

0/26††

With concomitant MTX exposure high rate MC, no indication of an increased rate CM. No studies with control group available

All TNF inhibitors, including studies not differentiating between them

-

10 cohorts (3 abstracts), 5 case controls (1 abstract), 2 register data (1 abstract), 32 case reports/series (7 abstracts)

Bortlik (2013); Casanova (2013); Chambers (2014); Diav-Citrin (2014); Giacuzzo (2014); Johnson (2011); Kalari (2014); Mahadevan (2013); Schnitzler (2011); Seirafi (2014); Verstappen (2011); Viktil (2012); Weber-Schoendorfer (2015); Zelinkova (2013)

2492 (1734/758)

265/2258 (11.7)

75/2110 (3.6)

No difference in MC or CM in pregnancies exposed to TNF inhibitors compared with controls

Anti TNF: update

RA (51%), PsA, AS, PsA, UC and CD

cohort (registry)

Bröms (2016)

22.232 (0/22.232)

NR

43/683 (6.3) in TNF exposed vs. 1019/21547 (4.7) TNF unexposed

CM (birth defects) slightly increased on anti TNF therapy compared to control group but not significant

Anti TNF: update

IBS, RA, PsA, JIA, systemic autoimmune rheumatic diseases, AS

cohort (registry)

Tsao (2019)

8607(0/8607)

28/100 (28.0) in biological exposed, 2230/8507 (26.2) in biological unexposed

0/100 biological exposed, 74/6277 (1.0) biological unexposed

No increased MC or CM

Anti TNF: update

RA, PsA, AS, JIA, IBD/psoriasis

cohort

Genest (2018)

46 (46/0)

2/46 (4.3) : 2/14 (14.2) TNFi therapy at conception and 0/34 TNFi therapy throughout pregnancy

1/46 (2.2): 1/14 (7.1) in TNFi conception group and 0/34 TNFi throughout pregnancy group

No increased MC or CM.

Anti TNF: update

RA, AS, PsA

cohort

Hoxha (2017)

38 (38/0)

5/38 (13.2): 2/24 (8.3) anti TNF at conception/1 trimester and 3/11 (27.3) anti TNF prior to conception group

2/38 (5.2): 1/24 anti TNF at conception/1 trimester group and 1/24 anti TNF prior to conception group

No increased MC or CM, when taken during first trimester.

Anti TNF: update

RA

cohort (registry)

Shimada (2019)

25(0/25)

2/15 (13.3) TNF at conception, 0/10 no TNF

0/25

No increased MC or CM.

Rituximab

-

1 register data, 20  case reports/series

-

256 (72/184)

48/210 (22.9)

6/172 (3.5)

Increased rate MC confounded by disease indication, no increased rate CMNo studies with control group available

Rituximab: update

ANCA-associated AAV

case report

Harris (2018)

1 (1/0)

0/1

0/1

-

Anakinra

 

1 register data, 3 case reports

-

40 (not reported)

4/40 (10.0)

2/34 (5.9)

No increased rate MC or CM No studies with control group available

Anakinra: update

AOSD; cryopyrin-associated periodic fever syndromes, TNF

cohort

Youngstein (2017)*

31 (0/31) (29 anakinra users)

1/29 (3.4) anakinra users (23 maternal, 6 paternal exposure)

0/28 anakinra users

No increased MC or CM

Anakinra: update

Obstetric APS

case series

Alijotas-Reig (2019)*

18 (18/0) (16 anakinra users)

3/13 (23.1) of anakinra users

0/13 anakinra users

MC and CM decreased

Anakinra: update

Systemic JIA (N=2) and AOSD (N=3)

case series

Smith (2018)

5 (5/0)

0/5

0/5

No increased MC or CM. 2 cases of oligohydramnios, possibly related to anakinra

Abatacept

-

1 case series, 1 case report

-

152 (94/58)

40/151 (26.5)

7/87 (8.0)

With concomitant MTX exposure high rate MC and CMNo studies with control group available

Tocilizumab

-

1 register data, 2 case series (2 abstracts)

-

218 (180/38)

47/218 (21.6)

5/128 (3.9)

With concomitant MTX exposure high rate MC, no indication of an increased rate CM

Tocilizumab: update

RA (90%), JIA (8%) and other indications

cohort (registry)

Hoelzenbein (2016)

288 (180/108)

39/180 (21.7) in prospective cohort 31/108 (28.7) in retrospective cohort

5/111 (4.5) prospective cohort & 3/108 (2.8) of retrospective cohort

No increased MC and CM risk

Tocilizumab: update

RA (87%), systemic JIA (1,6%), multicentric castleman disease

cohort (registry)

Nakajima (2016)

61 (0/61)

9/50 (18.0)

0/36

No increased MC and CM risk

Tocilizumab: update

RA

case series

Weber-Schoendorver (2016)

16 (16/0)

4/16 (25.0)

0/11

No increased MC and CM

Tocilizumab: update

RA

case series

Kaneko (2016)

4 (0/4)

1/4  (25.0)

0/3

No increased MC and CM risk of preconception TCZ

Ustekinumab

-

1 register data, 4 case reports/series (1 abstract)

-

108 (104/4)

15/108 (13.9)

1/58 (1.7)

No increased rate MC or CM No studies with control group available

Belimumab

-

1 register data, 1 case series (1 abstract)

-

153 (152/1)

41/153 (26.8)

7/71 (9.9)

High rate MC and CM. Concomitant medication possible confounder. No studies with disease-matched controls available

Belimumab: update

SLE

case report

Danve (2014)

1 (1/0)

0/1

1/1

A mild Ebstein’s anomaly was reported.

Belimumab: update

SLE

case report

Emmi (2016)

1 (1/0)

0/2

1/2

-

Belimumab: update

APS

case report

Gustavsen (2017)

1 (1/0)

0/3

1/3

-

Canakinumab: update

AOSD; cryopyrin-associated periodic fever syndromes, TNF

cohort

Youngstein (2017)*

31 (0/31) (8 canakinumab users)

1/8 (12.5) canakinumab users

0/7 canakinumab users

No increased MC or CM.

Update notes:

#Abbreviations for diagnoses incude: systemic lupus erythematodes (SLE), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), juvenile rheumatoid arthritis (JIA), psoriasis arthritis (PsA), multiple sclerosis (MS), Crohn’s Disease (CD), ankylosing spondylitis (AS), inflammatory bowel syndrome (IBS), ulcerative colitis (UC), Anti-neutrophil cytoplasm antibody–associated small vessel vasculitis (ANCA-associated AAV), adult onset Still’s Disease (AOSD), Sjögren’s syndrome (SS) and Behcet’s disease (BD)

*The studies by Alijotas-Reig (2019) and Youngstein (2017) have examined two medicines, which are described separately in the evidence table.

 

 

EULAR (2016) notes:

Strength of evidence based on previous consensus papers1 2 and new SLR and registry data.

*As the update publication did not include all non-biologic drugs, an additional search for the period 2006–2008 was performed for 10 drugs; NSAIDs, glucocorticoids, MTX,

cyclophosphamide, sulfasalazine, antimalarials, azathioprine, colchicine, ciclosporin and IVIG.

†Total reported pregnancies for a given drug, where CM and/or MC are reported, and where the pregnancies have been exposed in the window of susceptibility for the reported outcome.

‡Nominator represents exposed pregnancies with MC as outcome. Denominator represents the total number of exposed pregnancies where MC is reported.

§Nominator represents exposed pregnancies with CM in live births as outcome; mainly major CM but in some publications major and minor CM are not differentiated. Denominator

represents the total number of exposed pregnancies resulting in live births.

¶One cohort of 2295 pregnancies looks only at isolated clefts.

**Nominator includes CM in elective terminations in addition to CM in live births. Denominator includes elective terminations with anomalies in addition to live births.

††Several publications report congenital malformations for women using different TNF inhibitors; nominator/denominator reflects numbers in which each TNF inhibitor is reported

separately.

‡‡Publication after 15 April (replacing earlier abstract).

IVIG, intravenous immunoglobulin; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; SLR, systematic literature review; TNF, tumour necrosis factor.

 

 

 

 

 

 

 

Evidence table

Research question: What is the risk of infection in mother and child during pregnancy and postpartum in women with an inflammatory rheumatic disease treated with bDMARDs compared to no treatment with bDMARDs?

Drug

Diagnosis

Type of publication (prospective/ retrospective)

Author (year)

Total pregnancies

Number of

infections among mothers‡

(%)

Number of

Infections among children in first year§

(%)

Comments on infection risk for mothers and children using bDMARDS compared with background data

§

TNF inhibitors (infliximab (n=54), etanercept (n=41) and adalimumab (n=39) and other bDMARDs (n=18))

Autoimmune disease: inflammatory bowel disease, rheumatoid arthritis, psoriasis, juvenile idiopathic arthritis, systemic autoimmune rheumatic diseases and ankylosing spondylarthritis

Retrospective cohort study

Tsao, 2019

100

Ranging from 0% to 5%, depending on concomitant exposures

to DMARDs or glucocorticoids (absolute numbers not reported)

Ranging from 0% to 7%, depending on concomitant exposures

to DMARDs or glucocorticoids (absolute numbers not reported)

Authors: “Our findings suggest that there was

no difference in risk of serious postpartum infections in women who used biologics during pregnancy versus those

who did not. Similarly, we did not observe a difference in risk of serious infections during the first year of life in

infants born to mothers who used biologics during pregnancy compared with those who did not.”

TNF inhibitors (unspecified)

Rheumatoid

arthritis

Cohort study (retrospective)

Vinet, 2018

380

NR

12/380 (3.2%)

Authors: “We did not detect a marked excess risk associated with overall TNFi exposure during the preconception and gestational period. We observed a trend in the risk of serious infections in RA offspring exposed to infliximab, as opposed to other TNFi, during pregnancy.”

Etanercept (ETN)

Chronic inflammatory arthritis (cIA) and psoriasis (PsA)

Cohort study (retrospective)

Carman, 2017

4883: 3048 cIA and 1835 PsA

24/256 (9.4%) cIA, ETN exposed during pregnancy vs. 162/1512 (10.7%) cIA, ETN unexposed during pregnancy vs. 103/1280 (8.0%) in general population.

 

8/810 (9.9%) PsO, ETN exposed during pregnancy vs. 132/1349 (9.8%) PsO, ETN unexposed during pregnancy vs. 24/405 (5.9%) in general population.

 

NR

Number of infections among mothers during pregnancy were comparable between ETN exposed and ETN unexposed patients.

TNF inhibitors (unspecified)

Conditions included ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis and rheumatoid arthritis

Observational cohort study (retrospective)

Desai, 2017

776

<11 (Actual numbers are suppressed for counts <11 as required by data use agreement with the Centers for Medicare and Medicaid Services)

NR

Authors: “We observed no apparent increase in the risk associated with use of TNF inhibitors during pregnancy compared with non-biologics or steroids.”

TNF inhibitors (unspecified)

Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis

Prospective multicenter study

Hoxha, 2017

24 maternal exposure during pregnancy

1/24 (4.1%)

0/34

Authors: “The woman who suffered from post-partum infection had suspended ETN by the end of first trimester and gave birth at 40 week of gestation. Given the drug’s half-life, there does not seem to be any connection between it and the infection.”

TNF inhibitors (unspecified)

Inflammatory rheumatic diseases (various diagnoses)

Multicenter cohort study (prospective)

Bazzani, 2015

79

NR

NR

In discussion: “No infectious events were reported in the newborns”. However this was not a predefined outcome, it was not reported in the results, and it is unclear until when the newborns were followed up (up to 6 months?)

TNF inhibitors (unspecified)

Indications were rheumatoid arthritis (n=32), inflammatory bowel disease (n=16) systemic lupus erythematous (n=3) and other autoimmune conditions (n=5)

Database (retrospective cohort)

Cooper, 2014

56

NR

NR

4/56 neonatal complications reported. Neonatal complications include respiratory failure, seizures, jaundice, or sepsis. Other infections were not reported.

TNF inhibitors (unspecified)

Rheumatoid arthritis

Registry (retrospective)

Hyrich, 2006

32 patients during or immediately prior to pregnancy.

NR

NR

Maternal and neonatal infections were not reported.

TNF inhibitors (unspecified)

Rheumatoid arthritis

Case report

Roux, 2007

3

NR

1/2 (50%)

One patient opted for therapeutic termination. One infant was delivered healthy at 32 weeks, and one infant developed a urinary e. coli infection. At two years old the child is healthy and developing normally.

TNF inhibitors  (certolizumab pegol (n=9)

and etanercept (n=6))

Rheumatoid arthritis

Registry (retrospective)

Shimada, 2019

15 exposed during conception. All patients discontinued at the time of a positive pregnancy test except for one.

NR

0/13

Authors: “There was no case of neonatal infection or malformation.”

Certolizumab Pegol

Indications were rheumatic disease (n= 301) and Crohn’s disease (n= 235) and unknown (n= 43)

Database (prospective) of clinical reports

Clowse, 2018

528, 10 twins -> 538 outcomes

22/528 (4.2%)

NR

The frequency

of serious infections in the general population during pregnancy was consistent

with that reported in CZP-exposed patients

Certolizumab Pegol

Indications were rheumatic disease (n=78) and Crohn’s disease (n=132) and unknown (n=16)

Database (prospective and retrospective) of clinical reports

Clowse, 2015

339 with known outcomes (226 prospective and 113 retrospective)

Unclear

NR

N=5 Maternal infections reported.

Certolizumab Pegol

Rheumatoid arthritis (n=5) and spondyloarthritis (n=8)

Case series

Förger, 2016

13

3/13 (23.1%)

NR

Authors: “Three of our CZT treated patients suffered from infections, of whom one had a severe infection. Two of these patients had additional low-dose prednisone treatment. Both TNF-inhibitors and prednisone can increase the risk of serious infections.” “In pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause pre-maturity.”

Rituximab

Lymphoma, autoimmune cytopenias and other autoimmune diseases

Database (retrospective) of clinical reports worldwide

Chakravarty, 2011

153

NR

4/90 (4.5%)

11 pregnancies were complicated by hematologic complications and 4 by neonatal infections. Authors: “Given that the known mechanism of action of rituximab is

CD20+ B-cell depletion, perinatal and neonatal immunosuppression

and subsequent infection remain a serious concern.” “Although relatively few infections were reported in exposed

pregnancies to date, continued vigilance is essential for early

detection of potential infections complicating the pregnancy or the

neonate.”

Rituximab

Rheumatoid arthritis

Case report

Ton, 2011

1 (a twin), established 6 weeks after rituximab infusion

NR

0/2

No infections due to the medication given shortly before pregnancy were discovered.

Rituximab

De novo antineutrophil cytoplasmic

antibody (ANCA) associated vasculitis (AAV)

Case report

Harris, 2018

1

0/1

0/1

Authors: “Delivery occurred at 29 weeks gestational age due to preeclampsia worsening.” “Maternal and fetal CD + 19 cells were depleted at time of delivery with associated fetal lymphopenia in the absence of infection or other complications

related to Rituximab use.” “Neonatal birth

weight was 1010 g and the neonate spent 10 weeks in the neonatal intensive care unit before discharge in healthy condition.”

Adalimumab

Intestinal

Behcet’s Disease

Case report

Fujikawa, 2015

1

NR

NR

The patient delivered a healthy child without complications, no infections reported. Maternal infections were not reported.

Belimumab

Systemic lupus erythematous

Case report

Danve, 2015

1

0/1

0/1

Only a mild Epstein’s anomaly in the infant was reported.

Infliximab

Behçet’s disease

Case report

Mainini, 2014

1

0/1

0/1

The infant was delivered healthy without signs of infections and the mother stayed uneventful up to 6 months after pregnancy.

Anakinra

Adult onset Still’s disease

Case report

Fischer-Betz, 2011

2

NR

NR

Both delivered a healthy child without complications, no infections were reported. Maternal infections were not reported.





 

Risk of bias table

Research question: What is the risk of infection in mother and child during pregnancy and postpartum in women with an inflammatory rheumatic disease treated with bDMARDs compared to no treatment with bDMARDs?

Study reference

 

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?1

 

 

 

(unlikely/likely/unclear)

Bias due to  insufficiently long, or   incomplete follow-up, or differences in follow-up between treatment groups?2

 

 

(unlikely/likely/unclear)

 

Bias due to ill-defined or inadequately measured outcome ?3

 

 

 

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all  important prognostic factors?4

 

 

 

(unlikely/likely/unclear)

Carman, 2017

Unlikely: chronic inflammatory patients and psoriasis patients were sampled from the same population, and later divided into an exposed vs. unexposed group.

Unlikely: infants were followed until age 1, however we have only data about infections in mothers at baseline (any infection during pregnancy)

Unclear: it is unclear how the outcome “any infection during pregnancy” was defined and measured.

Likely: odds ratios and adjustment for important prognostic factors was done, as maternal infections was not a predefined outcome, but part of the baseline variables.

Tsao, 2019

Unlikely: woman for the source population were only included if they had a recorded diagnosis of one or more autoimmune diseases that could be treated with a biologic, and if they received this diagnosis at least at two doctor’s visits 60 days apart and within 2 years, any time prior to the date of conception. The woman were than divided into an biologic exposed and unexposed group.

Unlikely: all pregnant woman and their children were followed until their first year of life. Health care coverage was one of the inclusion criteria to ensure all children could be followed until the first year of age.

Unlikely: the outcome measures were defined: serious postpartum infections were defined as any episode of hospitalization, including the delivery period with one of more diagnostic codes for infection from the date of infection until 42 days post partum. Serious infections in infants were defined as any episode of hospitalization with one or more diagnostic code for infection anytime during the first year of life.

Unlikely: the adjusted OR (we reported only model 2) is adjusted for covariates and proxy variables such as (co)medication, comorbidities, health care utilisation. 1:5 match performance was used to match one exposed pregnancy with 5 unexposed pregnancies, than using logistic regression to calculate the odds ratios in the matched samples.

Desai, 2017

Unlikely: all patients with a recorded diagnosis of a systemic inflammatory condition, who used at least one prescription of an immunosuppressive agent, were sampled and later divided into a steroids, non biologic and biologic group.

Unlikely: the primary outcome of serious infection was measured until the end of pregnancy for all groups.

Unlikely: the outcome was measured as a hospital admission, using the predefined diagnostic codes for infection.

Unlikely: the hazard ratio was adjusted for several covariates such as maternal age, geographic region, insurance program, diagnosis, other medication conditions and medication.

Vinet, 2018

Unlikely: rheumatoid arthritis patients come all from the same sample, and were than divided in an exposed to bDMARD group, versus unexposed group.

Unlikely: all children were follow up until 12 months (if possible) and the mean follow up time was similar among groups (ranging from 285 to 296 days).

Unlikely: the outcome was measured as ≥1 hospitalization with infection as primary reason for admission, which has shown to have a high sensitivity and specificity.

Unlikely: the adjusted odds ratios were calculated, adjusted for >1 offspring from the same mother in the GEE method and adjusting for maternal age, pregestational diabetes mellitus, gestational diabetes mellitus, preterm birth and medications in the multivariate analysis.

Hoxha, 2017

Unlikely: patients with the diagnoses rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, treated with infliximab, etanercept, adalimumab or certolizumab pegol, were enrolled in the study and later divided into a group that used TNF inhibitors during conception and first semester and a group that had withdrawn TNF one to 6 months before pregnancy

Unlikely: the infants were followed at least until (first) National vaccination. Mean follow up was 20 months, ranging from 3-82 months. It is unlikely follow up periods differed among groups.

Unclear: maternal and infant infections were not predefined outcomes, but specified under maternal complications and under vaccinations. This information came from a 28-item form filled in by the rheumatologist about pregnancy complications and vaccine adverse events. It is unclear if this was systematically reported.

Likely: as maternal and infant infections were not predefined outcomes, these were only described under maternal complications and vaccinations. No outcome measures and effect sizes, and adjusting for confounding was thus done.

 

 

  1. Failure to develop and apply appropriate eligibility criteria: a) case-control study: under- or over-matching in case-control studies; b) cohort study: selection of exposed and unexposed from different populations.
  2. 2 Bias is likely if:  the percentage of patients lost to follow-up is large; or differs between treatment groups; or the reasons for loss to follow-up differ between treatment groups; or length of follow-up differs between treatment groups or is too short. The risk of bias is unclear if:  the number of patients lost to follow-up; or the reasons why, are not reported.
  3. Flawed measurement, or differences in measurement of outcome in treatment and control group; bias may also result from a lack of blinding of those assessing outcomes (detection or information bias). If a study  has hard (objective) outcome measures, like death,  blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
  4. Failure to adequately measure all known prognostic factors and/or failure to adequately adjust for these factors in multivariate statistical analysis.

 

Table of excluded studies clinical question 1 (EULAR update)

Author and year

Reason for exclusion

Abheiden 2017

Voldoet niet aan PICO (verkeerde middel)

Alarfaj 2014

Voldoet niet aan PICO (blootstelling vòòr zwangerschap)

Alijotas-Reig 2019

Voldoet niet aan PICO (verkeerde middel)

Andersen 2016

Voldoet niet aan PICO (verkeerde patiëntgroep)

Bertolaccini 2016

Voldoet niet aan PICO (geen klinische studie, muismodel)

Burmester 2017

Geen originele data

De Cock 2017

Voldoet niet aan PICO (blootstelling vòòr zwangerschap)

DeGuchi 2017

Voldoet niet aan PICO (verkeerde middel)

Eudy 2018

Voldoet niet aan PICO (geen specifieke uitkomsten per geneesmiddel)

Guillotin 2018

Geen originele data

Indraratna 2018

Geen originele data

Ismail 2016

Voldoet niet aan PICO (verkeerd middel)

Kaplan 2016

Geen originele data

Kawai 2019

Voldoet niet aan PICO (geïncludeerde reumapatiënten niet apart onderzocht)

Lu 2019

Voldoet niet aan PICO (verkeerd middel)

Maesawa 2018

Voldoet niet aan PICO (verkeerde patiëntgroep)

Mayer-Pickel 2017

Voldoet niet aan PICO (verkeerde patiëntgroep)

Ozturk 2016

Voldoet niet aan PICO (verkeerde patiëntgroep)

Perez-Aytes 2017

Geen originele data

Rottenstreich 2017

Voldoet niet aan PICO (verkeerde patiëntgroep)

Ruffati 2019

Geen originele data

Van Hoorn 2016

Voldoet niet aan PICO (verkeerd middel)

Verbruggen 2015

Voldoet niet aan PICO (verkeerd middel)

Yelnik 2018

Voldoet niet aan PICO (verkeerd middel)

Zbinden 2018

Voldoet niet aan PICO (geen specifieke uitkomsten per geneesmiddel)

Weber-Schoendorver 2015

Al door de EULAR geïncludeerd (duplicate)

 



 

 

Table of excluded studies clinical question 2

Author and year

Reason for exclusion

Aberra 2006

No original data.

Berthelot 2009

The outcome infection was not studied.

Bröms 2016

The outcome infection was not studied.

Burmester 2017

The outcome infection was not studied.

Diav-Citrin 2014

The outcome infection was not studied.

Ferrante 2014

No original data.

Komaki 2017

No original data.

Nakajima 2016

The outcome infection was not studied.

Viktil 2012

The outcome infection was not studied.

Vinet 2009

No original data.

Weber-Schoendorfer 2016

The outcome infection was not studied.

 

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 27-05-2024

Laatst geautoriseerd  : 21-02-2022

Geplande herbeoordeling  :

Voor het beoordelen van de actualiteit van deze richtlijn wordt de werkgroep niet in stand gehouden. Uiterlijk in 2026 bepaalt het bestuur van de Nederlandse Vereniging voor Reumatologie of de modules van deze richtlijn nog actueel zijn. Op modulair niveau is een onderhoudsplan beschreven. Bij het opstellen van de richtlijn heeft de werkgroep per module een inschatting gemaakt over de maximale termijn waarop herbeoordeling moet plaatsvinden en eventuele aandachtspunten geformuleerd die van belang zijn bij een toekomstige herziening (update). De geldigheid van de richtlijn komt eerder te vervallen indien nieuwe ontwikkelingen aanleiding zijn tot het starten van een herzieningstraject.

 

De Nederlandse Vereniging voor Reumatologie is regiehouder van deze richtlijn en eerstverantwoordelijke op het gebied van de actualiteitsbeoordeling van de richtlijn. De andere aan deze richtlijn deelnemende wetenschappelijke verenigingen of gebruikers van de richtlijn delen de verantwoordelijkheid en informeren de regiehouder over relevante ontwikkelingen binnen hun vakgebied.

 

Module

Regie-houder(s)

Jaar van autorisatie

Eerstvolgende beoordeling actualiteit richtlijn

Frequentie van beoordeling op actualiteit

Wie houdt er toezicht op actualiteit

Relevante factoren voor wijzigingen in aanbeveling

Preconceptionele begeleiding

NVR

2021

2026

Eens in 5 jaar

NVR

Nieuwe literatuur

Anticonceptie

NVR

2021

2026

Eens in 5 jaar

NVR

Nieuwe literatuur

Medicatiegebruik bij kinderwens

NVR

2021

2024

Eens in 3 jaar

NVR

Nieuwe literatuur, beschikbaarheid nieuwe middelen

Medicatiegebruik tijdens de zwangerschap

NVR

2021

2024

Eens in 3 jaar

NVR

Nieuwe literatuur, beschikbaarheid nieuwe middelen

Medicatiegebruik tijdens borstvoeding

NVR

2021

2024

Eens in 3 jaar

NVR

Nieuwe literatuur, beschikbaar-heid nieuwe middelen

Vaccinaties bij het kind

NVR

2021

2026

Eens in 5 jaar

NVR

Nieuwe literatuur

Organisatie van zorg

NVR

2021

2026

Eens in 5 jaar

NVR

Nieuwe

 

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging voor Reumatologie
Geautoriseerd door:
  • Nederlandse Vereniging voor Kindergeneeskunde
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Radiologie
  • Verpleegkundigen en Verzorgenden Nederland
  • Nederlandse Vereniging van Ziekenhuisapothekers
  • ReumaNederland
  • Nationale Vereniging ReumaZorg Nederland

Algemene gegevens

De richtlijnontwikkeling werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten.

Doel en doelgroep

Het doel van deze richtlijn is het verkrijgen van uniform en optimaal beleid ten aanzien van de medicamenteuze behandeling van mannen en vrouwen met een inflammatoire reumatologische aandoening en een kinderwens in het traject van veilig zwanger worden tot en met de eerste periode na de bevalling.

 

Bij het ontwikkelen van de richtlijn zijn vele partijen betrokken, waaronder reumatologen (NVR), gynaecologen (NVOG), kinderartsen (NVK), vertegenwoordigers vanuit Bijwerkingencentrum Lareb, verpleegkundigen (V&VN), apothekers (NVZA). Qua patiënteninbreng is ervoor gekozen om een focusgroep discussie te houden met vrouwen met verschillende inflammatoire reumatologische aandoeningen, die recent een zwangerschap hebben doorgemaakt.

 

De ontwikkeling van deze richtlijn is ondersteund door de Nederlandse Vereniging voor Reumatologie.

 

Afbakening van de richtlijn
Deze richtlijn beschrijft de zorg voor mannen en vrouwen met een inflammatoire reumatologische aandoening en een kinderwens tijdens de verschillende stadia rondom de zwangerschap. Module 1 beschrijft aanbevelingen ten aanzien van preconceptionele begeleiding, module 2 beschrijft anticonceptie, module 3 beschrijft medicatiegebruik bij kinderwens bij zowel de vrouw als de man, module 4 beschrijft medicatiegebruik tijdens de zwangerschap, module 5 beschrijft medicatie tijdens het geven van borstvoeding, en module 6 beschrijft vaccinaties bij het kind en mogelijke na-effecten. In module 7 wordt tenslotte ingegaan op de organisatie van pre- en periconceptionele zorg.

 

De richtlijn gaat niet in op de medicamenteuze behandeling van inflammatoire reumatologische aandoeningen in het kader van effectiviteit, of adviezen die voor alle zwangerschappen gelden. Voor deze en andere onderwerpen wordt verwezen naar de vigerende richtlijnen:

  • Medicamenteuze behandeling van Reumatoïde Artritis (NVR, 2019)
  • Medicamenteuze behandeling van SLE (NVR, in ontwikkeling)
  • Diagnostiek en behandeling van reuscel arteriitis (NVR, in ontwikkeling)
  • Onverklaarde subfertiliteit (NVOG, 2020)
  • Miskraam (NVOG, 2020)
  • Antitrombotisch beleid (NIV, 2020)
  • Oriënterend fertiliteitsonderzoek (NVOG, 2015)

 

Beoogde gebruikers van de richtlijn
Deze richtlijn is geschreven voor alle leden van de beroepsgroepen die betrokken zijn bij de zorg voor patiënten met een inflammatoire reumatische aandoening en een kinderwens of zwangerschap. Dit zijn onder meer reumatologen, gynaecologen, kinderartsen, apothekers,  reumaverpleegkundigen, verpleegkundig specialisten en physician assistants.

 

In de richtlijn spreken wij over ‘reumatoloog’. Naast de reumatoloog spelen in de reumatologie verpleegkundigen in toenemende mate een rol in het zorgproces. Er is onderscheid in gespecialiseerd reumaverpleegkundigen, verpleegkundig specialisten (VS) en physician assistants (PA). De VS en PA zijn bevoegd tot het zelfstandig aangaan van een behandelrelatie en het indiceren en uitvoeren van voorbehouden handelingen. Van oudsher is de hoofdbehandelaar de reumatoloog, maar met de huidige wetgeving kan de VS of PA ook optreden als hoofdbehandelaar. Daarnaast kan de gespecialiseerd reumaverpleegkundige, onder verantwoordelijkheid van de hoofdbehandelaar, handelingen uitvoeren. Wanneer wij in deze richtlijn spreken over reumatoloog, kan dit zowel de reumatoloog, VS of PA, of gespecialiseerd reumaverpleegkundige (onder verantwoordelijkheid van de hoofdbehandelaar) zijn.

Samenstelling werkgroep

De werkgroepleden zijn door hun beroepsvereniging gemandateerd voor deelname. De werkgroep is verantwoordelijk voor de integrale tekst van deze richtlijn.

 

Werkgroep:

  • Dr. R.J.E.M. (Radboud) Dolhain, reumatoloog, Erasmus MC, NVR (voorzitter)
  • Prof. dr. B. (Bart) van den Bemt, apotheker, klinisch farmacoloog, Sint Maartenskliniek, NVZA
  • Drs. D. (Dianne) Berendsen, reumatoloog, Ziekenhuisgroep Twente, NVR
  • Dr. M.A. (Marjon) de Boer, gynaecoloog perinatoloog, Amsterdam UMC, locatie VUmc, NVOG
  • Dr. I.E.M. (Irene) Bultink, reumatoloog, Amsterdam UMC, locatie VUmc, NVR
  • Dr. N. (Noortje) van Herwaarden, reumatoloog in opleiding, klinisch farmacoloog, Radboudumc, NVR
  • Dr. M.H.A. (Marc) Jansen (vanaf april 2020), kinderarts-immunoloog/reumatoloog, Wilhelmina Kinderziekenhuis, NVK
  • Dr. S.P. (Suzanne) Linn-Rasker, reumatoloog, Meander MC, NVR
  • Dr. A.G.M.G.J. (Annemarie) Mulders, gynaecoloog perinatoloog, Erasmus MC, NVOG
  • Dr. J.F. (Joost) Swart (tot oktober 2020), kinderreumatoloog, Wilhelmina Kinderziekenhuis, NVK
  • Drs. E. (Evelien) Ton, reumatoloog, Utrecht UMC, NVR
  • Prof. dr. A.M. (Astrid) van Tubergen, reumatoloog, Maastricht UMC, NVR
  • Drs. A.G.W. (Bernke) te Winkel, Wetenschappelijk medewerker, Teratologie Informatie Service, Lareb
  • H.M. (Hetty) Wintjes, verpleegkundig reumaconsulent, Erasmus MC, V&VN

 

Klankbordgroep:

  • Prof. dr. M.M. (Mirjam) van Weissenbruch, kinderarts-neonatoloog, Amsterdam UMC, locatie VUmc, NVK

 

Met ondersteuning van:

  • Dr. M. (Myrthe) van Vilsteren, senior beleidsmedewerker, NVR
  • Dr. A.A.O.M. (Aniek) Claassen, senior beleidsmedewerker, NVR

 

Met dank aan:

  • Drs. E.P. (Ilse) Jansma, literatuurspecialist
  • I. (Ingeborg) van Dusseldorp, literatuurspecialist

 

Belangenverklaringen

De KNMG-code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement, kennisvalorisatie) hebben gehad. Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van de NVR.

 

Werkgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

R. Dolhain

Reumatoloog

Geen

Speaking fees: Novartis, UCB Biopharma

Adviesraad: Galapagos

Unrestricted research grants: UCB Biopharma, Galapagos, ReumaNederland

Geen actie

B. van den Bemt

Medisch manager afdeling Farmacie, Sint Maartenskliniek Nijmegen

Senior onderzoeker, apotheek, Radboud University Medical Center Nijmegen

President European Society Clinical Pharmacy

Geen

Geen actie

D. Berendsen

Reumatoloog

Geen

Geen

Geen actie

M. de Boer

Gynaecoloog-perinatoloog in Amsterdam UMC

Geen

Geen

Geen actie

I. Bultink

Reumatoloog

Lid medisch actienetwerk Amnesty International, onbetaald vrijwilligerswerk

2017-2018: Lid adviesraad Genzyme Europe BV m.b.t. plaatsbepaling van de behandeling van patiënten met RA met sarilumab

Lid medische adviesraad van de Nationale Vereniging LE patiënten (NVLE)

Medisch adviseur Reumapatiëntenvereniging Amstelland en omstreken

Sprekersvergoedingen ontvangen van: Eli Lilly & Company Netherlands, MSD Corp., Amgen BV, UCB Biopharma, Roche Netherlands BV, Sanofi Genzyme, GSK

Geen actie

N. van Herwaarden

Reumatoloog in opleiding, Klinisch-farmacoloog in opleiding, Radboudumc/ Sint Maartenskliniek Nijmegen

Per 1-1-2021: commissielid; arts CMO Arnhem-Nijmegen (betaald)

Geen

Geen actie

M. Jansen

Kinderarts-fellow kinderimmunologie-reumatologie UMC Utrecht

Okt 2020-april 2021: Kinderarts Fundashon Mariadal Bonaire

Myositis werkgroep Nederland

Vaccinatiecommissie PRES

Docent bij Mijs-instituut (betaald)

Geen

Geen actie

S. Linn-Rasker

Reumatoloog, Meander MC Amersfoort

Secretaris Concilium NVR

Lid RGS

Docent Antonius Academie 1x per jaar

TOPIRA – studie, UMCU geïnitieerde studie, lokale hoofdonderzoeker Meander MC, sponsor Roche

Geen actie

A. Mulders

Gynaecoloog-perinatoloog Erasmus MC

Geen

Geen

Geen actie

J. Swart

Kinderreumatoloog

Geen

Sponsoring van JIA symposium in 2018 door

Geen actie

E. Ton

Reumatoloog

Geen

Geen

Geen actie

A. van Tubergen

Reumatoloog

Per 1 april 2020 bestuurslid NVR

Unrestricted research grant voor SpA-Net van Pfizer; AbbVie; UCB Biopharma; Novartis

Consultancy fee: Novartis

Geen actie

A. te Winkel

Wetenschappelijk medewerker Teratologie Informatie Service Lareb

Penningmeester bij stichting ENTIS (European Network Teratology Information Services), onbetaald

Bestuurslid LKPZ (Landelijk Kenniscentrum Psychiatrie en Zwangerschap), onbetaald

Projectleider bij ZonMw project: Exposure to immunosuppressive drugs in men wishing to conceive: The possible influence of paternal drug exposure of immunosuppressive drugs on fertility, pregnancy outcomes and infant’s health

Geen actie

M. van Weissenbruch

Kinderarts-neonatoloog

Geen

Geen

Geen actie

H. Wintjes

Verpleegkundig reumaconsulent

Geen

Sprekersvergoedingen ontvangen van Novartis, UCB Biopharma. Webinar Reumazorg Zuidwest Nederland.

Adviesraad UCB.

Scholing voor opleiding reumaconsulenten vanuit V&VN.

Geen actie

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door een focus groep discussie te organiseren met vrouwen met verschillende inflammatoire reumatische aandoeningen die recent één of meerdere zwangerschappen hebben doorgemaakt (zie ook bijlage 4: verslag focus groep discussie). De conceptrichtlijn is tevens voor commentaar voorgelegd aan ReumaNederland, Nationale Vereniging ReumaZorg Nederland en de NVLE.

Methode ontwikkeling

Evidence based

Implementatie

In de verschillende fasen van de richtlijnontwikkeling is rekening gehouden met de implementatie van de richtlijn (module) en de praktische uitvoerbaarheid van de aanbevelingen. Daarbij is uitdrukkelijk gelet op factoren die de invoering van de richtlijn in de praktijk kunnen bevorderen of belemmeren. Het implementatieplan is te vinden bij de aanverwante producten. De werkgroep heeft besloten geen indicatoren te ontwikkelen bij de huidige richtlijn, om de registratielast niet toe te laten nemen.

Werkwijze

AGREE
Deze richtlijn is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010), dat een internationaal breed geaccepteerd instrument is. Voor een stap-voor-stap beschrijving hoe een evidence-based richtlijn tot stand komt wordt verwezen naar het stappenplan Ontwikkeling van Medisch Specialistische Richtlijnen van het Kennisinstituut van de Federatie Medisch Specialisten.

 

Knelpuntenanalyse
Tijdens de voorbereidende fase inventariseerden de voorzitter van de werkgroep en de adviseur de knelpunten. Tevens zijn er knelpunten aangedragen door de V&VN, VIG, STZ, Bijwerkingencemtrum Lareb, NVMM, IGJ, KNOV, NHG, NIV, NVLE, NVK, ZINL, NVOG, NVR, ReumaNederland, ReumaZorg Nederland en NVLE via de invitational conference. Een verslag hiervan is opgenomen onder aanverwante producten.

 

Uitgangsvragen en uitkomstmaten
Op basis van de uitkomsten van de knelpuntenanalyse zijn door de voorzitter en de adviseur concept-uitgangsvragen opgesteld. Deze zijn met de werkgroep besproken waarna de werkgroep de definitieve uitgangsvragen heeft vastgesteld. Vervolgens inventariseerde de werkgroep per uitgangsvraag welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken.

 

Strategie voor zoeken en selecteren van literatuur
Voor de afzonderlijke uitgangsvragen werd aan de hand van specifieke zoektermen gezocht naar gepubliceerde wetenschappelijke studies in (verschillende) elektronische databases. Voor een aantal uitgangsvragen betekent dit dat de zoekstrategie van de ‘EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation’ werd geactualiseerd vanaf april 2015 (Gotestam Skorpen et al., 2016).

 

Wetenschappelijk onderzoek naar de veiligheid van medicijnen tijdens de zwangerschap kan niet worden uitgevoerd in een experimenteel onderzoeksdesign, vanwege ethische en veiligheidsbezwaren. De werkgroep heeft daarom besloten om geen studies te excluderen op basis van onderzoeksdesign, er zijn dus ook niet-vergelijkende studies meegenomen. De werkgroepleden selecteerden de via de zoekactie gevonden artikelen op basis van vooraf opgestelde criteria. De geselecteerde artikelen werden gebruikt om de uitgangsvraag te beantwoorden. De databases waarin is gezocht, de zoekstrategie en de gehanteerde selectiecriteria zijn te vinden in de module met desbetreffende uitgangsvraag.

 

Kwaliteitsbeoordeling individuele studies
Individuele vergelijkende studies werden systematisch beoordeeld, op basis van op voorhand opgestelde methodologische kwaliteitscriteria, om zo het risico op vertekende studieresultaten (risk of bias) te kunnen inschatten. Deze beoordelingen kunt u vinden in de Risk of Bias (RoB) tabellen. De gebruikte RoB instrumenten zijn gevalideerde instrumenten die worden aanbevolen door de Cochrane Collaboration: Cochrane – voor gerandomiseerd gecontroleerd onderzoek; ACROBAT-NRS – voor observationeel onderzoek.

 

Samenvatten van de literatuur
De relevante onderzoeksgegevens van alle geselecteerde artikelen werden overzichtelijk weergegeven in evidencetabellen. De belangrijkste bevindingen uit de literatuur werden beschreven in de samenvatting van de literatuur.

 

Beoordelen van de kracht van het wetenschappelijke bewijs
De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie (Schünemann, 2013). 

Het onderwerp van deze richtlijn maakt dat er vrijwel altijd bewijs van (zeer) lage kwaliteit is. Om o.a. ethische redenen kan er geen gerandomiseerd gecontroleerd onderzoek gedaan worden naar de veiligheid van geneesmiddelen tijdens bijvoorbeeld de zwangerschap, en zodoende is het wetenschappelijk bewijs van lage kwaliteit. In deze richtlijn is ervoor gekozen om ook studiedesigns te includeren welke volgens de GRADE-methode geen bewijskracht hebben (bijvoorbeeld case series). De werkgroep is van mening dat deze studies ook waardevolle informatie bevatten voor de desbetreffende uitgangsvragen.

 

GRADE

Definitie

Hoog
  • er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt zoals vermeld in de literatuurconclusie;
  • het is zeer onwaarschijnlijk dat de literatuurconclusie verandert wanneer er  resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Redelijk*
  • er is matige zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt zoals vermeld in de literatuurconclusie;
  • het is mogelijk dat de conclusie verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Laag
  • er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt zoals vermeld in de literatuurconclusie;
  • er is een reële kans dat de conclusie verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Zeer laag
  • er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt zoals vermeld in de literatuurconclusie;
  • de literatuurconclusie is zeer onzeker.

*in 2017 heeft het Dutch GRADE Network bepaald dat de voorkeursformulering voor de op een na hoogste gradering ‘redelijk’ is in plaats van ‘matig’

 

Formuleren van de conclusies
Gezien het wetenschappelijk bewijs van alle studie designs is meegenomen, en alle door de studies gedefinieerde uitkomstmaten, is het niet wenselijk om voor elke relevante uitkomstmaat, voor elk medicijn, een literatuurconclusie op te stellen. Er is besloten om per medicijn een overkoepelende conclusie te trekken, in plaats van per uitkomstmaat.

 

Overwegingen (van bewijs naar aanbeveling)
Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals de expertise van de werkgroepleden, de waarden en voorkeuren van de patiënt (patient values and preferences), kosten, beschikbaarheid van voorzieningen en organisatorische zaken. Deze aspecten worden, voor zover geen onderdeel van de literatuursamenvatting, vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’.

 

Formuleren van aanbevelingen
De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk. De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen.

Randvoorwaarden (Organisatie van zorg)
In de knelpuntenanalyse en bij de ontwikkeling van de richtlijn is expliciet rekening gehouden met de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, menskracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van een specifieke uitgangsvraag maken onderdeel uit van de overwegingen bij de bewuste uitgangsvraag. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van Zorg.

 

Indicatorontwikkeling
Gelijktijdig met het ontwikkelen van de conceptrichtlijn heeft de werkgroep overwogen om interne kwaliteitsindicatoren te ontwikkelen om het toepassen van de richtlijn in de praktijk te volgen en te versterken. De werkgroep heeft besloten geen indicatoren te ontwikkelen bij de huidige richtlijn, omdat de meeste aanbevelingen niet hard genoeg waren en er geen substantiële barrières zijn geïdentificeerd die implementatie van de aanbeveling zouden kunnen bemoeilijken.

 

Kennislacunes
Tijdens de ontwikkeling van deze richtlijn is systematisch gezocht naar onderzoek waarvan de resultaten bijdragen aan een antwoord op de uitgangsvragen. Bij elke uitgangsvraag is door de werkgroep nagegaan of er (aanvullend) wetenschappelijk onderzoek gewenst is om de uitgangsvraag te kunnen beantwoorden. Een overzicht van de onderwerpen waarvoor (aanvullend) wetenschappelijk onderzoek van belang wordt geacht, is als aanbeveling in de bijlage Kennislacunes beschreven (onder aanverwante producten).

 

Commentaar- en autorisatiefase
De conceptrichtlijn werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijn aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijn werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

 

Literatuur
Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348.

Gotestam Skorpen, C., Hoeltzenbein, M., Tincani, A., Fischer-Betz, R., Elefant, E., Chambers, C., . . . Ostensen, M. (2016). The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis, 75(5), 795-810. doi:10.1136/annrheumdis-2015-208840

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. doi: 10.1136/bmj.39500.677199.AE. Erratum in: BMJ. 2008;336(7654). doi: 10.1136/bmj.a139. PubMed PMID: 18483053.

Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten.

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