Pregnancy in rheumatic disease 3.4/5 (5)

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Definition

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 desire pregnancy. Pregnancy with rheumatic disease is usually possible, but the diseases and treatment can cause problems during pregnancy, so information and possible measures are important. Follow-up is often done in collaboration between the pregnant woman, GP, midwife, rheumatologist and gynaecologist/maternity clinic.

Pregnant_woman2

Planning

Before pregnancy with rheumatic disease, all risk factors should be limited as far as possible (Tanvig M, 2014). Moreover, the disease should have been in a calm, well-controlled phase for at least 6 months.

  • Stop smoking
  • Stop sniffing (references: Public Health; Kreyberg I, 2019)
    • Snus increases the risk of stillbirths, premature births, lower birth weight and cleft lip and palate.
  • Avoid alcohol.
  • Reduce significant excess weight.
  • Diseases such as diabetes, metabolic diseases and high blood pressure are treated as best as possible.
  • vitamins
    • Use folic acid supplements (at least 0,4mg daily). Supplementation of folic acid and the correct level of vitamin B12 reduces the risk of neural tube defect in the fetus / newborn (reference: Public Health).
    • If there is a vitamin B12 deficiency, this must be treated.
    • Any lack of vitamin D is avoided.

Infertility

Definition Infertility is involuntary childlessness and is present if one attempts, but does not become pregnant within a year or when miscarriages or stillbirths prevent from becom children. (World Health Organization, WHO). Rheumatic disease or associated drugs may be important. In general, it is recommended that the rheumatic disease has been peaceful, well controlled and stable for at least 6 months before any fertility attempt (reference: Vanni VS, 2019).

When should one be investigated for childlessness? It is generally recommended to seek advice from a doctor, usually a GP, if you have been trying to have a child for 12 months without success. Especially women who are 35 years of age or older or have rheumatic or other chronic diseases should not wait long. The doctor can refer you to one of the public clinics in Oslo, Bergen, Porsgrunn, Tromsø or Trondheim, depending on where you live in the country. You can also contact a gynecologist yourself, either a private practitioner or contact directly one of the private clinics that deal with assisted fertilization. There are private clinics in Oslo, Trondheim, Bergen and Haugesund.

Reasonr to infertility: The reason for infertility is found about as often in the woman as in the man.

Possible causes in the woman: Ovulation problem. May also be due to hormonal problems, PCO (polycystic ovaries), several immature egg sacs with few or no ovulations, damage to the fallopian tubes (the connection between the ovaries and the uterus), can occur after infections such as chlamydia or after operations in the abdomen, for example with appendicitis Problems with the uterus (uterus). It may exist myomas, septum in the uterine cavity or adhesions inside the uterine cavity. Endometriosis: Benign growth outside the uterus (such as ovaries and fallopian tubes) of tissue that is normally located inside the uterus. Treatment that damages the egg cells, such as certain types of chemotherapy. Especially high doses apply to rheumatic diseases Cyclophosphamide (Sendoxan)Methotrexate does not affect fertility. Reduced fertility due to age: Fertile age for women is often defined as 15-49 years) (Ref. WHO). Early Menopause. May be hereditary. Early menopause in one's own mother can be important. Unexplained infertility.

Possible causes of the man: Decreased or no sperm production. Can be caused by genetic conditions or infection of the testicles and epididymis. Hormonal causes. Drainage obstruction in the vas deferens. Can occur after surgery or infection. Impaired ability to have an erection or ejaculation. Drugs and anabolic steroids. Reduced sperm production when using: Sulfazalazine (Salazopyrin), Cortisone (Prednisolone) in high doses (rare cause), Methotrexate (rare cause), Azathioprine (Imurel) (rare cause), Cyclophosphamide (Sendoxan) may cause permanently reduced fertility; Freezing of sperm before treatment may be relevant. Testicular cancer. Unexplained infertility.

Other things that can affect fertility: Smoking, alcohol, being overweight. Some medicines that reduce fertility as long as they are used (inhibit ovulation in women) are NSAIDs (dikofenac, naproxen, ibumetin and more).

When must pregnancy with rheumatic disease be avoided? (Contraindications)

One advises against pregnancy in rheumatic disease in women with heart/lung disease Pulmonary hypertension, severe renal failure with GFR <30 ml/min or significantly reduced lung function. High disease activity should come under stable control a few months before conception. Please also see under comorbidity/complications below. Some medicines must also be stopped before pregnancy, while it may be important to continue with others (please read more below).

Medical checks

Not all antirheumatic drugs can be used in pregnancy with rheumatic disease, since some drugs can harm the fetus (see below). On the other hand, recurrence or worsening of the disease is unfavorable, especially when one is pregnant. In good time before planned pregnancy you should therefore discuss your medication use with your treating doctor and/or rheumatologist. General advice when planning a pregnancy can be found here (Norwegian Directorate of Health).

Detection of pregnancy. Urine test (pregnancy test) can detect pregnancy a few days after a missed period. If you are still in doubt as to whether you are pregnant, you can beta-hCG can be measured in blood (more accurate than in urine test). The blood test can detect pregnancy as early as nine days after fertilization, but the results vary widely from woman to woman and from pregnancy to pregnancy. Beta-hCG<5mlU/ml: not pregnant, beta-hCG 5-25mlU/ml: uncertain result: repeat the test after a couple of days, beta-hCG above 25mlU/ml: pregnancy is present.

The date of birth can after Naegel's rule is calculated by adding seven days to the date of the first bleeding day of the last period and counting nine months ahead. It is more accurate to calculate the due date from an ultrasound examination at week 18 of pregnancy. One then measures the diameter of the foetus's head as a sign of age based on growth.

In pregnancy with rheumatic disease. Normal pregnancy follow-up is most often with a GP, possibly also with a midwife. Specialist checks may be added.

  • A routine ultrasound examination is done in pregnancy week 18 and week 32 (with growth control week 32).
  • Additional checks are relevant in case of high rheumatic disease activity or proven antiphospholipid antibody (cardiolipin, beta-2-glycoprotein antibody, lupus anticoagulant). After individual assessment, an ultrasound examination can also be carried out in week 12 and week 24 in some cases (growth control in week 24).
  • When treated with TNF inhibitor in pregnancy, you can consider measuring the serum concentration in the pregnant woman in the second and third trimester. The values ​​should not exceed the reference ranges.
  • By using Prednisone or similar cortisone tablets are recommended glucose load test at 28 weeks of pregnancy to rule out the onset of pregnancy-related diabetes (diabetes)
  • How often rheumatological checks and follow-up at maternity clinics should be carried out depends on the rheumatological diagnosis and the individual course of the disease.
  • More information can be read at the pages of NKSR.

"Forbidden" drugs in pregnancy for rheumatic diseases

Conventional disease suppressing drugs (cDMARDs)

  • Methotrexate (Ebetrex, Metex, Methotrexate) should be stopped at least 1-3 months before pregnancy (reference: Samaritano LR, 2020), since the drug can damage the fetus (malformations in approx. 10%) and lead to miscarriage/stillbirth (in approx. 40%). Folic acid supplements, which are often given together with Methotrexate treatment, should be continued throughout pregnancy, even if Methotrexate is stopped. This is because Methotrexate can cause folic acid deficiency and the risk of Spina Bifida in fetus. Breast-feeding should be avoided because methotrexate is found in breast milk. Methotrexate does not affect fertility in either women or men.
  • Leflunomide (Arava) should not be used the last two years before pregnancy, since the drug remains in the body for a long time and birth defects and spontaneous abortions / stillbirths that could possibly be related to the treatment have been observed. However, a study among 51 pregnancies that had been exposed to leflunomide showed no malformations, miscarriages, premature births or too small children. The study nevertheless concludes that the numbers are too small to rule out harmful effects (reference: Berard A, 2018). If pregnancy is planned or occurs unexpectedly, "washing out" of the drug from the body is relevant. This is done after a special procedure with cholestyramine. In practice, leflunomide is not recommended for women who expect to become pregnant in the long term. Avoid breastfeeding
  • Mycophenolate (CellCept, Myfortic) can cause damage to the fetus (in approx. 25%) and lead to miscarriage/stillbirth (approx. 35%). Treatment must be stopped at least 6 weeks before pregnancy. Breastfeeding is not recommended (we still have too little data on safety)
  • Sendoxan (cyclophosphamide) must be stopped at least 3 months before pregnancy. Fetal malformations have been seen. If the medication is vital, the special indication must be assessed individually (less risk of harm to the fetus in the 2nd and 3rd trimester). Freezing of ovarian tissue may be relevant before Sendoxan treatment if later pregnancy is desired. Cyclophosphamide should not be used during breastfeeding.

tsDMARDs, JAK inhibitors

  • Tofacitinib (Xeljanz), baricitinib (Olumiant), filgotinib (Jyseleca) are JAK inhibitors that should be stopped well before pregnancy because they can be harmful. Small molecular size suggests that they pass to the fetus via the placenta during pregnancy and into breast milk during breastfeeding, but we still lack data for risks during pregnancy and breastfeeding (reference: Samaritano LR, 2020). Data (as of January 2023) do not indicate that fathers' use of JAK inhibitors will harm a foetus.

Blood pressure medications (anti-hypertensive)

  • 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 anti-hypertensive drugs that are suitable for pregnancy (such as Trandate)

"Blood thinning" drugs (anticoagulation)

  • Marevan can damage the fetus and should be changed before pregnancy or at the latest within the first 6 weeks of pregnancy.
  • Fragmin (in an equivalent treatment dose) can be used instead of Marevan. In some cases, Fragmin and Albyl-E are combined.
  • Persantin, Plavix, Brilique, Pradaxa, Eliquis are not recommended during pregnancy or breastfeeding.

Drugs that may not be used in parts of pregnancy for rheumatic disease

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:

  • The contents of the "Joint Catalogue" are based on legal conditions that must protect the manufacturer. Restrictive advice is therefore given on drug use during pregnancy and breastfeeding which is not always in line with updated recommendations. Reference: RELIS.

NSAIDs (non-steroidal anti-inflammatory drugs)

Do not use in the last third (last trimester) of pregnancy. End treatment no later than week 28 of pregnancy.

  • When used in the first part of pregnancy with rheumatic disease: Use the types that leave the body the fastest (short half-life), such as Ibuprofen (Ibux) or the naproxen.
  • Cox-2 inhibitors (Arcoxia, Celebra) should not be used during pregnancy due to lack of documentation (increased risk of miscarriage/stillbirth is possible). Little general data regarding safety during breastfeeding, but celecoxib (Celebra) is considered safe during breastfeeding
  • NSAIDs can be used during breastfeeding. Ibuprofen is preferred because of its short half-life (leaves the body quickly) 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 pregnancy; preferably below 7,5 mg/day)

  • Low doses do not lead to an increased 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.
  • Breast-feeding is uncomplicated if the Prednisolone dose does not exceed 20 mg/day (in that case breast-feeding should be postponed at least 4 hours after drug intake.
  • Cortisone can be injected into inflamed joints also to pregnant women

Acetylsalicylic acid (ASA, ASS)

Some disease-modifying drugs (Conventional Disease Modifying Drugs = cDMARDs)

  • Plaquenil (hydroxychlorokine). No increased incidence of malformations in fetuses or miscarriages/stillbirths. Can be used during breastfeeding
  • Imurel (azathioprine). At normal doses (up to 2 mg/kg body weight/day) there is no increased occurrence of malformations in fetuses or spontaneous abortions/stillbirths. Can be used during breastfeeding, but then it is recommended that the dose not exceed 100mg/day. If higher doses are necessary, the child should be followed up with blood tests.
  • Sandimune (Ciclosporin A). At normal doses, there is no increased incidence of malformations in fetuses or spontaneous abortions/stillbirths. The treatment can continue throughout the pregnancy where necessary. Can be used during breastfeeding (at normal 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 is recommended. Sperm cells can be affected by salazopyrine, so men who use Salazopyrin may have reduced fertility as long as the treatment is ongoing. By stopping the treatment for 3 months, the sperm normalizes.
  • Immunoglobulins (IVIG, Octagam, immunoglobulin infusions or injections). No increased incidence of malformations or miscarriages/stillbirths. Can be used during breastfeeding.
  • Tacrolimus (Prograf, Advagraf). No increased occurrence of malformations in fetuses or spontaneous abortions/stillbirths in humans (unlike in animal experiments). Can be used (in the lowest necessary dose) during pregnancy. Passes into breast milk, but no damage has been seen. Can be used during breastfeeding.
  • Colchicine. The incidence of miscarriages/stillbirths or malformations is not increased in fetuses if the total daily drug dose is 1mg or less. Avoid concurrent antibiotic treatment with macrolides (interaksjoner.no).

«Blood thinner (anticoagulation)». Calcium, Vitamin D and Folic Acid

  • Fragmin, Klexane, Heparin (blood thinner) can be used during pregnancy and breastfeeding.
  • Calcigran Forte (Calcium and Vitamin D). Calcium and vitamin D can be important dietary supplements also during pregnancy and can be used during breastfeeding. This as prevention of gestational osteoporosis.
  • Folic acid. All pregnant women are recommended to take 0,4 mg/day in the first part of pregnancy. After Methotrexate or Salazopyrin treatment, folic acid 1 mg/day is recommended throughout pregnancy.

Biological drugs and pregnancy

TNF inhibitors. There has been no proven increase in the incidence of malformations or spontaneous abortions/stillbirths during treatment 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 the pregnancy, the dose for the fetus increases (with the exception of certolizumab/Cimzia), depending on which of the drugs is possibly used. This increases the risk of infection in the newborn. If the pregnant woman has used a TNF inhibitor after the 22nd week of pregnancy, the children should not receive it live vaccines (MMR, Rotavirus vaccine, BCG for exposed persons) in the first 6 months of life. When in doubt, can Public Health contribute with supplementary information. TNF inhibitors can be used during breastfeeding. The sperm cells are not affected, so the treatment can be used among men who are going to become fathers (reference: SLV, 2019). On strict indication (great need for treatment) TNF inhibitors can also be given in the last trimester, but must be discontinued/discontinued several half-lives (see properties for each drug) before planned birth (reference: Samaritano LR, 2020). If the treatment must be continued, one should consider measuring the serum concentration. The medicationCertulizumab (Cimzia) almost does not transfer to the fetus during pregnancy, so that the sion in the pregnant woman in the 2nd and 3rd trimester. The values ​​should not exceed the reference ranges. switching from another TNF inhibitor can be considered.

All TNF inhibitors reduce the immune system of the pregnant woman, so increased attention to infections is important. Men using biological treatment do not need to stop treatment before or after conception. The drugs (TNF inhibitors) can be used during breastfeeding.

-TNF inhibitors and drug transfer to the fetus. Remicade, Inflectra, Remsima (infliximab), Simponi (golimumab) og Humira (adalimumab) is actively transported across the placenta (placenta) and to the fetus in the last 3 months of pregnancy. This results in higher drug doses in the blood of the fetus and in the newborn (160-179% of the mother's dose in umbilical cord blood). Enbrel and Benepali (etanercept) is transferred to a small extent from the placenta to the foetus/child. The drug dose in umbilical cord blood with Enbrel is 7-30% of the mother's 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. Cimzia (certolizumab). No demonstrated increased risk of birth defects or miscarriages/stillbirths. The dose found in umbilical cord blood is 2-8% of the level in the mother (reference: Mahadevan U, 2012).

Other biological drugs

MabThera (ritual simab). Direct damage to the fetus has not been shown, but the immunosuppressive effect lasts for many months and can cause infections and lack of vaccine effects in the fetus and newborn in the first year. One recommends that MabThera be changed to another treatment before pregnancy (reference: Samaritano LR, 2020). Use during pregnancy is only relevant if other drugs cannot be used and the need for treatment is great. One must then assume that the number of B cells (a type of white blood cell) is low, and the risk of infection increased in the newborn. Can be used by men who want to become fathers. Can be used during breastfeeding (reference: Samaritano LR, 2020).

RoActemra (tocilizumab). Studies have not shown an increased number of birth defects (reference: Hoeltzenbein M, 2016). It is generally recommended to stop or replace RoActemra with another drug before pregnancy. If the drug must nevertheless be used after the 22nd week of pregnancy, the child must not receive live vaccines for the first 6 months of life. Can be used by men who want to become fathers. Can be used during breastfeeding (reference: Samaritano LR, 2020).

Stelara (Ustekinumab) recommended to stop before pregnancy. There is a lack of documentation for use during pregnancy, and there is therefore uncertainty about the drug's safety in pregnancy. Use during pregnancy is only relevant if other drugs cannot be used and the need for treatment is great. If the drug must nevertheless be used after the 22nd week of pregnancy, the child must not receive live vaccines for the first 6 months of life. Can be used by men who want to become fathers. There are too few data to recommend use during breastfeeding.

Cosentyx (sekukinumab). Experience with treatment during pregnancy and breastfeeding is lacking. It is recommended to stop treatment before pregnancy. If the drug must nevertheless be used after the 22nd week of pregnancy, the child must not receive live vaccines for the first 6 months of life. Can be used by men who want to become fathers. There are too few data to recommend use during breastfeeding.

Benlysta (belimumab) recommended to stop before pregnancy. There is a lack of documentation on use during pregnancy and breastfeeding. There is therefore uncertainty about the drug's safety in pregnancy. Use during pregnancy is only relevant if other drugs cannot be used and the need for treatment is great. Can be used by men who want to become fathers. Not recommended for use during breastfeeding.

Kineret (anakinra) it is generally recommended to stop before pregnancy because there is little data on the drug's safety in pregnancy. Some people, however, have a great need for the drug, so that use during pregnancy is still relevant. This may apply to Still's disease. Can be used by men who want to become fathers. There are too few data to recommend use during breastfeeding.

Orencia (abatacept) passes from mother to fetus (active transport) during pregnancy. It is recommended to stop treatment before pregnancy. Can be used by men who want to become fathers. There are too few data to recommend use during breastfeeding.

Men who are planning to become fathers and are taking disease-modifying treatment (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, freezing of sperm before the start of treatment may be relevant to ensure the possibility of having children later. Literature: Crust CG, 2016.

Vaccines

Rheumatic Diagnoses & Pregnancy

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
  • Pregnant women with anti-SSA antibody are checked every one or two weeks between weeks 2 and 16 of pregnancy (until week 24 according to US guidelines, reference: Samaritano LR, 2020). The most important thing is to measure the fetal heart rate, which should not be too low.
  • 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 return spontaneously. AV block grade three is unlikely to be affected by cortisone treatment. The newborn will then have a pacemaker inserted
  • 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. In some cases of planned pregnancy due to rheumatic disease, egg freezing is therefore offered before treatment. Part of one ovary is operated on. The ovary (with accompanying eggs) is frozen (preserved) in a special freezer. If pregnancy is desired, eggs are put back 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: Kado R, 2020; Donnez et al., 2013 and Dittrich R et al Hum.Reprod (FertilProtect) 2014).

Literature

More information

Always consult your doctor


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