Pregnancy and Autoimmune Disease
Diseases of the Nervous System, Connective Tissue, and the Bowel
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Background: Pregnancies in women with chronic disease are on the rise. This pertains to autoimmune diseases in particular since these tend to affect women of childbearing age. The interaction between pregnancy and autoimmune disease may increase the risk of maternal, fetal, and obstetric complications; additional care may be required.
Methods: This review is based on a selective literature search in PubMed (2015–2020).
Results: In women with autoimmune diseases, the course of pregnancy is highly variable. Some autoimmune diseases tend to improve during pregnancy and do not to result in any serious obstetric complications. Others may worsen during pregnancy, with deterioration of the maternal condition as well as obstetric and perinatal complications. In systemic lupus erythematosus and myasthenia gravis, placental transfer of specific autoantibodies may cause fetal or neonatal disease.
Conclusion: The care of pregnant women with chronic diseases requires collaboration between specialists of the pertinent levels of care. A stable course of disease before conception, close interdisciplinary care, and pregnancy-compatible medication contribute to a reduction in maternal and perinatal complications.
Advances in the treatment of chronic diseases and the associated higher quality of life and life expectancy allow affected couples the opportunity to fulfill their desire to start a family. Furthermore, methods of reproductive medicine are available for those diseases that are often associated with subfertility.
It is no surprise, therefore, that a steady increase has been observed in recent decades in the number of pregnancies in women with chronic diseases. A Danish registry study reported a rise in prevalence from 3.7% to 15.8% between 1989 and 2013; a four- to eight-fold rise was demonstrated for the autoimmune diseases rheumatoid arthritis (from 0.1% to 0.73%), systemic lupus erythematosus (from 0.02% to 0.07%), chronic inflammatory bowel disease (from 0.3% to 1.09%), and multiple sclerosis (from 0.04% to 0.26%) (1). In a German investigation for the period 2002–2008, 21.4% of all pregnant women reported having a chronic disease (2).
Pregnancies in women with a preexisting disease are potentially high-risk pregnancies and are associated with a higher rate of maternal and obstetric complications. A recent US investigation of almost 1.5 million births found a 4.8-fold higher rate of severe maternal complications among women with preexisting diseases (0.5% severe complications in women without preexisting disease, 5.6% in the case of ≥ three comorbidities) (3). The same trend can be seen for maternal deaths: whereas direct causes of death such as preeclampsia, thromboembolism, or hemorrhage used to dominate the statistics, preexisting diseases or non-obstetric diseases that manifest for the first time during pregnancy have been the leading cause of maternal mortality for over 20 years (4).
Autoimmune diseases are characterized by a preponderance for females, as well as first manifestation during the reproductive phase. Thus, they are among the commonest preexisting diseases in pregnancy. At the same time, anticipated disease courses are highly variable, ranging from an improvement in symptoms, for example in rheumatoid arthritis, to an exacerbation involving maternal and fetal complications, as in systemic lupus erythematosus.
Although the causes of these differences are unclear, they have been linked to the complex immunological changes that take place during pregnancy. These are characterized by an immune tolerance to the paternally inherited antigens expressed by the fetus or trophoblast cells (e1). Obstetric complications typically comprise variably increased rates of miscarriage, intrauterine fetal death, fetal growth restriction, and preterm birth. The long-term effects arising from the altered intrauterine environment are increasingly attracting research attention; these relate to, for example, the development of cardiovascular and metabolic disorders (e2, e3, e4, e5).
After reading this article, the reader should:
- Be familiar with the principles of care of pregnant women with autoimmune diseases of the nervous system, connective tissue, and the bowel, and be able to identify the special features that arise as a result.
- Be aware of the options with regard to maternal and fetal monitoring in pregnancies of women with these preexisting diseases.
- Have gained knowledge of the various courses of disease and pregnancy as well as their treatment options.
According to the preexisting disease, affected women are treated by representatives of various levels of care. In the case of pregnancy, this team expands to include experts in maternal and fetal medicine as well as high-risk obstetrics. For some diseases, the respective German guidelines make reference to action pathways. However, maternity guidelines do not elaborate on the care of pregnant women with preexisting diseases (5).
The goal is a care plan that includes preconception counseling, as well as treatment during pregnancy, birth, and into the postpartum period. This also includes close collaboration between levels of care. It is important to ensure a care team with designated contacts, especially in complex cases where there is a high risk of complications in the course of pregnancy. Centralized care in institutions with appropriate expertise is another element that leads to a better outcome for both mother and newborn and is recommended for pregnant women with severe disease courses (e6).
An essential requirement for a successful course of pregnancy is stable disease before conception. Therefore, women with chronic diseases should plan their pregnancy. Furthermore, preconception counseling should take place to discuss, among other things, any anticipated interactions between the preexisting condition and pregnancy, as well as to review medications.
Pharmacological treatment during pregnancy and breastfeeding is characterized by three problems:
- Use of a potentially teratogenic drug during an unplanned and possibly unnoticed pregnancy
- Discontinuation of an indicated drug without medical consultation after pregnancy confirmation due to fear of a harmful effect on the unborn child
- Limited knowledge of the teratogenicity and/or fetotoxicity of drugs.
Very few drugs cause a clearly recognizable malformation pattern. Most birth defects have multifactorial origins, and indications of a teratogenic effect of a drug arise from the increase in relative risk. For an adequate assessment, the European Medicines Agency requires prospectively collected data from at least 1000 pregnancies associated with exposure in the first trimester (6). On the other hand, there is uncertainty with regard to several diseases as to whether the disease itself or the drugs used increase the risk of birth defects (e7, e8).
Ultimately, the prescription of drugs during pregnancy calls for special diligence and should be based on current data as well as the individual’s medical history and disease course, as established during a consultation (e9). The replacement of the FDA classes with the Pregnancy and Lactation Labeling Rule (7) takes this into account.
The following is a review of selected neurological, connective tissue, and gastroenterological autoimmune diseases with regard to their care in the context of pregnancy, childbirth, and the puerperium. The tables provide an overview of the diseases (Table 1), the drugs used (eTable), and fetal monitoring (Tables 2 and 3).
Multiple sclerosis and neuromyelitis optica spectrum disorders
The therapeutic spectrum of neuroimmunological diseases has significantly widened in recent years, which explains why pregnancy planning has a special role to play. The eTable, summarized from Krysko et al. (8) and Mao-Draayer et al. (9) provides an overview of the approved immunotherapies as well as the special approach used during pregnancy and lactation. If pregnancy occurs while a woman is on teratogenic medication, she should immediately present to a center for detailed counseling; detailed ultrasound examinations are also advised.
Multiple sclerosis primarily affects women and is diagnosed in young adulthood in more than two-thirds of cases. Interestingly, the incidence has been rising particularly among women in recent decades (e10). Pregnancies in women with multiple sclerosis are usually unaffected by the underlying disease, with no increased risk of a negative pregnancy outcome. Birth weight is lower compared to neonates born to healthy mothers (10). Pregnancy in affected patients usually leads to a reduction in the rate of flares in the final third of pregnancy and an increase in the first months following birth. Disease activity during pregnancy depends on the activity of the underlying disease as well as on the timing of discontinuation of the various immunotherapies (8). Pregnancies do not affect the long-term prognosis of the disease.
Stabilizing the disease prior to pregnancy is beneficial. Recent data suggest that using drugs with a prolonged biological effect in multiple sclerosis can also protect against disease activity during pregnancy (8, 11). Mild flares in multiple sclerosis (without relevant functional impairment) during pregnancy need not be treated with corticosteroids. In the case of severe flares, high-dose cortisone should be administered, or immunoadsorption or plasmapheresis carried out.
Mode of delivery and type of anesthesia do not affect the rate of flares in pregnant women with multiple sclerosis. Women with this disease should be supported in their wish to breastfeed. Breastfeeding does not increase the postpartum risk of flares. Preliminary results of as yet small cohorts in recent studies indicate that breastfeeding is still possible off-label during monoclonal antibody treatment (12) (eTable).
Neuromyelitis optica spectrum disorders represent a very rare spectrum of neuroimmunological diseases that follow a course involving flares and which affect in particular women. They can be associated with an increased rate of pregnancy complications (miscarriages), as well as severe flares. These disorders are listed in Table 1 as a separate entity. From a treatment perspective (azathioprine, mycophenolate mofetil, rituximab, satralizumab, eculizumab), there is a considerable overlap with other autoimmune diseases.
Myasthenia gravis has a bimodal age distribution with two peaks of incidence (in the third decade and after the sixth decade), with predominantly females affected in the younger age group. A distinction is made between a generalized and an ocular form, the latter having a better prognosis. An increased associated risk of preterm birth is mooted, but otherwise pregnancy complications do not appear to be increased (13, 14). A very recent analysis of US insurance data points to more respiratory complications in the mother and longer hospital stays (healthy women: 0.1%; women with myasthenia gravis: 2.26%) (15).
The course of myasthenia gravis in pregnancy varies widely from individual to individual. While the condition remains stable in many pregnant women, it can also worsen, and in a small proportion of women even improve. Worsening occurs in the first or second trimester and/or after birth.
Myasthenic crisis in pregnancy should be managed according to general treatment guidelines, for example, intravenous immunoglobulins or plasmapheresis (13, 14), and treated as an emergency by an interdisciplinary team. In the general treatment of myasthenia gravis, the lowest effective steroid dose should be selected. The administration of magnesium for preeclampsia in affected pregnant patients can lead to a critical worsening.
For the identification, diagnosis, and differential diagnosis of maternal disease-specific symptoms and complications, close cooperation should be ensured between experts in neurology, fetal and maternal medicine, as well as neonatology in the case of active disease.
Vaginal delivery is recommended also for women with myasthenia gravis; however, the mode of delivery should depend on the overall condition, i.e., respiratory/motor fatigue. Smooth muscle fibres, and thus uterine contractions, are not affected. However, muscular or perhaps also respiratory exhaustion may occur in the course of labor, potentially making vaginal operative delivery or cesarean section necessary.
Wherever possible, regional anesthetic techniques should be preferred. Epidural anesthesia is also possible. Certain drugs, such as a number of antibiotic classes as well as benzodiazepines, can exacerbate myasthenia gravis and should not be used (Box). Special fetal aspects resulting from the transplacental passage of pathogenic antibodies in myasthenia gravis are described in the section “Fetal monitoring.”
The prevalence of rheumatoid arthritis in women of childbearing age is around 0.2%. Women with rheumatoid arthritis have an approximately one-and-a-half to two-fold increased risk of hypertensive complications in pregnancy (7–10%), fetal growth restriction (15–20%), preterm birth (10–12%), and cesarean delivery (20–42%), even after adjusting for parity (16, 17). Venous thromboembolism occurs between two and four times more frequently than in healthy pregnant women (0.2–0.4%). Preterm birth and growth restriction have been associated with disease activity and higher glucocorticoid doses.
Rheumatoid arthritis activity tends to be favorably affected by pregnancy. Studies using validated instruments to measure disease activity found signs of improvement during pregnancy in 48–60% of women with previously active rheumatoid arthritis (18). Following delivery, 39–50% experienced a flare. For women wishing to become pregnant, conception should be planned for a time when disease activity is absent or low; in addition, maintenance therapy that is compatible with both pregnancy and lactation should be continued if possible, particularly in view of the high risk of flares following birth (19). Long-term pediatric sequelae due to the mother’s disease are not known.
Systemic lupus erythematosus
The initial manifestation of systemic lupus erythematosus predominantly occurs before the age of 30 years. Prevalence is estimated to be 55 per 100,000 in the female population. The incidence of fetal, maternal, and obstetric complications is significant; in addition to preterm birth and growth restriction, these include preeclampsia and thromboembolic disease (20). Disease activity is one of the most important risk factors. For example, the likelihood of preterm birth rises from 5.5% to 33.3% in the case of active systemic lupus erythematosus (21). The highest risk for preterm birth and preeclampsia arises from a combination of high clinical and serological activity. The risk is also increased in the case of positive antiphospholipid antibodies (aPL) and lupus nephritis. The likelihood of flares rises by 60% in pregnant compared to non-pregnant patients. This risk depends on disease activity prior to conception. Treatment with hydroxychloroquine reduces the rate of flares. How good the chances are for a pregnancy with few complications in stable systemic lupus erythematosus is demonstrated by the PROMISSE study, in which 80% of pregnancies had an uncomplicated course and severe flares occurred in only 5% of cases (22). The special fetal aspects resulting from the detection of autoantibodies to the ENA antigens SS-A/Ro and SS-B/La are explained in the section “Fetal monitoring” as well as in Tables 2 and 3. The same applies to women with primary or secondary Sjögren’s syndrome.
Antiphospholipid syndrome develops in the setting of systemic lupus erythematosus in approximately 20% of affected individuals. Antiphospholipid antibodies are associated with a higher risk of thrombosis and obstetric complications, most notably late miscarriage and placental insufficiency. Depending on the clinical and serological constellation, treatment consists of acetylsalicylic acid (ASA) and/or heparin (23).
Pregnancy in systemic lupus erythematosus should be planned after 6–12 months of absent or mild disease activity. During the preconception phase, treatment should be reviewed and an acceptable immunosuppressive therapy either continued or switched to in order to maintain remission. After a change in medication, tolerance and efficacy needs to be followed-up for 6 months. Hydroxychloroquine should always be continued or, if not contraindicated, newly initiated. Low-dose ASA for preeclampsia prevention is recommended in all patients.
In the case of renal involvement, it is best to plan pregnancy during inactive lupus nephritis (at least 6 months), namely, proteinuria <0.5 g/day, normal renal function, and normal blood pressure. In pregnancy, active nephritis is sometimes challenging to distinguish from preeclampsia, since an increase in proteinuria and blood pressure can be suggestive of both. Here, for example, evidence of erythrocyturia, a fall in complement, and symptoms typical of systemic lupus erythematosus should be considered. Acceptable immunosuppressive treatment should also be continued in this situation in order to maintain remission.
Chronic inflammatory bowel disease
The prevalence of chronic inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, is 300 and 400/100 000, respectively, with a peak incidence in the third/fourth decade of life (e11). In the past, many patients with these disorders were extremely reluctant regarding pregnancy and/or continuing disease-specific medication for fear of an unfavorable course (e12). There is evidence from older studies that these patients, as an overall cohort, have a somewhat higher risk for growth restriction and premature birth (e13).
Disease activity at the time of conception has the strongest effect on disease course during pregnancy. Therefore, current guidelines advise that conception be planned during a period of remission. However, the question of how long remission should have been stable remains unanswered—a period of around 6 months can be considered as realistic (24, 25). Under these conditions, about one-third of patients experience a flare during pregnancy. A recent study observed a significantly reduced incidence of recurrence when targeted treatment for inflammatory bowel disease was ongoing at the time of conception (26). This was associated with lower rates of hospitalization and prematurity as well as higher birth weights. On the other hand, active inflammatory bowel disease at the time of conception is associated with preterm birth, growth restriction, and, in all likelihood, a higher rate of early miscarriage (e14).
The long-term disease course is somewhat milder as a result of pregnancy (e15). During the postpartum period and lactation, there is an increased risk of flare that correlates with disease activity in the third trimester and possible treatment de-escalation during pregnancy and in the postpartum phase (e16).
Patients with perianal involvement should receive proctologic treatment in addition to primary, internal medical/gastroenterological, and obstetric/prenatal care. Visceral surgical co-treatment is reasonable in the presence of (intermittent) symptoms of bowel obstruction (25).
The drugs currently used do not have any negative effects on fertility in patients with inflammatory bowel disease. Methotrexate is used to maintain remission, but is strictly contraindicated in pregnancy and must be discontinued at least 3 months prior to conception.
Malnutrition is not an uncommon problem in patients with inflammatory bowel disease; therefore, screening and, if necessary, targeted interventions should be performed before as well as during pregnancy and lactation (27). The German Nutrition Society (Deutsche Gesellschaft für Ernährung) recommends that women take 550 µg/day folic acid as early as 4 weeks prior to conception and during the first trimester. According to the European guideline, iron (or ferritin) and folic acid levels should be monitored and, where necessary, supplemented in high doses (27). In addition to oral iron preparations, which are often poorly tolerated by these patients, modern dextran-free intravenous iron preparations represent an effective and well-tolerated substitution therapy for use in the second and third trimesters (28).
Clinical signs of increased disease activity are challenging to differentiate from symptoms that often develop during pregnancy, such as abdominal pain, nausea, rectal bleeding from hemorrhoids, and symptoms of anal stenosis/constipation. Fecal calprotectin—in contrast to hemoglobin, C-reactive protein, and albumin—is not altered by pregnancy and, as such, appears to be suitable as a predictor of impending flares (e17). Gastrointestinal ultrasound correlates well with fecal calprotectin and has a reliable negative predictive value of approximately 0.9; however, from the 20th gestational week onwards, it is often not possible to adequately visualize the terminal ileum (e18). Since endoscopy is usually not required to make a treatment decision, it should only be performed if strongly indicated (29, e19). In combination with pregnancy-related changes, scar tissue stenosis can progress to subileus or ileus, which may require resection.
With regard to delivery, the European guideline advises avoiding episiotomy, citing the risk of fistula formation (24). The few retrospective studies that have been conducted do not confirm this risk, but these must be interpreted with caution due to a possible selection bias; this also applies to the indication for elective cesarean section in patients with ileal pouch anal anastomosis (30). Crohn’s disease with manifest perianal fistulas or Crohn’s proctitis are indications for elective cesarean section.
If a mother is affected, the child’s risk of developing Crohn’s disease or ulcerative colitis is 2.7% and 3.7%, respectively (e20). There is no evidence of a developmental delay in the child as a result of targeted inflammatory bowel disease therapy during pregnancy (31).
The extent and methods of fetal monitoring are based on the individual risk of the pregnant woman, depending on her general and reproductive history as well as risks over the course of pregnancy (Table 2).
Risks in pregnant women with autoimmune diseases that require extended fetal diagnosis and monitoring are predominantly placenta-related disorders (preeclampsia/growth restriction), most notably in systemic lupus erythematosus and, according to recent data, likely also in Sjögren’s syndrome; less frequently, effects of drug therapy pose a risk.
The extent of growth restriction, gestational age, Doppler findings, and symptoms determine the intervals for the monitoring of fetal growth and wellbeing (e21, e22). Multimodal preeclampsia screening in the first trimester can predict the development of preeclampsia before the 37th gestational week in 75% of cases (e23) and reduce it by 60% in this high-risk group of patients through the administration of 150 mg ASA/day starting before the 16th week of gestation (e24). In the case of systemic lupus erythemathosus, the maternal risk factors are so severe that in the absence of preeclampsia screening, ASA prophylaxis should be given from 12 weeks’ gestation until birth (32, 33, e25, e26, e27, e28); due to the increased rate of peripartum maternal as well as neonatal intracerebral hemorrhage in some studies, this should be given only until the 36th week of gestation (e29, e30).
Transplacental transfer of IgG autoantibodies to the fetus occurs from around the 13th gestational week (e31). SS-A/Ro antibodies are present in 30–40% of pregnant women with systemic lupus erythematosus and in 60–70% of those with Sjögren’s syndrome. Together with SS-B/La antibodies, these can cause neonatal lupus erythematosus. Symptoms such as skin lesions, anemia, and thrombocytopenia are reversible postnatally upon the disappearance of maternal antibodies, but complete congenital heart block (CCHB)—often the only symptom of neonatal lupus erythematosus—is not. CCHB has high perinatal mortality as well as short- and long-term morbidity (Table 3) (34, 35, e32, e33).
Whereas anti-Ro52 (SS-A) antibodies can induce inflammation in the conduction system, and even myocarditis, Ro60 and La48 antibodies can have a modifying effect (e33-e37, 34, 35). Table 3 contains information on the management of pregnant women with known SS-A/Ro antibodies as well as on the diagnosis of immune-mediated CCHB in the fetus.
In the case of myasthenia gravis, acetylcholine receptor (AChR) autoantibodies that cross the placenta may decrease the number and/or function of AChR at the motor end-plate. AChR consists of two α-subunits, one β-, one δ-, and one γ-subunit (fetal form) in developing muscle fibers and, from the 30th gestational week, one ε-subunit (adult form) in the developed muscle fibers (e38). Maternal autoantibodies are mostly directed against the α-subunit. They can cause transient congenital myasthenia in 10–20% of newborns, characterized by hypotension, weak suckling, dysphagia, weak crying, and, in rare cases, respiratory weakness and aspiration. Acetylcholinesterase inhibitor therapy is indicated in such cases (14, 36, e39).
More rarely, autoantibodies are directed against the fetal γ-subunit. These may be present in isolation in asymptomatic pregnant women and cause fetal AChR inactivation syndrome (e40) in the form of arthrogryposis multiplex, rarely also fetal akinesia deformation sequence with multiple joint contractures and pulmonary hypoplasia (36, e39), as well as myopathy (e40, e41). The prenatal diagnosis in myasthenia gravis includes a careful assessment of joint position and motor function (e41).
Conflict of interest statement
Prof. Fischer Betz received honoraria for consultancy work from UCB. She received honoraria for lectures from Abbvie, Biogen, BMS, Chugai, GSK, Novartis, Medac, MSD, Pfizer, and UCB. She received travel cost reimbursement from Abbvie, Biogen, BMS, Chugai, GSK, Novartis, Medac, MSD, Pfizer, and UCB. She is a member of the board of the DGRH. She received writing support from UCB.
Prof. Hellwig received honoraria for consultancy work from Biogen, Roche, Merck, and Genzyme. She received reimbursement of congress participation fees from Biogen, Teva, Novartis, Roche, and Merck. She received travel cost reimbursement from Biogen, Teva, Novartis, and Merck. She received honoraria for preparing scientific advanced training events from Bayer, Biogen, Teva, Novartis, Roche, and Merck. For conducting clinical trials, she received funds from Merck, Roche, and Biogen. She received funds from Biogen, Bayer, Genzyme, Merck, Novartis, Teva, and Roche for a research project of her own initiation.
The remaining authors declare that no conflict of interests exists.
Manuscript received on 19 April 2021, revised version accepted on 1 October 2021.
Translated from the original German by Christine Rye.
Prof. Dr. med. Waltraut Maria Merz, M.Sc.
Universitätsklinikum Bonn, Zentrum für Geburtshilfe und Frauenheilkunde
Venusberg-Campus 1, 53127 Bonn, Germany
Cite this as:
Merz WM, Fischer-Betz R, Hellwig K, Lamprecht G, Gembruch U: Pregnancy and autoimmune disease: diseases of the nervous system, connective tissue, and the bowel. Dtsch Arztebl Int 2022; 119: 145–56. DOI: 10.3238/arztebl.m2021.0353
Department of Rheumatology and Hiller, Forschungszentrum University Hospital Düsseldorf: Prof. Dr. med. Rebecca Fischer-Betz
Katholisches Klinikum Bochum, Neurology Clinic,Clinic of Ruhr-Universität Bochum: Prof. Dr. med. Kerstin Hellwig
Department of Medicine II, Division of Gastroenterology and Endocrinology, University Medical Center Rostock: Prof. Dr. med. Georg Lamprecht
Department of Obstetrics and Prenatal Medicine, Center for Obstetrics and Gynecology, University Hospital Bonn: Prof. Dr. med. Ulrich Gembruch
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