Course BASIC_Graduate level learning material about the challenges of human reproductive medicine in a changing Europe

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

Teacher`s guide

Preconceptional and pregnancy care of women with autoimmune diseases

(Basic level)

Slide 2.  Define the aims of the study material

• To learn about the immunology of pregnancy
• To characterise special groups of pregnant women with autoimmune diseases
• To be able to provide a risk assessment during pregnancy for women with autoimmune diseases
• To be able to engage in adequate pre-pregnancy counselling
• To identify specific risks and preventive methods

Slide 3.
Explain gender differences concerning autoimmune diseases.

 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.

Slide 4. 
Explain the epidemiology of autoimmune diseases. 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, vasculites, autoimmune uveitis by sex.  Women seem to be more prone to the development of autoimmune diseases than men. 

Slide 5. 
The usual age at which an autoimmune disease is diagnosed in women often overlaps with the childbearing age. This chart shows how tendentially childbearing age increases gradually every year, thus more women might have chronic disease at the time of the pregnancy. (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 generation to fullfill their reproductive potential. 

Slide 6 
This is another graph which explains the increasing number of women who give birth at their late 30s. You can see that the number of births over 35 years of age increase 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
Explain why advanced age poses a risk in obstetrics. 

Explain the special fetal and maternal risks of pregnant women with inflammatory autoimmune conditions. 

Slide 8
Explain the adaptation of the immunsystem to the semiallogenic 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?

Explain 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. 

Explain how the autoimmune disease might influence the pregnancy and how the immunological chnges might lead to changes in the underlying autoimmune condition. 

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 affect 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. 

Slide 13
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.  

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. 

Slide 14
Explain the 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. 

Explain  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. 

Explain risk assessment based on antiphospholipid antibody screening. Elaborate on the syndrome, its diagnosis critera and potential risks during  pregnancy. 

Slide 15
Explain the importance of preconceptional pregnancy counselling and planning based on this slide. 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 condition elevates the risk of the pregnancy complications. 

Slide 16
Explain the value of interdisciplinarity in the treatment of pregnant women with autoimmune conditions.

Prepregnancy counselling is important to assess modifiable risk factors and optimize 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 medicaments are given and until the underlying autoimmune condition reaches a steady state in remission for ca 6 months. 

The prepregnency care might involve the adaptation of the immunosuppressive medications, might involve increased need of folic acid. Patients after methotrexate therapy or under ongoing sulphasalazine therapy need a significantly higher folic acid substitution (5 mg daily). The substitution should start four to twelve weeks before stopping contraception. In addition, folic acid intake should be continued throughout the entire pregnancy in the case of sulphasalazine intake during pregnancy and in the first 13 gestational weeks in the case of methotrexate intake before the pregnancy. 

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 pose a substantial risk to pregnancies? Explain why antibody testing is relevant for risk assessment in pregnancies with inflammatory autoimmune conditions. Address antiphospholipid antibodies and SSA and SSB antibodies especially. Explain how disease activity might be extrapolated from clinical and laboratory values (for example decrease of complement or increase of dsDNA antibody in lupus)

Slide 18
For successful pre-conceptional counselling, it is crucial to recognise this syndrome in 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.

Slide 19
Explain the relevance of SSA/SSB antibodies, which pose an increased risk of neonatal lupus. The incidence of neonatal lupus is rare 2 from 100 patients with SSA/SSB antibodies. 

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%. 

Explain possible risk reduction strategies and outcome of children with NLE. Address the use of Hydroxychloroquine for risk reduction.

Slide 21
Explain the obstetric risks of SLE. Connective tissue disorders, such as SLE and Sjögren syndrom or mixed connective tissue diseases might come with more 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
Explain that in rare cases pregnancy is contraindicated, as it puts the mother-to-be in a high risk for severe complications.  Pregnancy is contraindicated, in cases of pulmonary hypertension, active and current neurological and renal involvement, 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
Discuss that preparation for pregnancy is key to risk reduction.

Explain the different therapeutic interventions and their effect on the fetus.  

Slide 24 
Put congenital malformations and early miscarriage in context. Explain the background risks in healthy pregnant women and put that in relation to the teratogenous medications. Explain which aspects of a medication effect teratogen potential (half- life, placental crossing, enzymatic degradation, pregnancy week…)

Professional counselling is needed in the situation when unintentional pregnancy occurs under these therapies. It is always an individual decision to terminate 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 basis risk without any medication vary widely among these immunosuppressives. 

Slide 25
Discuss safe immunomodulatory medicament options. 

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.

Explain that registry data is important to collect information about medication use in the pregnancy. 

Common questions from the women planning pregnancy with immunosuppressive agents concern infections of the newborn and possible malformation. 

Studies does not show increased risk for infections or increased incidence of congenital malformations with many of the immunomodulatory medications. 

Some of the immunomodulatory medications can be administered, when benefit at a specific patient outweigh the risk of the medication. Be aware, that a stable disease course is key for risk reduction. 

Slide 27-30
BAsed on the case described on slide 27, discuss the individual aspect of the patient seeking advice. Assess the possible realistic risks, address the irrealistic fears and try to involve students and their suggestions for counselling in this discussion. 

Slide 27
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.