Preconceptional and pregnancy care of women with autoimmune diseases

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2021-1-HU01-KA220-HED-000027613 - COHRICE
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SYLLABUS

Preconceptional and pregnancy care of women with autoimmune diseases

(Basic level)

Slide 2. 

Aim of  the study material:

  • To learn about the immunology of pregnancy
  • To characterise groups of pregnant women with autoimmune diseases
  • To be aware of the maternal and fetal risks during pregnancy for women with autoimmune diseases
  • To understand why pre-pregnancy counselling is improtant
  • To understand specific risks

Slide 3.

 Autoimmune diseases occur far more often in women than in men. The interplay of genetic, environmental and hormonal factors all influence the development of the immune system. Differences between male and female are clear  in their susceptibility to autoimmune diseases but also to infectious diseases and cancer types.

Women differ from men in several clinical characteristics of their immune responses which suggest that they have stronger innate and adaptive immune responses.

Some examples for that are: 

  • Women have 40% less viral load by an acute HIV infection
  • Antibody responses to seasonal influenza vaccines are stronger in women
  • non-reproductive cancers, such as bladder, bowel, kidney, leukaemia, malignant melanoma, develop more often in male patients
  • specific infectious diseases such as Hepatitis B and tuberculosis affect male patients more often

Slide 4. 

Women suffer from autoimmune disease more often then men. On this slide we can see the incidence of some autoimmune diseases, such as SLE, RA, autoimmune thyroid diseases, inflammatory bowel diseases, vasculitis, autoimmune uveitis by sex.  Women seem to be more prone to the development of autoimmune diseases than men.

Slide 5.

Childbearing age increases gradually every year. (diagram OECD FAMILY DATABASE, oe.cd/fdb) 

This trend roots from societal attitudes and expectation, which puts women’s reproductive potential at risk.  Most OECD countries the average age of women at childbirth increased by 2 to 5 years between 1970 and 2019, with the largest increase (5.4 years) in the Czech Republic. With the exception of three Latin American countries (Colombia, Costa Rica and Mexico), where the mean age of women at childbirth has decreased by over two years since 1970. 

A woman’s peak reproductive years are between the late teens and late 20s. By age 30, fertility (the ability to get pregnant) starts to decline. This decline becomes more rapid once they reach 35 years of age.  By 45, fertility has declined so much that getting pregnant naturally is unlikely for most women. Education about the fertility aspects seems important for future generations to fulfil their reproductive potential. 

Slide 6 

You can see that the number of births over 35 years of age increased steadily between 2004 and 2016, which means that an increasing proportion of women will have an obstetric risk due to their increased age and comorbidities, as well as due to the increasing use of artificial reproductive techniques. This does not mean that fertility itself wasn’t declining with age!

Slide 7

Generally, advanced age comes with common co-morbidities like high blood pressure, diabetes mellitus, autoimmune diseases etc., which might complicate the course of the pregnancy and cause maternal and fetal morbidities.  The most common period for the diagnosis of autoimmune diseases lies between the 3rd and 4th decade of life, which intersects with family planning and pregnancy. 

Women with rheumatic diseases have fewer children than healthy women. Several factors are responsible for this: personal decisions, infrequent sexual intercourse, reduced fertility, fear of taking medication or an active underlying disease. 

But depending on the disease, the conditions differ significantly: female patients with inflammatory joint diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsoA), joint involvement with inflammatory bowel disease (CED), or axial axial spondyloarthropathy (SpA) have, in principle, an average fertility average fertility, but often need a longer time until conception. 25 percent of patients with RA take longer than 12 months to get pregnant. By comparison, in the healthy control group  rate of subfertility is 15.6 percent.  In women with systemic lupus erythematosus (SLE), fertility is not impaired, but ovarotoxic agent in the medical history can substantially decrease fertility potential, as well as long term activity of the underlying autoimmune diseases.

Slide 8

Adaptation of the immune system to pregnancy means different coping in different species:

The different species have developed different strategies of childbearing. Birds, reptiles and fish- for example - take care of their offspring outside of their bodies. This strategy puts the offspring in a greater danger to be a pray for predators, changing temperature and mechanical impacts, but this way the developing offspring does not interfere with the immune system of the mother.  On the contrary mammals, - for example humans-, bear their offspring in their body, which provides safety, constant temperature, energy and oxygen supply, however the childbearing animal has to adapt for the period of the pregnancy to tolerate the alloimmune fetus. 

Slide 11

What kind of changes happen in the immune system in pregnancy?  How do these changes influence the activity of the autoimmune disease?

According to an older theory about the immunological changes during pregnancy, there is a shift between Th1 and Th2 type immune response and Th2 dominance characterises pregnancy. This immunological shift helps to prefer anti-inflammatory cytokine function and through that the maintenance of pregnancy and acceptance of the allo-immune fetus. 

Women with autoimmune disease might experience an exacerbation of the underlying disease. Observations suggested that connective tissue disorders (for example SLE or Sjögren´s syndrome) are more likely to flare up during pregnancies, while other autoimmune diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, multiple sclerosis psoriasis arthritis are less likely to gain activity during pregnancy. The reason might lie in the immunological changes causative to the autoimmune disease. Systemic lupus erythematosus can be characterised with an active Th2 type immune cell activation. If the immunological changes during pregnancy also activate these cells, the autoimmune disease might become more active. This theory however does not hold entirely. 

Slide 12

New immunological studies showed, that when considering the immunological changes in pregnancy we have to differentiate according to the three phases of the pregnancy. A pro-inflammatory microenvironment is crucial for normal implantation and parturition, whereas a tolerogenic environment is induced during the course of pregnancy to enable normal placentation and fetal growth. The local immunological changes in the placenta and decidua will ensure the success of a pregnancy.  The cytokine profile at the decidua is the result of the interplay of fetal cells and hormones, and that the TH1–TH2 paradigm should be replaced by a more complex paradigm involving TH1, TH2, TH17 and Treg cells.

The first phase  describes the period from implantation to early placentation. At this point a mainly innate immune cells such as  NK cells, dendritic cells, macrophages, neutrophils and type 3 innate lymphoid cells (ILC3s) are responsible for the proinflammatory immune milleu consisting of IFNγ, IL-1, TNF, IL-6, IL-17 and the IL-6 family cytokine leukaemia inhibitory factor (LIF). Pro-inflammatory M1 macrophages secreting IL-23 or IL-12 as well as LIF; decidual NK cells are poorly cytolytic but produce cytokines and chemokines, such as IFNγ and vascular endothelial growth factor, that promote spiral artery remodelling. These factors are essential for successful implantation.

To avoid rejection at the feto-maternal interface in the second phase of the pregnancy a tolerogenic state develops rapidly. Oestrogen, cells and regulatory proteins act on decidual stromal cells and tolerogenic dendritic cells, expand FOXP3+ Treg cells, change the function of the rapidly increasing number of natural killer (NK) cells and downregulate effector T (Teff) cells. Anti-inflammatory cytokine production increases. As a result, the semi allogenic fetus will be tolerated. 

In the third stage of the pregnancy- at parturition- again a pro-inflammatory microenvironment is crucial. Innate immune cells, such as neutrophils and macrophages infiltrate the decidua and the chorioamniotic membranes during term labour and secrete matrix metalloproteinases, IL-1, IL-6, TNF and nitric oxide.

Slide 12

All of the above mentioned changes will effect the activity of the autoimmune disease during pregnancy.  Well controlled autoimmune diseases have less risk of activity during pregnancy, while active disease periconceptionally poses a risk for flare. This characteristic lies in the nature of the immunological shifts during pregnancy.  

On the other hand autoimmune disease itself might influence the process of the placentation and with that, just like in the partially known pathophysiology of preeclampsia, might influence placenta function, morphology, structure, which all affect the risk for preeclampsia, fetal growth restrictions and preterm birth. All of which are relevant possible risks in a pregnancy with autoimmune disease.  

Slide 13

This seminar will explain the interplay of pregnancy and autoimmune diseases on the example of inflammatory rheumatic diseases (IRD), which is a large group of different autoimmune diseases. These diseases, tend to be systemic and thus effect the immune response of the patients in its entirety. 

By understanding the effect of IRD on pregnancy and vice versa, we can extrapolate the influence of other systemic autoimmune diseases on the course of the pregnancy. However, each individual autoimmune condition might have specific aspects on pregnancy. Unfortunately, this the scope of the seminar does not allow to discuss each systemic autoimmune disease separately.  

Autoimmune conditions often affect women of childbearing age and often delay family planning for those affected. The effect of pregnancy on the activity of the autoimmune condition but also the possible influence of the autoimmune condition on the ongoing pregnancy raise concerns and uncertainties in patients.  In recent decades, as multiple treatment options have been established that can control disease activity, awareness regarding childbearing in autoimmune diseases has grown. Evidence proves that reaching remission or low disease activity before conception is of utmost importance to minimise risk of flare during pregnancy as well as to minimise the risk of pregnancy complications.

We will focus on systemic lupus erythematosus, and rheumatic arthritis as important examples of IRD in pregnancies. Organ specific autoimmune diseases like M.Basedow, autoimmune thyreoiditis, autoimmune hepatitis will not be discussed here. 

Not only the pregnancy will have an effect on the autoimmune disease, but the autoimmune disease also poses a risk on the course of the pregnancy. 

Maternal inflammatory phenotype at conception will affect the crucial immunological processes at implantation, which in turn can have a negative effect on placentation, on the development of the spiral arteries and might lead to early miscarriage, preterm rupture of membranes, placental insufficiency, preeclampsia or preterm birth. 

Slide 14

In summary we can see complications relating to the underlying rheumatic disease during pregnancy, such as flare, cardial, pulmonal, haematological, renal problems. Some patients experience obstetric or thrombotic or both complications related to antiphospholipid antibodies, which commonly are associated with autoimmune diseases. 

On the other hand the prevalence of pregnancy complications, such as preterm birth, intrauterine growth restriction, small for gestational age newborn, preeclampsia are increased in patients with rheumatic diseases. 

Antiphospholipid antibodies, when fulfilling clinical an laboratory criteria for antiphospholipid syndrome pose a substantial risk to develop preeclampsia, stillbirth, miscarriage and placental insufficiency.  Existing obstetric APLAS should be taken as a serious risk factor in the ongoing pregnancy. 

Slide 15

This slide shows on the example of SLE, how the activity of the underlying rheumatic disease affects pregnancy complications. We can see that highly active autoimmune conditions elevate the risk of pregnancy complications. For that reason, preconceptional pregnancy planning is quintessential for risk reduction in the pregnancy.

Slide 16

The particular strength of professional care for pregnant women with inflammatory rheumatic diseases lies in the joint interdisciplinary consultation of a rheumatologist and a gynaecologist. Prepregnancy counselling is important to assess modifiable risk factors and optimise disease activity and therapy before conception. 

The following points should be considered in order to optimise the course of pregnancy: 

Risk modification by adequate weight control, healthy and balanced diet and abstinence from nicotine, review and change of medications, and risk assessment based on disease activity and antibody profile and previous obstetric history should be done. 

Effective contraceptive methods should be suggested until no teratogenic medications are given and until the underlying autoimmune condition reaches a steady state in remission for 6 months. 

The prepregnency care might involve the adaptation of the immunosuppressive medications, might involve increased need of folic acid in the case of methotrexate or sulphasalazin. 

In addition, due to the increased risk of osteoporosis, it is useful to check the serum vitamin D level. 

Vaccination status, including antibody titres, should be consistently checked. In the case of inadequate protection against varicella, rubella, measles, mumps, the patient should be vaccinated with a live vaccine before receiving immunosuppressants. 

Contraception may only be discontinued one month after vaccination. The flu vaccination and pertussis (inactivated vaccine) is always recommended during pregnancy and should be administered in the second trimester if possible. 

Slide 17

Which antibodies are highly relevant in the pregnancy?

For a careful obstetric risk assessment apart form the antibodies, that indicate a possible disease activation antiphospholipid antibody and SSA and SSB antibodies are relevant for the pregnancy. 

Antiphospholipid antibody syndrome (APLAS) can occur as a primary disease or secondary to rheumatic diseases, in particular to connective tissue disorders. Potential pregnancy complications include recurrent pregnancy loss, an increased risk of hypertension in pregnancy, pre-eclampsia, eclampsia, HELLP syndrome, fetal growth restriction, stillbirth, and thromboembolic events such as venous and arterial venous and arterial thrombosis incl. amaurosis fugax and insults.

Slide 18

For successful pre-conceptional counselling, it is crucial to recognise this syndrome on time. Questions about a history of thrombosis or previous pregnancy complications such as preterm birth, stillbirth, intrauterine growth restriction, recurrent early abortions or late abortion are important. Therapeutically, APLAS can and should be treated in pregnancy with platelet aggregation inhibitors such as ThromboASS® and/ or  low-molecular-weight heparins. Recent guidelines help to make treatment decisions in cases of antiphospholipid antibodies with or without rheumatic diseases in order to avoid overtreatment and risk of bleeding, but to reach oprimal risk reduction. (Suggested reading: Tektonidou MG, Andreoli L, Limper M, et al. Ann Rheum Dis 2019;78:1296–1304)

Slide 19

SSA/SSB antibodies pose an increased risk of neonatal lupus.

Neonatal lupus (NLE) is an acquired disease, caused by the transplacental transfer of SSA and SSB autoantibodies. There are two forms of NLE:  1. Cutaneous NLE, characterised by a temporary (transient) rash, usually developing during the first few weeks of life and disappearing within 6 months after birth. 2. Cardiac NLE: characterised by fetal and neonatal congenital atrio-ventricular (AV) block. The local inflammatory process caused by SSA and SSB antibodies in the developing fetal heart result in fibrosis of the electrical conduit system and can cause a partial or total dissociation of atrial and ventricle system.  The severity of such conduction abnormalities may vary among affected infants meaning there can be first-, second-, or third-degree blocks, the latter most serious. Children with total AV block usually receive a pacemaker. This means that long-term survival is between 87 and 95 percent. Morbidity and mortality is highly influenced by the gestational age at birth. 

Slide 20

Pregnant women with SSA/SSB antibodies in the context of Sjögren's syndrome or SLE  have a risk (ca.2%) of fetal AV block. In the subsequent pregnancy, the risk of recurrence is much higher with an estimated 20%.  This is a very relevant increase in risk, for that reason prepregnancy risk assessment based on previous pregnancies is necessary, as well as therapy plan and  detailed discussion of risk and to date still suboptimal therapy possibilities if AV block occures. 

Slide 21

This slide show a suggested way of counselling patients with connective tissue disorders, such as SLE and Sjögren syndrom or mixed connective tissue diseases, which  might come with more and specific  obstetric complications.  For that reason, prepregnancy counselling is of utmost importance. 

In cases of active severe disease with SLE, the preterm birth rate is significantly increased at 58 percent (vs. 8 percent in the control group) as well as other pregnancy complications. 

Slide 22

 Pregnancy is rarely contraindicated. In cases of pulmonary hypertension, active and current neurological and renal involvement due to the autoimmune disease pregnancy might be contraindicated, as the mortality of pregnant women is 20-fold higher in this case. 

 In mild forms of the disease, there is no contraindication for pregnancy, however, clinical remission should be targeted for six months before conception.

Slide 23

As discussed before, optimizing the activity of the underlying autoimmune disease before conception is key to an uneventful course of pregnancy. For that reason, therapeutic intervention and immunosuppression is often required before and throughout pregnancy.  

In the last 20 years there was an enormous improvement in the therapy of inflammatory rheumatic diseases. Thanks to the wide availability of biological DMARDS (disease-modifying antirheumatic drugs) many patients can have a symptom free life and feel the need to fulfil their family planning.  

This table represents in red the medications, which are contraindicated in pregnancy, green the medications, which can be administered and yellow: the medications, where only insufficient data exist in pregnancy.

Pregnant women are not allowed to take part in drug trials, although this group of women often also need the continuation fo the therapy throughout the pregnancy. This is the reason of the scarcity of the data concerning many biological medications, which might be administered throughout pregnancy.  Uptodate and careful assessment of the data concerning  pregnancy is important for counselling.  Websites, such as Reprotox, or Embryotox as well as uptodate guidelines of medical societies (EULAR, ACR, BSA, etc) , specific registries of the medications are useful sources for these discussions.

Slide 24 

When assessing risk of a certain medication used during pregnancy, one has to consider the background risk of the healthy population without medications for early miscarriage and congenital malformations.

Even in healthy parents, without any medication, 15 -20% of pregnancies result in early pregnancy loss and 3-5% of these parents give birth to children with congenital malformations. These are statistical facts that have to be communicated to the advice seeking couple as we start or progress with immunomodulation during pregnancy.  

There are only a few immunomodulatory medications, which are contraindicated during pregnancy. This means, that they have to be ideally preconceptionally discontinued.  Some of these medications persist in the blood stream years after discontinuation. Some of them have substantially shorter half-life. 

Professional counselling is needed in the situation when unintentional pregnancy occurs under these therapies. It is always an individual decision of the couple to terminate or carry on  a pregnancy, which has to be based on an interdisciplinary (obstetric, rheumatology, embryology) detailed counselling. Exact time of discontinuation, absolute and relative risks of early miscarriage and congenital malformations need to be stated.

As seen in this table, the relative risks of congenital malformations and miscarriages compared to the background risk without any medication vary widely among these immunosuppressives. 

Slide 25

Medications that are considered safe periconceptionally, during pregnancy and lactation. This group include salazopyrin, antimalarials such as Resochin® or Quensyl® and azathrioprine (Imurek®). Salazopyrin® or other 5-ASA preparations are often used for inflammatory joint disease or inflammatory bowel disease. 

Antimalarials not only have a favourable effect on the course of the autoimmune disease but they effectively reduce the risk of NLE. Disease activity in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthropathy, or inflammatory bowel disease often require intensified therapy with TNF alpha blockers. 

A good example of the continuous revision of recommendations and surveillance from the expert community concerning medication use in pregnancy is the heated discussions over the February, 2023 recommendation by the European Medicines Agency (EMA) to update the background section of the summary of product characteristics and the patient information leaflet for the use of hydroxychloroquine in pregnancy. The EMA changed the patient information according to one single study from 2021 (Huybrechts KF, et al. Am J Obst Gynecol 2021), which found a slightly elevated congenital malformation risk in patients on high dose HCQ. There was an upheaval of the scientific community concerning this change, as it was lacking substantial scientific evidence and might lead to promoting uncertainty of patients, doctors and pharmacists, which may in turn lead to worsening disease control and obstetric outcome in the targeted patient group. (K Schreiber et al. Lancer Rheumatology, 2023)

Slide 26

Before the registry data became available, it was common to generally advise women against taking biologics during conception, pregnancy or breastfeeding, or lactation.

Common questions from the women planning pregnancy with TNF alpha blockers concern infections of the newborn and possible malformation. Studies does not show increased risk for infections or increased incidence of congenital malformations.

Slide 27

Case 1

A 37 years old female patient comes for discussing her family planning. 

She suffers from rheumatoid arthritis for 2 years. Her rheumatologist started low dose methotrexate, which she takes regularly in the last year. She has never been pregnant before, did not suffer from a thrombosis or any other coagulation problem. She uses a combined oral contraceptive not to get pregnant under a teratogenic drug. 

During the discussion one can notice a lot of concernes on her part: 

She asks if the baby will also be sick after the births?  Will her disease be more active during or after pregnancy?  Is a change in medication risky for her? What is the best timing to change her medication? Are there risks during the pregnancy concerning the baby? Should she at all get pregnant with such a condition?

Slide 28

The discussion of teratogenic risk is difficult and needs to be put in context of the individual patient. Absolute and relative background risk of congenital malformations need to be discussed especially in those cases where unintended pregnancies under teratogenic medication occurred. 

The importance of disease control has to be highlighted for the patient, as disease control optimises obstetric  and disease flare risk.

Slide 29

In an optimal case- like here- the patient comes before pregnancy.  At this counselling specificities about the underlying disease have to be discussed, a detailed risk assessment should be carried out , and  concerns should be addressed.

Slide 30

In order to integrate gynaecological aspects in the counselling, and with that optimise therapy plan we have to be aware of the aspects which might influence the fertility of a couple. One aspect is certainly the underlying disease, but there are some other aspects, which are independent from that. The main predictor for a woman's fertility is her age and body mass index. The highest fertility is between 20-30 years, and there is a rapid decline after 35. For that reason, if the optimisation of the rheumatic therapy needs a longer period (for example 6 months), fertility preservation might elevate the chances to reach pregnancy. Interdisciplinary counselling should include possible methods of fertility preservation as well as ART options if medically indicated, (suggested reading ACR guidelines, Arthritis & Rheumatology Vol. 72, No. 4, April 2020, pp 529–556

Slide 31

In summary, we have to be aware, that:

Family planning should be addressed in every patient with autoimmune disease of reproductive age.

Treatment of patients before/during pregnancy and lactation should aim to prevent disease activity in the mother and not harm the foetus.

The risk of drug therapy to the child should be weighed against the risk of untreated maternal disease to the patient and child.  

The decision on drug therapy should be based on an agreement between rheumatologist, gynaecologist and patient in an interdisciplinary and participative manner.

Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the Foundation for the Development of the Education System. Neither the European Union nor entity providing the grant can be held responsible for them.