Pregnancy and Rheumatic Disease 4/5 (4)

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Image reference: File photo, Canwest News Service [Public domain], via Wikimedia Commons

Rheumatic diseases and pregnancy

  • The information below is general and intended to supplement the individual advice that the doctor can provide

Young women with inflammatory rheumatic diseases such as Rheumatoid arthritis (arthritis), Systemic lupus (SLE) and other Systemic connective tissue diseases: og vasculitides that Takayasu arteritis og Behcet's disease often want pregnancy.

  • Diseases and / or drug treatment may involve risk to the pregnant woman or to the unborn child / fetus
  • In good time before pregnancy, patients should discuss their drug use with the attending physician and / or rheumatologist
  • For some of the systemic connective tissue diseases (see below), it is recommended that pregnancies be followed at hospitals with access to rheumatologists (for assessment of disease activity, disease complications and medications), gynecologist / maternity department (follow-up pregnancy and fetal condition) and advanced newborn ward (In case of early birth or severe illness in newborn / infant)
  • Not all drugs against rheumatic diseases can be used during pregnancy since some medications may harm the fetus (see below)
  • In case of doubt if a pregnancy is present beta-hCG can be measured in blood (More accurate than urine test). Measurement in blood can show pregnancy already from nine days after conception, but varies widely from woman to woman and from pregnancy to pregnancy
    • Beta-hCG <5mlU / ml: not pregnant
    • Beta-hCG 5-25mlU / ml: unsure result: repeat the sample after a few days
    • Beta-hCG over 25mlU / ml: pregnancy is present
  • If a pregnancy should end in spontaneous abortion, the vascular need not be the rheumatic disease or the drugs
    • A study from the Norwegian Medical Birth Register based on over 400.000 pregnancies between 2009 and 2013 showed that 12,8% change in spontaneous abortion. Among women aged 25-29 years, the incidence was 10% and then increased with age (reference: Magnus MC, 2019)
  • Infertility or reduced fertility can occur in rheumatic disease and will be described in more detail here
  • General advice when planning pregnancy can be found here (The Norwegian Directorate of Health)

Prior to pregnancy, other risk factors should be limited as far as possible (Tanvig M, 2014)

  • Stop smoking
  • Stop sniffing (references: Public Health; Kreyberg I, 2019)
    • Snuff increases the risk of stillbirth, premature birth, lower birth weight and lip-palate
  • Avoid alcohol
  • Reduce significant overweight
  • Diseases such as Diabetes, Metabolism and high blood pressure are best treated
  • vitamins
    • Use Folic Acid Supplements (at least 0,4mg daily)
    • If vitamin B12 deficiency needs to be treated
    • Supplements of folic acid and proper vitamin B12 levels reduce the risk of neural tube defect in the fetus / newborn (reference: Public Health)
    • Any lack of vitamin D is avoided

Medical checks

  • Common pregnancy monitoring in the GP, or even in the midwife, is recommended
  • Routine ultrasound examination during pregnancy week 18 and week 32 (with growth control week 32)
  • After individual evaluation, ultrasound examination is also carried out in week 12 and week 24 in some cases (witch check in week 24)
    • Additional controls are relevant for high rheumatic disease activity or detected antifosfolipid antibody (cardiolipin, beta-2 glycoprotein antibody, lupus anticoagulant)
    • When using TNF inhibitors during pregnancy, one should consider measuring serum concentrations in the pregnant and second trimester. The values ​​should not exceed the reference ranges
  • When using Prednisolone or similar cortisone tablets, glucose loading tests at gestational age 28 are recommended to exclude the onset of pregnancy-related diabetes (diabetes)
  • How frequent rheumatological checks and follow-up at maternity ward should be performed depends on the rheumatological diagnosis and the individual course of illness

“Forbidden” medications during pregnancy

Disease Modifying Drugs (DMARDs)

  • Methotrexate (Ebetrex, Metex, Methotrexate) must be stopped at least 1-XNUM months before pregnancy, since the drug may harm the fetus (malformations of about 3%) and cause miscarriage / death (in about 10%). Folic acid supplements (often co-administered with Metotrexate treatment) should continue throughout pregnancy even if Metotrexate is stopped. This is because methotrexate can cause folic acid deficiency associated with risk Spina Bifida in the unborn
    • Breastfeeding should generally be avoided because methotrexate is found in breast milk
    • Methotrexate does not affect fertility, neither in women nor men
  • Leflunomide (Arava) should not be used the last two years before pregnancy, since birth defects and spontaneous abortions / deaths have been observed. The drug stays long in the body. If pregnancy is planned or unexpectedly occurring, "wash out" of the drug from the body will be important. This is done following a special procedure with cholestyramine. In practice, leflunomide is not recommended for women who expect to become pregnant in the long term.
    • However, a study among 51 pregnancies that had been exposed to leflunomide showed no malformations, miscarriages, premature births or infants. However, the study concludes that the figures are too small to exclude adverse effects (reference: Berard A, 2018)
    • Avoid breastfeeding
  • Mycophenolate (CellCept, Myfortic) can cause damage to the fetus (in about 25%) and lead to miscarriage / stillbirth (about 35%). Treatment should be stopped at least 6 weeks prior to pregnancy.
      • Breastfeeding is not recommended (we have yet to have enough data on safety)
  • Sendoxan (cyclophosphamide) should be stopped at least 3 months prior to pregnancy. Fetal malformations (at 25%) are seen. If the drug is vital, special indication must be assessed individually (less risk of fetal harm in 2. and 3 trimester).
    • Freezing of ovarian tissue may be relevant before Sendoxan treatment if later pregnancy is desired
    • Do not use during breastfeeding

Blood Pressure Medications (antihypertensive drugs)

  • Blood pressure medications like ACE inhibitors (Enalapril, Renitec, Zestoretic, Zanipress, etc.) AT-II receptor antagonists and others usually need to be replaced with other types of antihypertensive drugs suitable for pregnancy (such as Trandate)

"Blood thinning" drugs (anticoagulation)

  • Warfarin can harm the fetus and should be replaced before pregnancy or at the latest within the first 6 weeks of pregnancy. Fragmin (in the corresponding treatment dose) can be used in place of warfarin. In some cases, Fragmin and Albyl-E are combined
  • Persantin, Plavix, Brilique, Pradaxa, Eliquis are not recommended during pregnancy or lactation

Drugs that can be used in parts of the pregnancy

The "Felleskatalogen" is a Norwegian list of information about medicines. It is used by doctors, other healthcare professionals and patients (patient edition). One must, however, be aware of the following:

NSAIDs (Non-steroidal anti-inflammatory drugs)

Do not use in the last third (last trimester) of pregnancy. Finish the treatment at the latest in pregnancy week 28-30

  • Use the types that go fastest out of the body (short half-life), such as Ibuprofen (Ibux) or naproxen
  • Cox-2 inhibitors (Arcoxia, Celebra) should not be used in pregnancy due to lack of documentation (increased risk of miscarriage / fetal death is possible)
    • Few general data on breastfeeding safety, but celekoxib (Celebra) may probably by used during breastfeeding
  • NSAIDs can be used during breastfeeding. Ibuprofen is preferred because of short half-life (rapid excretion from the body) and one has long experience with the drug
  • Keep in mind that NSAIDs and Cox-2 inhibitors may inhibit ovulation and, consequently, cause transient impairment of pregnancy. Ovulation is inhibited after 10 days of use of diclofenac (Voltaren) (75%), naproxen (Naproxen-E) (25%) and etoricoxib (Arcoxia) (33%) (Reference: S Salman, EULAR 2015)

Cortisone

Prednisone (Over time, the dose should be low throughout the pregnancy, preferably below 10-15 mg / day)

  • Low doses do not increase the risk of malformations in the fetus
  • The lowest possible dose is important in order not to affect the growth of the fetus and to reduce the risk osteoporosis, diabetes and other possible cortisone side effects in pregnant women. Supplements with calcium and vitamin D (for example Calcigran Forte) is relevant
  • Breastfeeding is uncomplicated if the Prednisolone dose is not above 50 mg / day (in that case breastfeeding should be delayed at least 4 hours after drug intake

Cortisone can be injected into inflamed joints also to pregnant women

Acetylsalicylic Acid (ASA)

  • Acetylsalicylic acid (Albyl-E)
    • Often, treatment is discontinued 3 weeks before expected birth control, but treatment may continue throughout pregnancy and breastfeeding if necessary
    • If the indication is prevention of preeclampsia (pregnancy poisoning), treatment is often started from week of pregnancy 12 (reference: Rolnik DL, 2017)

Some Disease Modyfying Drugs (DMARDs)

  • Plaquenil (hydroxychlorokine)
    • No increased incidence of malformations in fetuses or spontaneous abortions / deaths
    • Can be used during breastfeeding
  • Imurel (azathioprine)
    • At usual doses (up to 2mg / kg body weight / day), there is no increased incidence of malformations in fetuses or spontaneous abortions / fetal deaths
    • Can be used during breastfeeding, but it is recommended that the dose is not over 100mg / day and one should not breastfeed the nearest 5 hours after the tablet intake. If higher doses are required, the child should be followed up with blood tests
  • Sandimune (Ciclosporin A)
    • At common doses, there is no increased incidence of malformations in the unborn child or spontaneous abortions / fetal deaths. The treatment can continue throughout pregnancy where necessary
    • Can be used during breastfeeding (at usual doses)
  • Salazopyrin can be used during pregnancy if the dose is below 2 grams / day, but it is recommended to stop treatment two weeks before expected birth. There is otherwise an increased risk of jaundice (hyper-bilirubinemia) in the newborn.
    • Folic acid supplements recommended
    • Sperm can be affected by salazopyrin, so that men who use Salazopyrin may have reduced fertilization as long as treatment is ongoing
    • Stopping treatment for 3 months normalizes the semen
  • Immunoglobulins (Ivig, Octagam, Immunoglobulin Infusions or Injections)
    • No increased incidence of malformations or spontaneous abortions / deaths
    • Can be used during breastfeeding
  • Tacrolimus (Prograf, Advagraf)
    • No increased incidence of malformations in fetus or spontaneous abortions / fetal deaths in humans (as opposed to animal testing). Can be used (at the lowest required dose) during pregnancy
    • Goes into breast milk, but no damage is seen. Can be used during breastfeeding
  • Colchicine
    • The incidence of spontaneous abortions / fetal deaths or malformations is not increased in fetuses if the total daily drug dose is 1mg or less. Avoid simultaneous antibiotic treatment with macrolides (interaksjoner.no)

“Blood Thinning (Anticoagulation)”. Calcium, vitamin D and folic acid

Biological treatment

TNF inhibitors

No increased incidence of malformations or spontaneous abortions / stillbirths has been shown with TNF inhibitors. These drugs do not pass (via the placenta) to the fetus in the first trimester (first 1/3 of pregnancy). Later in pregnancy, the dose of the fetus increases (with the exception of certolizumab / Cimzia), depending on which medication may be used. This increases the risk of infection in the newborn. The children should therefore not receive live vaccines (MMR, Rotavirus vaccine) for the next 6 months of life. TNF inhibitors can be used during breastfeeding. The sperm are not affected, so treatment can be used among men who will become fathers (reference: SLV, 2019).

  • Generally, it is recommended to discontinue treatment in case of proven pregnancy, but exceptions may be made
  • All TNF inhibitors reduce the immune system to the pregnant, so that increased attention to infections is important. Males who use biological treatment do not need to stop treatment before or after fertilization.
  • If you have to use TNF inhibitors in pregnancy, it is generally recommended to stop treatment at the latest by week 20 (within 3 months before expected birth), except after careful consideration of need and risk. Transition to certulizumab (Cimzia) may be an alternative (Please see below)
  • If treatment is to be continued, one should assess the serum concentration of the pregnant in 2. and in 3. trimester. The values ​​should not exceed the reference ranges
  • If, nevertheless, the implant is used during the last part of the pregnancy, the child should not get alive vaccines first six months after birth (applicable to Rota virus vaccine and BCG for vulnerable persons). By doubt, can Public Health provide supplementary information
    • Drug change to Certulizumab (Cimzia) which almost does not go to the fetus should be considered as an alternative
    • The medications (TNF inhibitors) can be used during breastfeeding
  • Remicade, Inflectra, Remsima (infliximab) and Humira (adalimumab) are transported actively across the placenta and to the fetus during the last 3 months of pregnancy. This results in higher drug doses in the blood to the fetus and in the newborn (160% of maternal dose in umbilical cord blood).
  • Enbrel (etanercept) goes slightly from the placenta to the fetus / child. The drug dose in umbilical cord blood at Enbrel is 7-30% of maternal blood level (reference: Mahadevan U, 2012), but it is generally recommended to stop etanercept in pregnancy week 30-32. In special cases, Enbrel may be used throughout the pregnancy.
    • Drug change to certolizumab (Cimzia) which passes even less to the fetus can be considered as an alternative
    • Breastfeeding is allowed
  • Benepali (etanercept) is very similar to Enbrel, but experience with use in pregnancy is limited
  • Humira (adalimumab) Goes to the fetus about as if you were infected (please see above) and is not recommended during the last three months of pregnancy. In umbilical cord blood in the newborn, the dose may be 179% of maternal level at birth (reference: Mahadevan U, 2012)
  • Simponi (golimumab)
    • Breastfeeding is allowed
  • Cimzia (Certolizumab)
    • No evidence of increased risk of birth defects or spontaneous abortions / fetal deaths
    • The dose found in umbilical cord blood is 2-8% of the level of the mother (reference: Mahadevan U, 2012)
    • May be used throughout the pregnancy if necessary
    • Can be used during breastfeeding

Other biological drugs

  • MabThera (ritual simab). Direct fetal harm is not shown, but the immunosuppressive effect persists for many months and can lead to infections and lack of vaccine effects in fetuses and newborns in the first year
    • One recommends that MabThera be changed to another treatment before pregnancy. Someone (reference: Flint J, 2016) recommend to discontinue MabThera at least 6 months prior to pregnancy
    • Use during pregnancy is only applicable if other medications can not be used and the treatment requirement is high. One must then assume that the number of B cells (a type of white blood cells) is low and the infection risk increased in the newborn
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • RoActemra (tocilizumab). Studies have not shown an increased number of birth defects (reference: Hoeltzenbein M, 2016). Due to lack of documentation and uncertainty, it is recommended to replace RoActemra with another drug 3 months before pregnancy (reference: Flint J, 2016)
    • Use during pregnancy is only applicable if other medications can not be used and the treatment requirement is high
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • Stelara (Ustekinumab) Recommended stoped before pregnancy. One lacks documentation for use during pregnancy, and there is therefore uncertainty about the safety of the drug in pregnancy.
    • Use during pregnancy is only applicable if other medications can not be used and the treatment requirement is high
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • Cosentyx (sekukinumab). Experience with treatment during pregnancy and lactation is lacking. It is recommended to use safe contraception 20 weeks after discontinuation of treatment, ie, at least 5 months before pregnancy.
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • Benlysta (belimumab) it is recommended to stop before pregnancy. One is missing documentation for use during pregnancy. There is therefore uncertainty about the safety of the drug in pregnancy.
    • Use during pregnancy is only applicable if other medications can not be used and the treatment requirement is high
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • Kineret (anakinra) Recommended stop before pregnancy. There is insufficient data to assess the safety of the drug during pregnancy
    • Use during pregnancy is still applicable if other medications can not be used and the treatment requirement is high. This may apply for Stills disease.
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding
  • Orencia (abatacept) goes from mother to fetus (active transport) in pregnancy. It is recommended to stop treatment 3 months before pregnancy.
    • Can be used by men who want to become fathers
    • There is insufficient data to recommend use during breastfeeding

Men who plan to become fathers and use DMDs (DMARDs)

It is not necessary to stop the treatment before fertilization for most drugs (note possible exceptions: see Salazopyrin above). For men who have to take Sendoxan treatment can Freezing of sperm Before starting treatment be relevant to ensure the possibility of having children later

Literature

Vaccines

Rheumatic Diagnosis & Captivity

Antiphospholipid Antibodies (APL), Antifosfolipid Syndrome (ApLs) & Pregnancy

Behcet's disease & pregnancy

Rheumatoid arthritis (arthritis) og Juvenile arthritis

Osteoporosis in pregnancy

Systemic sclerosis & Pregnancy

Systemic lupus (SLE) and pregnancy

Takayasu arteritis & Pregnancy

Anti-SSA (Ro52) antibody and pregnancy

Atrioventricular heart block (Av block) describes a rare condition in which the electrical connection between the anterior chamber and the main chamber of the heart is blocked. In a fetal heart, it causes a slow heart rate, which can lead to fetal death in 10-30% of cases or the need for pacemaker treatment in newborns or toddlers (third-degree AV block). AV block is divided into the first degree, second degree and third degree block, of which grade one and two can be reversed spontaneously or with drugs. It is uncertain whether third-degree heart block is also possible to influence with drugs.

AV block of a fetus or newborn occurs almost only in pregnancies where mother has The antibody SSA (Ro antsitoff), especially in the form of Ro52 (p200 epitope). Except for SSA antibodies, the AV block in the fetus is seen at low metabolism in the pregnant, but there are few reported cases. The SSA antibody often occurs when the connective tissue diseases SLE or Sjögren's syndrome is present, but in most cases (75%) there is no such rheumatic disease. Fortunately, AV block occurs in the fetus only for approx. 1-2% of pregnancies where anti-SSA is present and very low levels of anti-SSA are unlikely to be significant. For women who have previously had fetus with AV-book, there is a risk that it will happen again 18-20% in new pregnancies.

  • AV block occurs in pregnancy week 16-26 and is detected by ultrasound examination of the fetus
  • Pregnants with anti-SSA antibody may be recommended for ultrasound examination before week 16. The gynecologist / obstetrician assesses how frequent controls are needed for each patient. Some check every one or every two weeks between the week of pregnancy 2 and 16
  • If previously detected AV block (previous pregnancy), check frequently
  • Treatment of AV block can be done with some types of cortisone (dexamethasone, betamethasone), but the effect is uncertain. AV block grade one and grade two can go back spontaneously. AV block grade three is hardly affected by cortisone treatment. The newborn will then get inserted pacemaker
  • It is discussed if too low levels of Vitamin D can increase the risk of AV block. Vitamin D measurement before pregnancy is recommended

Freezing of eggs (cryopreservation) before scheduled chemotherapy (Sendoxan) treatment in rheumatic disease

It is known that larger doses Sendoxan (cyclophosphamide) reduces the ability to become pregnant later. Therefore, in some cases, freezing of egg cells is offered prior to treatment. Part of one ovary is operated out. The ovary (with associated eggs) is frozen down (preserved) in a special freezer. If pregnancy is desired, eggs are returned later.

The method of putting eggs back is unfortunately not yet optimal. It is (per 2014) just described 99 cases where eggs are inserted and only 20 of these resulted in successful pregnancies and births (about 20%). However, the method is under development and better results are expected in the future. (Current literature: Donnez et al., 2013 and Dittrich R et al Hum Reprod (Fertil Protect) 2014)

Literature

More information

Always consult your doctor


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