key: cord-0059829-dh1uiin1 authors: Narayan, Bhaskar; Nelson-Piercy, Cathy title: Physiological Changes of the Immune System During Pregnancy date: 2020-05-12 journal: Principles and Practice of Maternal Critical Care DOI: 10.1007/978-3-030-43477-9_15 sha: 17ab3350923c58bd436847581e381268c19cb0ab doc_id: 59829 cord_uid: dh1uiin1 Pregnancy is a unique immunological state, during which there are pro-inflammatory changes as well as increased immune tolerance. A shift occurs from a Th1- towards a Th2-predominant immunological profile. As a consequence, certain infections cause more severe disease in pregnancy. The immunological changes also influence the activity of autoimmune diseases, which are relatively common in pregnant women and may require critical care admission. Identifying autoimmune flares may be more challenging during pregnancy, as some features may overlap with normal pregnancy and/or pre-eclampsia. Many immunosuppressive treatments can be used during pregnancy and should not be withheld if clinically indicated. • Pregnancy is a unique immunological state, during which there are proinflammatory changes as well as increased immune tolerance. A shift occurs from a Th1-towards a Th2predominant immunological profile. • Certain infections cause more severe disease in pregnancy, resulting in higher mortality and morbidity. • The immunological changes also influence the activity of acute and chronic autoimmune diseases, which are a relatively common cause of morbidity before, during and after pregnancy. A significant proportion of pregnant women presenting to hospital with these conditions require critical care admission. It is essential that intensive care physicians are able to recognise and manage these patients appropriately. • Identifying autoimmune flares may be more challenging during pregnancy, as some of the symptoms and signs may overlap with normal pregnancy and/or pre-eclampsia. • Many immunosuppressive and immunomodulatory treatments can be used during pregnancy and should not be withheld if clinically indicated. The innate immune response also provides a defence against infection. The inflammatory state may (in combination with hormonal and other factors) contribute to systemic illness such as nausea and vomiting of pregnancy [1] . The adaptive immune system undergoes more complex changes, including diminished cytotoxic responses and enhanced regulatory responses. As part of the normal adaptive immune response, the Th1 subgroup of CD4 T-cells express cytokines such as IFN-γ and TNF-α and play a key role in cytotoxic immune responses. Overactivity of the Th1 system may play a role in the development of certain autoimmune diseases [2] . The Th2 subgroup express cytokines such as IL-4, IL-5 and IL-13 and are involved with humoral (antibody) responses and protection against some parasites. Overactivity of the Th2 system is thought to be implicated in the pathogenesis of allergies and atopy [3] . During normal pregnancy, there is a physiological shift in the maternal T-cell response towards a Th2 state. This finding was initially reported in several studies using mouse models of pregnancy and later confirmed in human studies [4] . In addition, a subset of CD4 T-cells, known as T-reg cells, are important regulators of the maternal immune response and tolerance to the fetus [5] . These cells produce IL10 and TGFβ, thereby suppressing local immunity [6] . During pregnancy, the population of T-reg cells increases [7] . However, when exposed to inflammatory stimuli (such as influenza or listeria), T-reg cells can rapidly differentiate into an additional class known as Th17 cells, which are highly inflammatory and associated with preterm labour and infectionrelated miscarriage [5] . In mouse models of pregnancy, T-reg depletion results in rejection of the fetus [8] . Women with recurrent miscarriage [7] or pre-eclampsia [9, 10] have lower numbers of decidual and circulating T-reg cells, compared to healthy human pregnant controls. The changes in the innate and adaptive immune systems are driven by a number of cytokine and endocrine factors. Prostaglandin E (PGE 2 ) and TGFβ enhance the proliferation and function of T-reg cells [11] . High levels of progesterone and oestrogen during pregnancy modulate the immune response by suppressing Th1 and Th17 responses and promoting Th2 and T-reg responses [12, 13] . As previously described, the first stage of pregnancy is pro-inflammatory, allowing implantation and placentation, as well as protection against infection during this crucial period. The subsequent shift towards an immunologically tolerant, anti-inflammatory Th2-predominant state allows rapid growth and development of the fetus in the second trimester of pregnancy [14] . Finally, in the third trimester, there is a return to a more pro-inflammatory state. An influx of immune cells into the myometrium and increased production of pro-inflammatory cytokines culminate in contraction of the uterus and delivery of the baby [14, 15] . This may be one of the reasons maternal infection is associated with preterm labour; amniotic fluid TNFα and IL-1 levels are significantly increased in women with preterm labour and infection [15] . In addition to enabling implantation, tolerance, growth and delivery of the fetus, the physiological changes occurring in the immune system during pregnancy have significant clinical implications related to infection and autoimmune disease. Pregnant women do not appear to have increased susceptibility to most infections (although there are a few notable exceptions including listeria and falciparum malaria-discussed below) [16] . However, with certain infections, there is an increased risk of severe disease resulting in a higher rate of mortality and morbidity than the general population [16] . In some (but not all) cases, this is related to the altered systemic immune status of the mother. Influenza is an important cause of maternal morbidity and mortality. The 2009 H1N1 pandemic strain was particularly virulent, and pregnant women were at much higher risk of developing severe, complicated infections and respiratory failure. In the USA, there were 280 intensive care unit admissions and 56 deaths among the 788 reported cases of influenza in pregnant women in the first 8 months of the pandemic. Initial data do not suggest that pregnant women are more susceptible to infection with SARS-CoV-2 (the coronavirus responsible for the COVID-19 pandemic), although severe disease leading to hospital admission is more common in the third trimester. Women over the age of 35 and those with obesity, hypertension and diabetes are at increased risk. In a nationwide study in the UK, 9% of pregnant women admitted required respiratory support, which is similar to the non-pregnant population [17, 18] . The reasons for this increased severity in pregnancy are not completely understood. The Th2predominant T-cell profile may reduce viral clearance [19] . Animal models suggest that when the host is infected with influenza virus, the altered immunological state of pregnancy is associated with higher levels of pro-inflammatory mediators (IL-6, IL-1α, G-CSF and COX-2) in the lung tissue [20] . Hepatitis E usually causes a mild self-limiting illness in the nonpregnant population. However, it can cause severe disease in pregnancy, with a significant proportion progressing to fulminant hepatitis with a mortality rate varying from 30 to 100% [21] . The mechanisms are still unclear but may involve the human transcription factor NF-κB, which plays a key role in regulating the immune response to infection [22] . NF-κB is downregulated during normal pregnancy [23] . Animal experiments in mice studying the p65 component of NF-κB have shown its important role in liver development and regeneration and that mice lacking p65 develop liver degeneration due to widespread apoptosis [21] . This led to human studies, which have found that the activity of the p65 component of NF-κB was greatly diminished in peripheral blood mononuclear cells and post-mortem liver biopsy specimens in pregnant women (compared to the nonpregnant population) with fulminant hepatic failure (FHF) [24] . This suggests that the absence or reduced activity of NF-κB p65 is associated with severe liver damage in pregnant women that develop FHF. Falciparum malaria may cause particularly severe disease in pregnancy because the parasites sequester in the placenta, causing inflammation and necrosis. Pregnant women are also more susceptible to hypoglycaemia [25, 26] . Acute infection appears to be more frequent in pregnant women [27] . Various explanations have been put forward, such as increased attractiveness to mosquitos [28] and impaired ability to limit parasite replication [27] . Acquired immunity against malaria is also diminished in women during their first pregnancy; they are susceptible to severe P. falciparum disease due to placental malaria causing a lack of immunity to placenta-specific cytoadherence proteins [29] . In subsequent pregnancies, immunity against placental-adherent strains may develop, reducing the risk of adverse effects of malaria on the mother and fetus. Certain other infections are notable for the higher rate of mortality and morbidity in pregnancy but probably for reasons unrelated to the altered systemic immune status of the mother. Listeria monocytogenes has a particular predilection for the placenta and fetus; therefore, invasive listeriosis is much more common in pregnant women, but this is likely to be because the nonpregnant population lack the placental entry point for infection [16] . Rubella, CMV and parvovirus B19 are significant in pregnancy due to the deleterious effects on the fetus rather than because of increased susceptibility or the maternal immune response in pregnancy. Maternal infection is usually subclinical or mildly symptomatic [25, 30] . Maternal HIV infection has major implications around mother-to-child transmission [31] , but pregnancy does not affect disease progression [25, 32] . Around 10-25% of the general population of patients with autoimmune diseases presenting to emergency departments require hospital admission [33] , and up to 30% of these patients require intensive care admission [34] . Mortality ranges from 17 to 55% in case series from the general population of patients with autoimmune diseases admitted to the intensive care unit [35] . More than two-thirds of maternal deaths in industrialised countries occur in women known to have medical comorbidities [36] , and autoimmune diseases contribute directly and indirectly to these deaths [37] . It is therefore unsurprising that autoimmune diseases are frequent causes of morbidity during pregnancy. Pregnant women with autoimmune diseases have higher rates of obstetric and non-obstetric complications (e.g. pre-eclampsia, thromboembolism, infection), poor pregnancy outcomes (i.e. fetal growth restriction, preterm delivery,) as well as pregnancy loss ( Fig. 15.1 ). Good disease control improves not only maternal but also pregnancy outcomes [38] . The altered immune state of pregnancy has an effect on the activity of several autoimmune diseases, which is summarised in Fig. 15 .2. The shift from a Th1-to a Th2-predominant state is relevant here. Hormonal changes contribute significantly to this; high levels of circulating oestrogen (as seen in pregnancy) have been shown to modulate the cytokine profile and suppress disease activity in experimental models of rheumatoid arthritis [39] and multiple sclerosis [40] . In humans, diseases that are driven by a Th1 response, including rheumatoid arthritis [41, 42] , multiple sclerosis [43] , psoriasis [44] and Graves' disease [45] , tend to improve during pregnancy [13] . However, they may flare postpartum, possibly due to a rapid fall in oestrogen levels in this period, resulting in a diminished Th2 response and consequently tipping the balance back in favour of a Th1 response [13] . In contrast, diseases that are driven by a Th2 response, including atopic eczema, SLE and systemic sclerosis, have a higher rate of flaring during pregnancy compared to the nonpregnant population [13, 44] . Active flares of autoimmune disease should be treated aggressively to minimise adverse consequences for both mother and fetus. Corticosteroids are usually the first-line treatment and can be used at any stage of pregnancy if clinically indicated. Dosing varies according to patient condition and should generally adhere to that administered to nonpregnant patients (see some details under subheadings). As with nonpregnant patients, steroids should be given at the lowest possible dose to control disease activity, but high doses should not be withheld if clinically indicated. Prednisolone and methylprednisolone are extensively metabolised by the placenta, and the fetal exposure is less than 10% of the maternal dose. Several large studies have not found any significant adverse effect on the fetus (major malformations, prematurity, low birthweight) attributable to these drugs [46] . However, treatment with these drugs has been associated with an increased maternal risk of gestational hypertension and diabetes. There are also good safety data [47] in pregnancy for disease-modifying drugs, such as hydroxychloroquine, sulfasalazine, mesalazine and azathioprine, and the calcineurin inhibitors ciclosporin and tacrolimus. Non-steroidal antiinflammatory drugs (NSAIDS) may also be used in the first and second trimesters [47, 48] . The newest class of immunomodulatory treatment is the "biologic" agents. These are monoclonal antibodies against specific targets involved in the disease process. There is now good evidence that infliximab, adalimumab, etanercept and certolizumab do not have any significant associations with a particular pattern of congenital malformations or adverse pregnancy outcomes. The use of these drugs in pregnancy is discussed further below in the section about antibodies and the placental barrier. Intravenous immunoglobulin (IVIg) and therapeutic plasma exchange (TPE) can both be used in pregnancy [49] [50] [51] and should not be withheld if clinically indicated. It is important to note that IVIg and TPE are associated with risks of thromboembolism and fluid shifts in all patients, in particular those already at increased risk, such as critically ill and/or pregnant patients. The indica-tions for these treatments would be the same as for nonpregnant patients. The aims of IVIg and TPE would vary slightly depending on the disease indication for treatment. For example, in GBS [52] , there may be amelioration of disease and improved/faster recovery (see below). These treatments will be selected in addition to other supportive therapies such medications, physiotherapy, time and patience. A similar treatment principle would apply to conditions like immune thrombocytopenia purpura (Chap. 5) and myasthenia gravis (Chap. 26). Methotrexate, mycophenolate mofetil, leflunomide and cyclophosphamide are teratogenic and should be avoided during pregnancy if possible. It is therefore important to address the use of these drugs in pre-pregnancy counselling and to aim for optimal disease control with an alternative drug prior to conception. However, the successful use of cyclophosphamide (500 mg IV pulsed dose every 2 weeks for 6 doses) in the second and third trimesters has been reported in the treatment of refractory life-threatening SLE and rapidly progressive interstitial lung disease [53] . This is a challenging scenario, and such decisions should only be reached after a detailed and frank discussion between the intensivist, treating physician, obstetrician and patient and/or her family (if she is unable to provide input). In the context of critical illness with a risk of death (or serious/ permanent disability or organ damage), with no other effective treatment options, the conclusions of such discussions might be to use cyclophosphamide to prioritise maternal health while accepting the significant risk of fetal harm or loss. Of note, there are also data describing safe use of cyclophosphamide as part of chemotherapy regimens to treat breast cancer [54] and lymphomas [55] in pregnancy after 12 weeks gestation (Fig. 15.3) . Systemic lupus erythematosus (SLE) is an idiopathic autoimmune condition which has multiorgan involvement. The disease process is incompletely understood, involving immune complex deposition resulting in widespread inflammation. There is polyclonal B-cell activa-tion and antinuclear antibody production. There are also complement deficiencies and impaired T-cell regulation, which leads to a diminished ability to clear these immune complexes [56] . SLE is particularly prone to flaring during pregnancy. As many as 60% of women with preexisting SLE experience a flare during or soon after pregnancy, compared with 40% of nonpregnant women over the same period [57] . The risk of flaring during pregnancy is highest for women with active disease at the time of conception, particularly if they have lupus nephritis [58] . SLE disease activity varies by organ system. Musculoskeletal flares are less common, while renal and hematologic flares are more common [59] . Severe morbidity requiring critical care may result from flares of lupus nephritis, interstitial lung disease, cardiovascular disease, neuropsychiatric lupus, thrombosis, thrombocytopenia or opportunistic infections. Treatment of acute severe flares involves highdose corticosteroids (e.g. pulsed IV methylprednisolone 500-1000 mg/day for 3 days followed by prednisolone 0.25-0.5 mg/kg/day) [60, 61] . Non-steroidal anti-inflammatory drugs (NSAIDs) Acceptable for short -term use up to 28 weeks gestation. Avoid use in third trimester. Corticosteroids (prednisolone/methylprednisolone) Can be used throughout pregnancy if clinically indicated. Not associated with any increased risk of congenital malformations, although there is an increased risk of diabetes and hypertension in the mother. Fluorinated corticosteroids (e.g. dexamethasone and beclomethasone) are less metabolised by the placenta and should be avoided unless treating a fetal problem. Can be used throughout pregnancy if clinically indicated. Not associated with any increased risk of congenital malformations. Sulfalazine, mesalazine Can be used throughout pregnancy if clinically indicated. Not associated with any increased risk of congenital malformations. Women taking sulfasalazine during pregnancy should also receive folate supplementation of at least 2mg/day. Can be used throughout pregnancy if clinically indicated. Not associated with any increased risk of congenital malformations. Ciclosporin, tacrolimus Can be used throughout pregnancy if clinically indicated. Not associated with any increased risk of congenital malformations. May require higher doses during pregnancy to maintain levels within therapeutic range. No evidence of a teratogenic effect-can be used in first trimester if clinically indicated. If possible, stop at 20 weeks gestation. Continued use throughout pregnancy can be justified if clinically indicated. No evidence of a teratogenic effect-can be used in first trimester if clinically indicated. If possible, stop at 28 weeks gestation. No evidence of a teratogenic effect-can be used in first trimester if clinically indicated. If possible, stop at 28 weeks gestation. Certolizumab pegol L imited evidence, but early data suggest compatibility with all three trimesters of pregnancy and do not show any evidence of a teratogenic effect. Rituximab, golimumab, abatacept, tocilizumab, belimumab,anakinra. Limited data, although registry and observational data suggest that unintentional exposure to these drugs in the first trimester is unlikely to be harmful. Data too limited to make any recommendation for use in pregnancy. Can be used throughout pregnancy if clinically indicated. Therapeutic Plasma Exchange (TPE) C an be used throughout pregnancy if clinically indicated. Teratogenic. Avoid during pregnancy. These drugs should be withdrawn before a planned pregnancy. Leflunomide Cyclophosphamide Identifying SLE flares may be more challenging during pregnancy, as some of the symptoms and signs may overlap with normal pregnancy (e.g. lethargy, facial flushing, oedema, mild anaemia and thrombocytopenia) [62] . Good clinical judgement and specific laboratory tests such as declining serum complement levels and/or rising anti-dsDNA antibody titres may aid diagnosis of a lupus flare during pregnancy. One of the biggest challenges is the differentiation between pre-eclampsia and a lupus nephritis flare. Both conditions may present with hypertension, proteinuria and deteriorating renal function. Here again, falling complement levels and rising anti-dsDNA antibody titres make lupus nephritis more likely, as does the detection of an active urinary sediment. A history of lupus nephritis also increases the likelihood of a renal flare in pregnancy, although lupus nephritis may present for the first time during pregnancy [56] . Despite these distinguishing features, the only investigation that can definitively distinguish preeclampsia from lupus nephritis is renal biopsy. This is not usually performed during pregnancy due to the risk of bleeding complications. It may occasionally be indicated in the first or second trimester if it is felt that the result is likely to alter management, for example, if appropriate treatment with immunosuppressive agents may allow prolongation of the pregnancy (see Chap. 31) [56] . If pre-eclampsia and lupus flare cannot be differentiated beyond 24-28 weeks gestation (when the fetus is viable) and maternal health is significantly compromised, then multidisciplinary discussion should be undertaken regarding early delivery. Delivery will both cure the pre-eclampsia and enable renal biopsy to guide immunosuppressive therapy if lupus nephritis is confirmed. Guillain-Barre syndrome (GBS) is an acute immune-mediated polyneuropathy (Box 15.1). It presents as an acute, monophasic paralysing illness, usually provoked by a preceding infection. Although the condition has been reported in pregnancy [63] , it is a rare condition, and there are insufficient data to make recommendations other than to manage the condition in the same way as in the nonpregnant patient. Respiratory failure is common (17-30%) [64] and is the usual reason for admission to the intensive care unit. Forced vital capacity (FVC) of less than 20 mL/ kg is the widely accepted threshold to consider invasive ventilation. FVC does not change significantly in pregnancy [65] , so a low FVC measurement should be attributed to genuine neuromuscular weakness rather than to the pregnancy. Indeed, the increased oxygen and ventilatory demands and the decreased lung compliance in pregnancy may result in more rapid exhaustion, decompensation and respiratory embarrassment. These patients must be closely observed for any early signs of respiratory muscle weakness, with a low threshold to admit to the high dependency or intensive care unit. A 33-year-old female attends the antenatal unit at 21 weeks gestation, with a 5-day history of progressive weakness. She is struggling to walk and reports that she is more breathless than usual. She was previ-ously fit and well, although she did report a diarrhoeal illness a few weeks prior to this presentation. She has been assessed by the neurology team, who have concluded that she has Guillain-Barre syndrome. A critical care opinion has been requested, as she is slightly dyspnoeic, although she is able to communicate in full sentences. The patient is very concerned about the safety and availability of treatment options for her condition, given that she is pregnant. In this case, the patient was observed on the critical care unit but fortunately did not deteriorate to the point of needing invasive ventilation. She responded well to IVIg, was discharged from the ICU after 5 days and made a full recovery over the following 8 weeks. She delivered a healthy baby by spontaneous vaginal delivery at 39 weeks. Treatment of pregnant women with GBS is the same as that in nonpregnant patients. There is clear evidence that IVIg and plasma exchange (one or the other, not both in combination) is of benefit in GBS [52, 66] . Corticosteroids are ineffective and may even delay recovery [67] . Both plasma exchange and IVIg can be used in pregnancy. Trials have demonstrated that plasma exchange is associated with reduced duration of mechanical ventilation, reduced time to motor recovery and reduced time to walking without assistance [52] . If plasma exchange is used, care must be taken to avoid hypovolaemia or fluid overload. There may be a transient prolongation of prothrombin and activated partial thromboplastin times due to removal of clotting factors. Although significant bleeding is uncommon, this effect can be avoided by using plasma rather than albumin as the replacement fluid [68] . IVIg is equally as efficacious as plasma exchange and is often used as first-line therapy due to its relative ease of use. A suggested dosing regimen for IVIg is 0.4 g/kg/day for 5 days [69] . IVIg therapy is associated with an increased risk of thromboembolic events, particularly in patients with additional thrombotic risk factors [70] . Pregnancy is a pro-thrombotic state, and immobile patients in the critical care unit are at particularly high risk of venous thromboembolism. Adequate thromboprophylaxis (usually with low molecular weight heparin) is therefore essential. An important function of the placenta is to form a selective barrier between the maternal and fetal circulation. Most low molecular weight compounds (<500 Da) can move across the placenta by passive diffusion. Certain ions and amino acids are also actively transported. In contrast, high molecular weight compounds do not usually traverse the placenta, but an important exception is immunoglobulin G (IgG), which has a molecular mass of approximately 160 kDa. Of the five antibody classes, IgG is the only class that crosses the placenta in significant quantities, although it is only transferred in significant quantities after 16 weeks gestation [71] . This is clinically relevant for three main reasons: • Neonatal "passive" immunity to infection • Effects of autoantibodies on the fetus/neonate • Implications for use of "biologic" drugs The neonatal immune system is immature and unable to mount an adequate adaptive immune response when exposed to pathogens during or soon after birth. Placental transfer of maternal IgG antibodies therefore plays an important role in protecting the neonate against infection during the initial weeks and months of life. For example, if the mother has circulating antibodies to pathogens such as varicella zoster virus, herpes simplex virus, or measles (due to prior vaccination or exposure to the pathogen), then these antibodies are detectable in the neonate too. This "passive" immunisation confers a degree of protection against these infections. This physiological process can be and often is exploited by vaccinating the mother during pregnancy for specific diseases (e.g. pertussis) [72, 73] . Similarly, IVIg has been used extensively in pregnancy without adverse effect on the fetus. It does cross the placenta (as it is IgG) but there is no association with harm. Indeed, IVIg is actually used to treat neonatal sepsis. Certain autoimmune conditions are associated with autoantibodies that may have a direct adverse effect on the fetus. Patients with these conditions, for a variety of reasons, often require critical care admission; it is therefore vital that intensive care physicians are aware of the potential immunological complications specific to pregnancy. Anti-Ro/SSA antibodies may be present in mothers with Sjogren's syndrome, SLE or rheumatoid arthritis [74] . Women with these autoimmune conditions should be screened for the presence of these antibodies in order to inform the treating neonatologist following delivery. These antibodies cross the placenta and are associated with fetal cardiac abnormalities and transient neonatal cutaneous lupus [75] . The risk of congenital heart block is 1-5%, and there is also a risk of myocardial inflammation, endocardial fibroelastosis or atrioventricular (AV) valve apparatus dysfunction [76] . The risk is particularly high if a previous fetus has been affected. Several other autoimmune disease-associated IgG antibodies can cross the placenta to cause harm to the fetus. These are summarised in Fig. 15 .4. However, it is important to note that the presence/titres of these antibodies don't necessarily correlate with the degree of pathology. Most "biologic" drugs are monoclonal derivatives of IgG and therefore cross the placenta. Infliximab and adalimumab are monoclonal antibodies against TNFα. Etanercept is a fusion molecule comprising of a soluble TNFα receptor and the Fc-fragment of IgG1. These drugs can be initiated or continued during pregnancy if clinically indicated. In the intensive care setting, they are likely to be used in combination with corticosteroids to treat acute flares or de novo inflammatory disease. In mothers treated with these drugs, fetal exposure is minimal in the first trimester, and there is no evidence of a teratogenic effect [48, 77] . However, from 16 weeks gestation onwards, the antibody molecules are actively transported across the placenta and, by the third trimester, can result in higher drug levels in the fetus/neonate than in the mother. To minimise neonatal levels at birth, these drugs are often discontinued in the second trimester (by 20 weeks for infliximab and 28 weeks for adalimumab or etanercept). However, if the drug is required to control active maternal inflammatory disease, it is acceptable to continue treatment throughout pregnancy. Moreover, while there have been theoretical concerns about neonatal immune suppression, data from the PIANO registry [77] are reassuring: third trimester anti-TNFα use had no effect on infant growth, development or immune development in the first year of life, and a systematic review [78] found no increased risk of infections up to 1 year of age. The British Society of Rheumatologists and European League Against Rheumatism have recently issued detailed guidance [47, 48] on this topic. All of these drugs may be detectable in breast milk at very low levels, but they are very poorly absorbed via the oral route, so breastfeeding is considered safe [48] . There are a number of newer anti-TNFα drugs, some of which have been modified to alter the pharmacokinetic profile. Certolizumab pegol is a monoclonal antigen-binding fragment (Fab) of an anti-TNFα antibody (lacking the Fc region) that has been conjugated with polyethylene glycol. It has low rates of placental transfer, and early data suggest that it is compatible with all three trimesters of pregnancy. Safety data are limited for rituximab, golimumab, abatacept, tocilizumab, belimumab and anakinra, although registry and observational data suggest that unintentional fetal exposure to these drugs in the first trimester is unlikely to be harmful [48] . The immunological changes in pregnancy are complex. There are pro-inflammatory changes as well as increased immune tolerance, with a shift from a Th1-towards a Th2-predominant immunological profile. Certain infections, such as influenza, hepatitis E and falciparum malaria, tend to cause more severe disease in pregnancy, with higher morbidity and mortality. Pregnancy also influences the activity of autoimmune diseases, which are relatively common in women of childbearing age. Severe flares of autoimmune disease often require critical care admission for observation and treatment. Identifying autoimmune flares may be more challenging during pregnancy, as Fig. 15 .4 Autoimmune disease-associated antibodies and the potential direct effects on the fetus during and after pregnancy some features may overlap with normal pregnancy and/or pre-eclampsia. Some autoimmune diseases are associated with antibodies that cross the placenta, with potential to affect the fetus. 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