DÄ internationalArchive9/2022Pregnancy and Autoimmune Disease

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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

Merz, W M; Fischer-Betz, R; Hellwig, K; Lamprecht, G; Gembruch, U

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.

LNSLNS

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).

Learning objectives

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.

Care

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).

Pregnancy, birth, and the puerperium in autoimmune diseases of the nervous system, connective tissue, and the bowel
Table 1
Pregnancy, birth, and the puerperium in autoimmune diseases of the nervous system, connective tissue, and the bowel
Drugs for the treatment of autoimmune diseases of the nervous system, connective tissue, and the bowel during pregnancy and lactation
eTable
Drugs for the treatment of autoimmune diseases of the nervous system, connective tissue, and the bowel during pregnancy and lactation

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

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.”

Infobox with important addresses
Box
Infobox with important addresses

Rheumatoid arthritis

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).

Fetal monitoring

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).

Recommended prenatal tests for the purposes of diagnosis and monitoring
Table 2
Recommended prenatal tests for the purposes of diagnosis and monitoring

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).

Approach for pregnant women with known SS-A/Ro antibodies and for women diagnosed with fetal congenital complete heart block (CCHB)
Table 3
Approach for pregnant women with known SS-A/Ro antibodies and for women diagnosed with fetal congenital complete heart block (CCHB)

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.

Corresponding author
Prof. Dr. med. Waltraut Maria Merz, M.Sc.
Universitätsklinikum Bonn, Zentrum für Geburtshilfe und Frauenheilkunde
Venusberg-Campus 1, 53127 Bonn, Germany
waltraut.merz@ukbonn.de

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

Supplementary material

eReferences, eTables:
www.aerzteblatt-international.de/m2021.0353

1.
Jølving LR, Nielsen J, Kesmodel US, Nielsen RG, Beck-Nielsen SS, Nørgård BM: Prevalence of maternal chronic diseases during pregnancy – a nationwide population based study from 1989 to 2013. Acta Obstet Gynecol Scand 2016; 95: 1295–304 CrossRef MEDLINE
2.
Kersten I, Lange AE, Haas JP, et al.: Chronic diseases in pregnant women: prevalence and birth outcomes based on the SNiP-study. BMC Pregnancy Childbirth 2014; 14: 75 CrossRef MEDLINE MEDLINE
3.
Brown CC, Adams CE, George KE, Moore JE: Associations between comorbidities and severe maternal morbidity. Obstet Gynecol 2020; 136: 892–901 CrossRef
4.
Knight M, Bunch K, Tuffnell D, et al. (eds): Saving lives, improving mothers’ care: lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity. Oxford 2019; 2015–7.
5.
Richtlinien des Gemeinsamen Bundesausschusses über die ärztliche Betreuung während der Schwangerschaft und nach der Entbindung („Mutterschafts-Richtlinien“): In der Fassung vom 10. Dezember 1985 (veröffentlicht im Bundesanzeiger Nr. 60 a vom 27. März 1986) zuletzt geändert am 20. August 2020 veröffentlicht im Bundesanzeiger AT 23.11.2020 B3 in Kraft getreten am 24. November 2020.
6.
European Medicines Agency/Committee for Medicinal Products for Human Use (EMEA/CHMP): Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling. London 2008.
7.
Department of Health and Human Services Food and Drug: Content and format of labeling for human prescription drug and biological products: requirements for pregnancy and lactation labeling 2014. www.federalregister.gov/documents/2014/12/04/2014-28241/content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements-for (last accessed on 8 February 2022).
8.
Krysko KM, Graves JS, Dobson R, et al.: Sex effects across the lifespan in women with multiple sclerosis. Ther Adv Neurol Disord 2020; 13: 1756286420936166 CrossRef MEDLINE PubMed Central
9.
Mao-Draayer Y, Thiel S, Mills EA, et al.: Neuromyelitis optica spectrum disorders and pregnancy: therapeutic considerations. Nat Rev Neurol 2020; 16: 154–70 CrossRef MEDLINE
10.
Hellwig K, Haghikia A, Gold R: Parenthood and immunomodulation in patients with multiple sclerosis. J Neurol 2010; 257: 580–3 CrossRef MEDLINE
11.
Kümpfel T, Thiel S, Meinl I, et al.: Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: a cohort study from Germany. Neurol Neuroimmunol Neuroinflamm 2020; 8: e913 CrossRef MEDLINE PubMed Central
12.
Ciplea AI, Langer-Gould A, Vries Ad, et al.: Monoclonal antibody treatment during pregnancy and/or lactation in women with MS or neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2020; 7: e723 CrossRef MEDLINE PubMed Central
13.
Altintas A, Dargvainiene J, Schneider-Gold C, et al.: Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG). Ther Adv Neurol Disord 2020; 13: 1756286420949808 CrossRef MEDLINE PubMed Central
14.
Grover KM, Sripathi N: Myasthenia gravis and pregnancy. Muscle Nerve 2020; 62: 664–72 CrossRef MEDLINE
15.
Nicholls-Dempsey L, Czuzoj-Shulman N, Abenhaim HA: Maternal and neonatal outcomes among pregnant women with myasthenia gravis. J Perinat Med 2020; 48: 793–8 CrossRef MEDLINE
16.
Kishore S, Mittal V, Majithia V: Obstetric outcomes in women with rheumatoid arthritis: results from nationwide inpatient sample database 2003–2011. Semin Arthritis Rheum 2019; 49: 236–40 CrossRef MEDLINE
17.
Wallenius M, Salvesen KÅ, Daltveit AK, Skomsvoll JF: Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand 2014; 93: 302–7 CrossRef MEDLINE
18.
Jethwa H, Lam S, Smith C, Giles I: Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J Rheumatol 2019; 46: 245–50 CrossRef MEDLINE
19.
Sammaritano LR, Bermas BL, Chakravarty EE, et al.: 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 2020; 72: 529–56 CrossRef MEDLINE
20.
Bundhun PK, Soogund MZS, Huang F: Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001–2016. J Autoimmun 2017; 79: 17–27 CrossRef MEDLINE
21.
Skorpen CG, Lydersen S, Gilboe I-M, et al.: Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study. Ann Rheum Dis 2018; 77: 264–9 CrossRef MEDLINE
22.
Buyon JP, Kim MY, Guerra MM, et al.: Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015; 163: 153–63 CrossRef MEDLINE PubMed Central
23.
Tektonidou MG, Andreoli L, Limper M, et al.: EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78: 1296–304 CrossRef MEDLINE
24.
van der Woude CJ, Ardizzone S, Bengtson MB, et al.: The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis 2015; 9: 107–24 CrossRef MEDLINE
25.
Mahadevan U, Robinson C, Bernasko N, et al.: Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Inflamm Bowel Dis 2019; 25: 627–41 CrossRef CrossRef
26.
Rottenstreich A, Shifman Z, Grisaru-Granovksy S, Mishael T, Koslowsky B, Bar-Gil Shitrit A: Factors associated with inflammatory bowel disease flare during pregnancy among women with preconception remission. Dig Dis Sci 2021; 66: 1189–94 CrossRef MEDLINE
27.
Forbes A, Escher J, Hébuterne X, et al.: ESPEN guideline: clinical nutrition in inflammatory bowel disease. Clin Nutr 2017; 36: 321–47 CrossRef MEDLINE
28.
Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J: UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020; 188: 819–30 CrossRef MEDLINE
29.
Ludvigsson JF, Lebwohl B, Ekbom A, et al.: Outcomes of pregnancies for women undergoing endoscopy while they were pregnant: a nationwide cohort study. Gastroenterology 2017; 152: 554–63.e9 CrossRef MEDLINE
30.
Foulon A, Dupas J-L, Sabbagh C, et al.: Defining the most appropriate delivery mode in women with inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2017; 23: 712–20 CrossRef MEDLINE
31.
Mahadevan U, Long MD, Kane SV, et al.: Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology 2021; 160: 1131–9 CrossRef MEDLINE
32.
ACOG Committee: Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018; 132: e44–e52 CrossRef MEDLINE
33.
National Institute for Health and Care Excellence: Hypertension in pregnancy: diagnosis and management (NG133). www.nice.org.uk/guidance/ng133 (last accessed on 8 February 2022).
34.
Pruetz JD, Miller JC, Loeb GE, Silka MJ, Bar-Cohen Y, Chmait RH: Prenatal diagnosis and management of congenital complete heart block. Birth Defects Res 2019; 111: 380–8 CrossRef MEDLINE PubMed Central
35.
Fredi M, Andreoli L, Bacco B, et al.: First report of the Italian registry on immune-mediated congenital heart block (Lu.Ne Registry). Front Cardiovasc Med 2019; 6: 11 CrossRef MEDLINE PubMed Central
36.
Gilhus NE: Myasthenia gravis can have consequences for pregnancy and the developing child. Front Neurol 2020; 11: 554 CrossRef MEDLINE PubMed Central
e1.
Mor G, Aldo P, Alvero AB: The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017; 17: 469–82 CrossRef MEDLINE
e2.
Han VX, Patel S, Jones HF, et al.: Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Transl Psychiatry 2021; 11: 71 CrossRef MEDLINE PubMed Central
e3.
Luyckx VA, Brenner BM: Birth weight, malnutrition and kidney-associated outcomes—a global concern. Nat Rev Nephrol 2015; 11: 135–49 CrossRef MEDLINE
e4.
Warrington NM, Beaumont RN, Horikoshi M, et al.: Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet 2019; 51: 804–14 CrossRef MEDLINE PubMed Central
e5.
Huang T, Wang T, Zheng Y, et al.: Association of birth weight with type 2 diabetes and glycemic traits: a Mendelian randomization study. JAMA Netw Open 2019; 2: e1910915.
e6.
Mylotte D, Pilote L, Ionescu-Ittu R, et al.: Specialized adult congenital heart disease care: the impact of policy on mortality. Circulation 2014; 129: 1804–12 CrossRef MEDLINE
e7.
Li DK, Yang C, Andrade S, Tavares V, Ferber JR: Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011; 343: d5931 CrossRef MEDLINE PubMed Central
e8.
Patel SS, Burns TL: Nongenetic risk factors and congenital heart defects. Pediatr Cardiol 2013; 34: 1535–55 CrossRef MEDLINE
e9.
Embryotox – Arzneimittelsicherheit in Schwangerschaft und Stillzeit. www.embryotox.de (last accessed on 8 February 2022).
e10.
Orton SM, Herrera BM, Yee IM, et al.: Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006; 5: 932–6 CrossRef
e11.
Ng SC, Shi HY, Hamidi N, et al.: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017; 390: 2769–78 CrossRef
e12.
Selinger CP, Eaden J, Selby W, et al.: Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views. J Crohns Colitis 2013; 7: e206–13 CrossRef MEDLINE
e13.
O’Toole A, Nwanne O, Tomlinson T: Inflammatory bowel disease increases risk of adverse pregnancy outcomes: a meta-analysis. Dig Dis Sci 2015; 60: 2750–61 CrossRef MEDLINE
e14.
Meyer A, Drouin J, Weill A, Carbonnel F, Dray-Spira R: Pregnancy in women with inflammatory bowel disease: a French nationwide study 2010–2018. Aliment Pharmacol Ther 2020; 52: 1480–90.
e15.
Riis L, Vind I, Politi P, et al.: Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am J Gastroenterol 2006; 101: 1539–45 CrossRef MEDLINE
e16.
Yu A, Friedman S, Ananthakrishnan AN: Incidence and predictors of flares in the postpartum year among women with inflammatory bowel disease. Inflamm Bowel Dis 2020; 26: 1926–32 CrossRef MEDLINE PubMed Central
e17.
Tandon P, Leung K, Yusuf A, Huang VW: Noninvasive methods for assessing inflammatory bowel disease activity in pregnancy: a systematic review. J Clin Gastroenterol 2019; 53: 574–81 CrossRef MEDLINE
e18.
Flanagan E, Wright EK, Begun J, et al.: Monitoring inflammatory bowel disease in pregnancy using gastrointestinal ultrasonography. J Crohns Colitis 2020; 14: 1405–12 CrossRef MEDLINE
e19.
Cappell MS: Risks versus benefits of gastrointestinal endoscopy during pregnancy. Nat Rev Gastroenterol Hepatol 2011; 8: 610–34 CrossRef MEDLINE
e20.
Santos MPC, Gomes C, Torres J: Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2018; 31: 14–23 CrossRef MEDLINE PubMed Central
e21.
Kehl S, Dötsch J, Hecher K, et al.: Intrauterine growth restriction. Guideline of the German Society of Gynecology and Obstetrics (S2k-Level, AWMF Registry No. 015/080, October 2016). Geburtshilfe Frauenheilkd 2017; 77: 1157–73 CrossRef MEDLINE PubMed Central
e22.
Lees CC, Stampalija T, Baschat A, et al.: ISUOG practice guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol 2020; 56: 298–312 CrossRef MEDLINE
e23.
O’Gorman N, Wright D, Poon LC, et al.: Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation. Ultrasound Obstet Gynecol 2017; 49: 751–5 CrossRef CrossRef
e24.
Rolnik DL, Wright D, Poon LC, et al.: Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377: 613–22 CrossRef MEDLINE
e25.
Seo MR, Chae J, Kim YM, et al.: Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia. Lupus 2019; 28: 722–30 CrossRef MEDLINE
e26.
Canti V, Scarrone M, Lorenzo R de, et al.: Low incidence of intrauterine growth restriction in pregnant patients with systemic lupus erythematosus taking hydroxychloroquine. Immunol Med 2021: 1–7 CrossRef MEDLINE
e27.
Liu Y, Zhang Y, Wei Y, Yang H: Effect of hydroxychloroquine on preeclampsia in lupus pregnancies: a propensity score-matched analysis and meta-analysis. Arch Gynecol Obstet 2021; 303: 435–41 CrossRef MEDLINE
e28.
Guillotin V, Bouhet A, Barnetche T, et al.: Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: a systematic review and meta-analysis. Joint Bone Spine 2018; 85: 663–8 CrossRef MEDLINE
e29.
Duley L, Meher S, Hunter KE, Seidler AL, Askie LM: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2019; 2019 CrossRef MEDLINE PubMed Central
e30.
Hastie R, Tong S, Wikström A-K, Sandström A, Hesselman S, Bergman L: Aspirin use during pregnancy and the risk of bleeding complications: a Swedish population-based cohort study. Am J Obstet Gynecol 2021; 224: 95.e1–95.e12 CrossRef MEDLINE
e31.
Ciobanu AM, Dumitru AE, Gica N, Botezatu R, Peltecu G, Panaitescu AM: Benefits and risks of IgG transplacental transfer. Diagnostics (Basel) 2020; 10: 58 CrossRef MEDLINE PubMed Central
e32.
Mofors J, Eliasson H, Ambrosi A, et al.: Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero. Ann Rheum Dis 2019; 78: 696–703 CrossRef MEDLINE
e33.
Limaye MA, Buyon JP, Cuneo BF, Mehta-Lee SS: A review of fetal and neonatal consequences of maternal systemic lupus erythematosus. Prenat Diagn 2020; 40: 1066–76 CrossRef MEDLINE
e34.
Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK: Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004; 110: 1542–8 CrossRef MEDLINE
e35.
Hutter D, Silverman ED, Jaeggi ET: The benefits of transplacental treatment of isolated congenital complete heart block associated with maternal anti-Ro/SSA antibodies: a review. Scand J Immunol 2010; 72: 235–41 CrossRef MEDLINE
e36.
Izmirly PM, Saxena A, Sahl SK, et al.: Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis 2016; 75: 1161–5 CrossRef MEDLINE PubMed Central
e37.
Jobe AH, Goldenberg RL: Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am J Obstet Gynecol 2018; 219: 62–74 CrossRef MEDLINE
e38.
Saxena A, Stevens J, Cetin H, et al.: Characterization of an anti-fetal AChR monoclonal antibody isolated from a myasthenia gravis patient. Sci Rep 2017; 7: 14426 CrossRef MEDLINE PubMed Central
e39.
Gilhus NE, Hong Y: Maternal myasthenia gravis represents a risk for the child through autoantibody transfer, immunosuppressive therapy and genetic influence. Eur J Neurol 2018; 25: 1402–9 CrossRef MEDLINE
e40.
Hacohen Y, Jacobson LW, Byrne S, et al.: Fetal acetylcholine receptor inactivation syndrome: a myopathy due to maternal antibodies. Neurol Neuroimmunol Neuroinflamm 2015; 2: e57 CrossRef MEDLINE PubMed Central
e41.
Tjon JK, Tan-Sindhunata GM, Bugiani M, et al.: Fetal akinesia deformation sequence, arthrogryposis multiplex congenita, and bilateral clubfeet: is motor assessment of additional value for in utero diagnosis? A 10-year cohort study. Prenat Diagn 2019; 39: 219–31 CrossRef MEDLINE PubMed Central
e42.
Lamb CA, Kennedy NA, Raine T, et al.: British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68: 1–106 CrossRef MEDLINE PubMed Central
e43.
Wagner N, Assmus F, Arendt G, et al.: Impfen bei Immundefizienz: Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (IV) Impfen bei Autoimmunkrankheiten, bei anderen chronisch-entzündlichen Erkrankungen und unter immunmodulatorischer Therapie. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2019; 494–515 CrossRef MEDLINE
e44.
Briggs GG, Towers CV, Freeman RK: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Philadelphia, PA: Wolters Kluwer 2017.
e45.
Litwinska M, Litwinska E, Lisnere K, Syngelaki A, Wright A, Nicolaides KH: Stratification of pregnancy care based on risk of pre-eclampsia derived from uterine artery doppler at 19–24 weeks’ gestation. Ultrasound Obstet Gynecol 2021; 58: 360–8 CrossRef MEDLINE
e46.
Chaoui R, Heling K, Mielke G, Hofbeck M, Ge mbruch U: [Quality standards of the DEGUM for performance of fetal echocardiography]. Ultraschall Med 2008; 29: 197–200 CrossRef MEDLINE
e47.
Merz E, Eichhorn KH, Kaisenberg C, Schramm T: [Updated quality requirements regarding secondary differentiated ultrasound examination in prenatal diagnostics (= DEGUM level II) in the period from 18 + 0 to 21 + 6 weeks of gestation]. Ultraschall Med 2012: 33: 593–6.
e48.
Kozlowski P, Burkhardt T, Gembruch U, et al.: [DEGUM, ÖGUM, SGUM and FMF Germany recommendations for the implementation of first-trimester screening, detailed ultrasound, cell-free DNA screening and diagnostic procedures]. Ultraschall Med 2019: 40: 176–93 CrossRef MEDLINE
e49.
Phoon CKL, Kim MY, Buyon JP, Friedman DM: Finding the “PR-fect” solution: what is the best tool to measure fetal cardiac PR intervals for the detection and possible treatment of early conduction disease? Congenit Heart Dis 2012: 7: 349–60 CrossRef MEDLINE MEDLINE
e50.
Sonesson SE, Ambrosi A, Wahren-Herlenius M: Benefits of fetal echocardiographic surveillance in pregnancies at risk of congenital heart block: single-center study of 212 anti-Ro52-positive pregnancies. Ultrasound Obstet Gynecol 2019: 54: 87–95 CrossRef MEDLINE
e51.
Bergman G, Wahren-Herlenius M, Sonesson SE: Diagnostic precision of doppler flow echocardiography in fetuses at risk for atrioventricular block. Ultrasound Obstet Gynecol 2010: 36: 561–6 CrossRef MEDLINE
e52.
Kan N, Silverman ED, Kingdom J, Dutil N, Laskin C, Jaeggi E: Serial echocardiography for immune-mediated heart disease in the fetus: results of a risk-based prospective surveillance strategy. Prenat Diagn 2017: 37: 375–82 CrossRef MEDLINE
e53.
Saito M, Silverman E, Golding F, et al.: Effects of transplacental dexamethasone therapy on fetal immune-mediated complete heart block. Fetal Diagn Ther 2021: 48: 183–8 CrossRef MEDLINE
e54.
Cuneo BF, Sonesson S-E, Levasseur S, et al.: Home monitoring for fetal heart rhythm during anti-Ro pregnancies. J Am Coll Cardiol 2018: 72: 1940–51 CrossRef MEDLINE
e55.
Cuneo BF: Fetal bradycardia. In: Yagel S, Silverman NH, Gembruch U (eds): Fetal cardiology: embryology, genetics, physiology, echocardiographic evaluation, diagnosis, and perinatal management of cardiac diseases. Boca Raton: CRC Press, Taylor & Francis Group 2019; 515–29.
e56.
Strasburger JF, Wacker-Gussmann A: Congenital heart block in subsequent pregnancies of SSA/Ro-positive mothers: cutting recurrence in half. J Am Coll Cardiol 2020; 76: 303–5 CrossRef MEDLINE PubMed Central
e57.
Friedman DM, Kim M, Costedoat-Chalumeau N, et al.: Electrocardiographic QT intervals in infants exposed to hydroxychloroquine throughout gestation. Circ Arrhythm Electrophysiol 2020; 13: e008686 CrossRef
Department of Obstetrics and Prenatal Medicine, Center for Obstetrics and Gynecology, University Hospital Bonn: Prof. Dr. med. Waltraut Maria Merz, M. Sc.
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
Infobox with important addresses
Box
Infobox with important addresses
Pregnancy, birth, and the puerperium in autoimmune diseases of the nervous system, connective tissue, and the bowel
Table 1
Pregnancy, birth, and the puerperium in autoimmune diseases of the nervous system, connective tissue, and the bowel
Recommended prenatal tests for the purposes of diagnosis and monitoring
Table 2
Recommended prenatal tests for the purposes of diagnosis and monitoring
Approach for pregnant women with known SS-A/Ro antibodies and for women diagnosed with fetal congenital complete heart block (CCHB)
Table 3
Approach for pregnant women with known SS-A/Ro antibodies and for women diagnosed with fetal congenital complete heart block (CCHB)
Drugs for the treatment of autoimmune diseases of the nervous system, connective tissue, and the bowel during pregnancy and lactation
eTable
Drugs for the treatment of autoimmune diseases of the nervous system, connective tissue, and the bowel during pregnancy and lactation
1.Jølving LR, Nielsen J, Kesmodel US, Nielsen RG, Beck-Nielsen SS, Nørgård BM: Prevalence of maternal chronic diseases during pregnancy – a nationwide population based study from 1989 to 2013. Acta Obstet Gynecol Scand 2016; 95: 1295–304 CrossRef MEDLINE
2.Kersten I, Lange AE, Haas JP, et al.: Chronic diseases in pregnant women: prevalence and birth outcomes based on the SNiP-study. BMC Pregnancy Childbirth 2014; 14: 75 CrossRef MEDLINE MEDLINE
3.Brown CC, Adams CE, George KE, Moore JE: Associations between comorbidities and severe maternal morbidity. Obstet Gynecol 2020; 136: 892–901 CrossRef
4.Knight M, Bunch K, Tuffnell D, et al. (eds): Saving lives, improving mothers’ care: lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity. Oxford 2019; 2015–7.
5.Richtlinien des Gemeinsamen Bundesausschusses über die ärztliche Betreuung während der Schwangerschaft und nach der Entbindung („Mutterschafts-Richtlinien“): In der Fassung vom 10. Dezember 1985 (veröffentlicht im Bundesanzeiger Nr. 60 a vom 27. März 1986) zuletzt geändert am 20. August 2020 veröffentlicht im Bundesanzeiger AT 23.11.2020 B3 in Kraft getreten am 24. November 2020.
6.European Medicines Agency/Committee for Medicinal Products for Human Use (EMEA/CHMP): Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling. London 2008.
7.Department of Health and Human Services Food and Drug: Content and format of labeling for human prescription drug and biological products: requirements for pregnancy and lactation labeling 2014. www.federalregister.gov/documents/2014/12/04/2014-28241/content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements-for (last accessed on 8 February 2022).
8.Krysko KM, Graves JS, Dobson R, et al.: Sex effects across the lifespan in women with multiple sclerosis. Ther Adv Neurol Disord 2020; 13: 1756286420936166 CrossRef MEDLINE PubMed Central
9.Mao-Draayer Y, Thiel S, Mills EA, et al.: Neuromyelitis optica spectrum disorders and pregnancy: therapeutic considerations. Nat Rev Neurol 2020; 16: 154–70 CrossRef MEDLINE
10.Hellwig K, Haghikia A, Gold R: Parenthood and immunomodulation in patients with multiple sclerosis. J Neurol 2010; 257: 580–3 CrossRef MEDLINE
11.Kümpfel T, Thiel S, Meinl I, et al.: Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: a cohort study from Germany. Neurol Neuroimmunol Neuroinflamm 2020; 8: e913 CrossRef MEDLINE PubMed Central
12.Ciplea AI, Langer-Gould A, Vries Ad, et al.: Monoclonal antibody treatment during pregnancy and/or lactation in women with MS or neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2020; 7: e723 CrossRef MEDLINE PubMed Central
13.Altintas A, Dargvainiene J, Schneider-Gold C, et al.: Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG). Ther Adv Neurol Disord 2020; 13: 1756286420949808 CrossRef MEDLINE PubMed Central
14.Grover KM, Sripathi N: Myasthenia gravis and pregnancy. Muscle Nerve 2020; 62: 664–72 CrossRef MEDLINE
15.Nicholls-Dempsey L, Czuzoj-Shulman N, Abenhaim HA: Maternal and neonatal outcomes among pregnant women with myasthenia gravis. J Perinat Med 2020; 48: 793–8 CrossRef MEDLINE
16.Kishore S, Mittal V, Majithia V: Obstetric outcomes in women with rheumatoid arthritis: results from nationwide inpatient sample database 2003–2011. Semin Arthritis Rheum 2019; 49: 236–40 CrossRef MEDLINE
17.Wallenius M, Salvesen KÅ, Daltveit AK, Skomsvoll JF: Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand 2014; 93: 302–7 CrossRef MEDLINE
18.Jethwa H, Lam S, Smith C, Giles I: Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J Rheumatol 2019; 46: 245–50 CrossRef MEDLINE
19.Sammaritano LR, Bermas BL, Chakravarty EE, et al.: 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 2020; 72: 529–56 CrossRef MEDLINE
20.Bundhun PK, Soogund MZS, Huang F: Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001–2016. J Autoimmun 2017; 79: 17–27 CrossRef MEDLINE
21.Skorpen CG, Lydersen S, Gilboe I-M, et al.: Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study. Ann Rheum Dis 2018; 77: 264–9 CrossRef MEDLINE
22.Buyon JP, Kim MY, Guerra MM, et al.: Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015; 163: 153–63 CrossRef MEDLINE PubMed Central
23.Tektonidou MG, Andreoli L, Limper M, et al.: EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78: 1296–304 CrossRef MEDLINE
24.van der Woude CJ, Ardizzone S, Bengtson MB, et al.: The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis 2015; 9: 107–24 CrossRef MEDLINE
25.Mahadevan U, Robinson C, Bernasko N, et al.: Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Inflamm Bowel Dis 2019; 25: 627–41 CrossRef CrossRef
26.Rottenstreich A, Shifman Z, Grisaru-Granovksy S, Mishael T, Koslowsky B, Bar-Gil Shitrit A: Factors associated with inflammatory bowel disease flare during pregnancy among women with preconception remission. Dig Dis Sci 2021; 66: 1189–94 CrossRef MEDLINE
27.Forbes A, Escher J, Hébuterne X, et al.: ESPEN guideline: clinical nutrition in inflammatory bowel disease. Clin Nutr 2017; 36: 321–47 CrossRef MEDLINE
28.Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J: UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020; 188: 819–30 CrossRef MEDLINE
29.Ludvigsson JF, Lebwohl B, Ekbom A, et al.: Outcomes of pregnancies for women undergoing endoscopy while they were pregnant: a nationwide cohort study. Gastroenterology 2017; 152: 554–63.e9 CrossRef MEDLINE
30.Foulon A, Dupas J-L, Sabbagh C, et al.: Defining the most appropriate delivery mode in women with inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2017; 23: 712–20 CrossRef MEDLINE
31.Mahadevan U, Long MD, Kane SV, et al.: Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology 2021; 160: 1131–9 CrossRef MEDLINE
32.ACOG Committee: Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018; 132: e44–e52 CrossRef MEDLINE
33.National Institute for Health and Care Excellence: Hypertension in pregnancy: diagnosis and management (NG133). www.nice.org.uk/guidance/ng133 (last accessed on 8 February 2022).
34.Pruetz JD, Miller JC, Loeb GE, Silka MJ, Bar-Cohen Y, Chmait RH: Prenatal diagnosis and management of congenital complete heart block. Birth Defects Res 2019; 111: 380–8 CrossRef MEDLINE PubMed Central
35.Fredi M, Andreoli L, Bacco B, et al.: First report of the Italian registry on immune-mediated congenital heart block (Lu.Ne Registry). Front Cardiovasc Med 2019; 6: 11 CrossRef MEDLINE PubMed Central
36.Gilhus NE: Myasthenia gravis can have consequences for pregnancy and the developing child. Front Neurol 2020; 11: 554 CrossRef MEDLINE PubMed Central
e1.Mor G, Aldo P, Alvero AB: The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017; 17: 469–82 CrossRef MEDLINE
e2.Han VX, Patel S, Jones HF, et al.: Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Transl Psychiatry 2021; 11: 71 CrossRef MEDLINE PubMed Central
e3.Luyckx VA, Brenner BM: Birth weight, malnutrition and kidney-associated outcomes—a global concern. Nat Rev Nephrol 2015; 11: 135–49 CrossRef MEDLINE
e4.Warrington NM, Beaumont RN, Horikoshi M, et al.: Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet 2019; 51: 804–14 CrossRef MEDLINE PubMed Central
e5.Huang T, Wang T, Zheng Y, et al.: Association of birth weight with type 2 diabetes and glycemic traits: a Mendelian randomization study. JAMA Netw Open 2019; 2: e1910915.
e6.Mylotte D, Pilote L, Ionescu-Ittu R, et al.: Specialized adult congenital heart disease care: the impact of policy on mortality. Circulation 2014; 129: 1804–12 CrossRef MEDLINE
e7.Li DK, Yang C, Andrade S, Tavares V, Ferber JR: Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011; 343: d5931 CrossRef MEDLINE PubMed Central
e8.Patel SS, Burns TL: Nongenetic risk factors and congenital heart defects. Pediatr Cardiol 2013; 34: 1535–55 CrossRef MEDLINE
e9.Embryotox – Arzneimittelsicherheit in Schwangerschaft und Stillzeit. www.embryotox.de (last accessed on 8 February 2022).
e10.Orton SM, Herrera BM, Yee IM, et al.: Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006; 5: 932–6 CrossRef
e11.Ng SC, Shi HY, Hamidi N, et al.: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017; 390: 2769–78 CrossRef
e12.Selinger CP, Eaden J, Selby W, et al.: Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views. J Crohns Colitis 2013; 7: e206–13 CrossRef MEDLINE
e13.O’Toole A, Nwanne O, Tomlinson T: Inflammatory bowel disease increases risk of adverse pregnancy outcomes: a meta-analysis. Dig Dis Sci 2015; 60: 2750–61 CrossRef MEDLINE
e14.Meyer A, Drouin J, Weill A, Carbonnel F, Dray-Spira R: Pregnancy in women with inflammatory bowel disease: a French nationwide study 2010–2018. Aliment Pharmacol Ther 2020; 52: 1480–90.
e15.Riis L, Vind I, Politi P, et al.: Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am J Gastroenterol 2006; 101: 1539–45 CrossRef MEDLINE
e16.Yu A, Friedman S, Ananthakrishnan AN: Incidence and predictors of flares in the postpartum year among women with inflammatory bowel disease. Inflamm Bowel Dis 2020; 26: 1926–32 CrossRef MEDLINE PubMed Central
e17.Tandon P, Leung K, Yusuf A, Huang VW: Noninvasive methods for assessing inflammatory bowel disease activity in pregnancy: a systematic review. J Clin Gastroenterol 2019; 53: 574–81 CrossRef MEDLINE
e18.Flanagan E, Wright EK, Begun J, et al.: Monitoring inflammatory bowel disease in pregnancy using gastrointestinal ultrasonography. J Crohns Colitis 2020; 14: 1405–12 CrossRef MEDLINE
e19.Cappell MS: Risks versus benefits of gastrointestinal endoscopy during pregnancy. Nat Rev Gastroenterol Hepatol 2011; 8: 610–34 CrossRef MEDLINE
e20.Santos MPC, Gomes C, Torres J: Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2018; 31: 14–23 CrossRef MEDLINE PubMed Central
e21.Kehl S, Dötsch J, Hecher K, et al.: Intrauterine growth restriction. Guideline of the German Society of Gynecology and Obstetrics (S2k-Level, AWMF Registry No. 015/080, October 2016). Geburtshilfe Frauenheilkd 2017; 77: 1157–73 CrossRef MEDLINE PubMed Central
e22.Lees CC, Stampalija T, Baschat A, et al.: ISUOG practice guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol 2020; 56: 298–312 CrossRef MEDLINE
e23.O’Gorman N, Wright D, Poon LC, et al.: Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation. Ultrasound Obstet Gynecol 2017; 49: 751–5 CrossRef CrossRef
e24.Rolnik DL, Wright D, Poon LC, et al.: Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377: 613–22 CrossRef MEDLINE
e25.Seo MR, Chae J, Kim YM, et al.: Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia. Lupus 2019; 28: 722–30 CrossRef MEDLINE
e26.Canti V, Scarrone M, Lorenzo R de, et al.: Low incidence of intrauterine growth restriction in pregnant patients with systemic lupus erythematosus taking hydroxychloroquine. Immunol Med 2021: 1–7 CrossRef MEDLINE
e27.Liu Y, Zhang Y, Wei Y, Yang H: Effect of hydroxychloroquine on preeclampsia in lupus pregnancies: a propensity score-matched analysis and meta-analysis. Arch Gynecol Obstet 2021; 303: 435–41 CrossRef MEDLINE
e28.Guillotin V, Bouhet A, Barnetche T, et al.: Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: a systematic review and meta-analysis. Joint Bone Spine 2018; 85: 663–8 CrossRef MEDLINE
e29.Duley L, Meher S, Hunter KE, Seidler AL, Askie LM: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2019; 2019 CrossRef MEDLINE PubMed Central
e30.Hastie R, Tong S, Wikström A-K, Sandström A, Hesselman S, Bergman L: Aspirin use during pregnancy and the risk of bleeding complications: a Swedish population-based cohort study. Am J Obstet Gynecol 2021; 224: 95.e1–95.e12 CrossRef MEDLINE
e31.Ciobanu AM, Dumitru AE, Gica N, Botezatu R, Peltecu G, Panaitescu AM: Benefits and risks of IgG transplacental transfer. Diagnostics (Basel) 2020; 10: 58 CrossRef MEDLINE PubMed Central
e32.Mofors J, Eliasson H, Ambrosi A, et al.: Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero. Ann Rheum Dis 2019; 78: 696–703 CrossRef MEDLINE
e33.Limaye MA, Buyon JP, Cuneo BF, Mehta-Lee SS: A review of fetal and neonatal consequences of maternal systemic lupus erythematosus. Prenat Diagn 2020; 40: 1066–76 CrossRef MEDLINE
e34.Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK: Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004; 110: 1542–8 CrossRef MEDLINE
e35.Hutter D, Silverman ED, Jaeggi ET: The benefits of transplacental treatment of isolated congenital complete heart block associated with maternal anti-Ro/SSA antibodies: a review. Scand J Immunol 2010; 72: 235–41 CrossRef MEDLINE
e36.Izmirly PM, Saxena A, Sahl SK, et al.: Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis 2016; 75: 1161–5 CrossRef MEDLINE PubMed Central
e37.Jobe AH, Goldenberg RL: Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am J Obstet Gynecol 2018; 219: 62–74 CrossRef MEDLINE
e38.Saxena A, Stevens J, Cetin H, et al.: Characterization of an anti-fetal AChR monoclonal antibody isolated from a myasthenia gravis patient. Sci Rep 2017; 7: 14426 CrossRef MEDLINE PubMed Central
e39.Gilhus NE, Hong Y: Maternal myasthenia gravis represents a risk for the child through autoantibody transfer, immunosuppressive therapy and genetic influence. Eur J Neurol 2018; 25: 1402–9 CrossRef MEDLINE
e40.Hacohen Y, Jacobson LW, Byrne S, et al.: Fetal acetylcholine receptor inactivation syndrome: a myopathy due to maternal antibodies. Neurol Neuroimmunol Neuroinflamm 2015; 2: e57 CrossRef MEDLINE PubMed Central
e41.Tjon JK, Tan-Sindhunata GM, Bugiani M, et al.: Fetal akinesia deformation sequence, arthrogryposis multiplex congenita, and bilateral clubfeet: is motor assessment of additional value for in utero diagnosis? A 10-year cohort study. Prenat Diagn 2019; 39: 219–31 CrossRef MEDLINE PubMed Central
e42.Lamb CA, Kennedy NA, Raine T, et al.: British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68: 1–106 CrossRef MEDLINE PubMed Central
e43.Wagner N, Assmus F, Arendt G, et al.: Impfen bei Immundefizienz: Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (IV) Impfen bei Autoimmunkrankheiten, bei anderen chronisch-entzündlichen Erkrankungen und unter immunmodulatorischer Therapie. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2019; 494–515 CrossRef MEDLINE
e44.Briggs GG, Towers CV, Freeman RK: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Philadelphia, PA: Wolters Kluwer 2017.
e45.Litwinska M, Litwinska E, Lisnere K, Syngelaki A, Wright A, Nicolaides KH: Stratification of pregnancy care based on risk of pre-eclampsia derived from uterine artery doppler at 19–24 weeks’ gestation. Ultrasound Obstet Gynecol 2021; 58: 360–8 CrossRef MEDLINE
e46.Chaoui R, Heling K, Mielke G, Hofbeck M, Ge mbruch U: [Quality standards of the DEGUM for performance of fetal echocardiography]. Ultraschall Med 2008; 29: 197–200 CrossRef MEDLINE
e47.Merz E, Eichhorn KH, Kaisenberg C, Schramm T: [Updated quality requirements regarding secondary differentiated ultrasound examination in prenatal diagnostics (= DEGUM level II) in the period from 18 + 0 to 21 + 6 weeks of gestation]. Ultraschall Med 2012: 33: 593–6.
e48.Kozlowski P, Burkhardt T, Gembruch U, et al.: [DEGUM, ÖGUM, SGUM and FMF Germany recommendations for the implementation of first-trimester screening, detailed ultrasound, cell-free DNA screening and diagnostic procedures]. Ultraschall Med 2019: 40: 176–93 CrossRef MEDLINE
e49.Phoon CKL, Kim MY, Buyon JP, Friedman DM: Finding the “PR-fect” solution: what is the best tool to measure fetal cardiac PR intervals for the detection and possible treatment of early conduction disease? Congenit Heart Dis 2012: 7: 349–60 CrossRef MEDLINE MEDLINE
e50.Sonesson SE, Ambrosi A, Wahren-Herlenius M: Benefits of fetal echocardiographic surveillance in pregnancies at risk of congenital heart block: single-center study of 212 anti-Ro52-positive pregnancies. Ultrasound Obstet Gynecol 2019: 54: 87–95 CrossRef MEDLINE
e51.Bergman G, Wahren-Herlenius M, Sonesson SE: Diagnostic precision of doppler flow echocardiography in fetuses at risk for atrioventricular block. Ultrasound Obstet Gynecol 2010: 36: 561–6 CrossRef MEDLINE
e52.Kan N, Silverman ED, Kingdom J, Dutil N, Laskin C, Jaeggi E: Serial echocardiography for immune-mediated heart disease in the fetus: results of a risk-based prospective surveillance strategy. Prenat Diagn 2017: 37: 375–82 CrossRef MEDLINE
e53.Saito M, Silverman E, Golding F, et al.: Effects of transplacental dexamethasone therapy on fetal immune-mediated complete heart block. Fetal Diagn Ther 2021: 48: 183–8 CrossRef MEDLINE
e54.Cuneo BF, Sonesson S-E, Levasseur S, et al.: Home monitoring for fetal heart rhythm during anti-Ro pregnancies. J Am Coll Cardiol 2018: 72: 1940–51 CrossRef MEDLINE
e55.Cuneo BF: Fetal bradycardia. In: Yagel S, Silverman NH, Gembruch U (eds): Fetal cardiology: embryology, genetics, physiology, echocardiographic evaluation, diagnosis, and perinatal management of cardiac diseases. Boca Raton: CRC Press, Taylor & Francis Group 2019; 515–29.
e56. Strasburger JF, Wacker-Gussmann A: Congenital heart block in subsequent pregnancies of SSA/Ro-positive mothers: cutting recurrence in half. J Am Coll Cardiol 2020; 76: 303–5 CrossRef MEDLINE PubMed Central
e57.Friedman DM, Kim M, Costedoat-Chalumeau N, et al.: Electrocardiographic QT intervals in infants exposed to hydroxychloroquine throughout gestation. Circ Arrhythm Electrophysiol 2020; 13: e008686 CrossRef