antifosfolipidos3

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39 Pregnancy in the Rheumatic DiseasesELIZA F. CHAKRAVARTY MEGAN E. CLOWSE

whereby a shift of helper T cells toward a Th2 dominant state, possibly induced by increasing levels of progesterone, is necessary to establish and maintain a normal pregnancy. This theory was consistent with earlier observations that systemic lupus erythematosus (SLE, a Th2-predominant disease) may be exacerbated by pregnancy, whereas Th1-mediated autoimmune diseases (rheumatoid arthritis [RA], multiple sclerosis, and psoriasis) appear to be characterized by clinical improvement during pregnancy.1 More recently, however, it is becoming increasingly clear that many more components of both the innate and adaptive immune systems are involved in normal pregnancy.2-5 Furthermore, many of the immunologic changes during pregnancy may be preferentially located at the maternal-fetal interface and may not be accurately sampled using peripheral blood. The trophoblast and placenta, once considered passive media-tors of maternal-fetal immune trafficking, have been increas-ingly recognized as playing active roles in mediating inflammation, as well as in host defense.2 Taken together, it is evident that understanding the immune regulation of a healthy pregnancy remains elusive, much less understand-ing how pregnancy-related immunologic changes interplay with an abnormal immune system stemming from preexist-ing autoimmunity.

Nonetheless, it is imperative to go beyond inferring that individual diseases tend to behave in well-defined ways during pregnancy and look at an individual womans risk for adverse pregnancy outcomes. Fortunately, the majority of women with autoimmune diseases who desire children will have safe and relatively uncomplicated pregnancies. However, despite significant advances in the management of pregnancy in women with autoimmune diseases, one can argue that the rates of adverse pregnancy outcomes remain unacceptably high for some conditions.

Further complicating the issue of pregnancy in women with autoimmune diseases is the continuation or discon-tinuation of disease-modifying agents in anticipation of or discovery of a pregnancy. Some medications are known or suspected teratogens and should be avoided during preg-nancy, whereas others may be considered safer to use with less evidence of embryotoxicity. As much as it may be desir-able to manage disease during pregnancy with the minimum amount of medications necessary, the risks of medication exposure during pregnancy must be balanced with the risks of untreated active inflammatory disease and its potential for adverse pregnancy outcomes.

A few general principles apply to all women with autoim-mune diseases who are contemplating pregnancy or who discover an inadvertent pregnancy. First and foremost, open communication between provider and patient is critical to all aspects of contraception and pregnancy planning. In the

KEY POINTS

The majority of women with autoimmune diseases will have healthy and uneventful pregnancies, and the risk-benefit ratios for medication use during pregnancy will improve pregnancy outcomes and reduce maternal and fetal risks.

The best outcomes result from conception occurring when the disease is in remission or clinically quiescent.

With few exceptions, clinical or laboratory parameters are unable to predict whether underlying disease activity will improve, worsen, or remain the same during pregnancy.

Potentially teratogenic medications should ideally be discontinued several months before conception.

At times women with underlying autoimmune disease require ongoing disease-modifying or immunosuppressive therapy during pregnancy to treat persistently active disease or flare-ups.

U.S. Food and Drug Administration pregnancy categories for medication safety for use during pregnancy are not routinely updated and may not accurately reflect increased experience during pregnancy.

Increased rates of premature delivery or small-forgestational age infants may be seen in many autoimmune diseases.

The majority of autoimmune diseases display a female pre-dominance, and, with the exception of giant cell arteritis, may present during the childbearing years. With improved treatment options for many autoimmune diseases that may prevent or retard functional disability or progressive organ damage from active disease, an increasing number of affected women will be able to face the physical challenges of child-bearing and childrearing and may consider pregnancy as an important component of a fulfilling life. When considering pregnancy in women with underlying autoimmune diseases, one must take several things into account: (1) the effects of underlying disease on pregnancy outcomes; (2) effects of a pregnancy, with all of its immunologic and physiologic changes, upon an autoimmune disease; and (3) safe use of medications for effective control of autoimmune disease while avoiding adverse effects to the pregnancy or fetus.

In order for the fetal semiallograft to survive and grow during 9 months of exposure to the maternal immune system, the maternal immune system must undergo a complex modulation of the innate and humoral immune system, much of which is not well understood. Pregnancy had long been understood as a Th2-predominant condition,

541CHAPTER 39 | PREgnAnCy in THE RHEumATiC DisEAsEs

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ideal situation, family planning discussions are conducted before a woman becomes pregnant. Open and frank discus-sion of the risks of pregnancy outcomes regarding underly-ing disease activity and medication use should be continued throughout pregnancy. It has become increasingly evident that pregnancy outcomes are optimized when conception occurs during periods of disease quiescence and when disease control can be maintained throughout pregnancy. This requires preconceptional management of autoimmune disease using medications that are safe should they be required to be continued into pregnancy to maintain disease control. Additionally, comorbid conditions including hypertension and hyperglycemia should be well controlled before conception. Consultation with specialists in maternal-fetal medicine may be helpful for comanagement of the pregnant patient with autoimmune diseases to ensure the proper monitoring for and management of disorders of pregnancy are undertaken in a timely manner. For the patient who discovers an inadvertent pregnancy during periods of active disease or with exposure to potentially teratogenic medications, counseling by both a rheumatolo-gist and maternal-fetal medicine specialist should be offered so that the woman can make well-informed choices regard-ing her pregnancy. Healthy infants have been born with documented exposure to the most teratogenic medications, and patients may want to continue pregnancies despite early antenatal exposure.

SYSTEMIC LUPUS ERYTHEMATOSUS

Because SLE primarily affects women in their reproductive years and these patients have normal fertility, pregnancy is a frequently encountered dilemma. Fortunately, the major-ity of these pregnancies will progress without complication and result in the delivery of a healthy baby by a healthy mother. Almost half of these pregnancies, however, will encounter complications including increased lupus activity, pregnancy loss, preterm birth, and preeclampsia. The key to pregnancy success is careful planning for pregnancy, which includes timing to avoid conception during periods of disease activity and alteration of medications to avoid tera-togenicity but maintain disease quiescence.

Pregnancy Outcomes

Retrospective studies of women with SLE have noted an increased rate of pregnancy loss when compared with healthy women. Among 203 women with SLE, 166 of their friends, and 177 of their relatives, pregnancy loss was twice as common (21% in SLE vs. 14% in friends and 8% in rela-tives, P < .0001) and preterm birth was three times more frequent (12% in SLE vs. 4% in friends and relatives, P < .0001).6 Prospective cohorts of SLE pregnancies report a more modest pregnancy loss rate, but these cohorts probably miss some early pregnancy losses that occur before presenta-tion in the rheumatology clinic. What they notably show is a rate of stillbirth, typically defined as a pregnancy loss after 20 weeks gestation that is 5- to 10-fold higher than that of the general population (Figure 39-1). In a meta-analysis of 37 studies of SLE pregnancies (12 prospective and 25 ret-rospective), there is a higher than expected rate for miscar-riage, stillbirth, and neonatal death (infant death at

542 PART 4 | BROAD issuEs in THE APPROACH TO RHEumATiC DisEAsE

applies to women with high overall disease activity, with isolated proteinuria greater than 500 mg/24 hr, or isolated thrombocytopenia.12 Disease activity in the second and third trimesters is less often associated with pregnancy loss but can double the rate of preterm delivery.11

The most important predictors of SLE activity in preg-nancy are increased SLE activity in the 6 months before conception, the frequency of SLE flare in the years before pregnancy, and the cessation of immunosuppressive medica-tions. Among women with high-activity SLE in the 6 months before conception, 58% had high-activity SLE during pregnancy. On the other hand, of women with rela-tively quiet SLE before pregnancy, only 8% had high activ-ity in pregnancy.11 The cessation of hydroxychloroquine (HCQ) before or concurrent with conception is associated with a high rate of SLE flare, particularly in the second and third trimesters. Because these flares are predominantly in the skin and joints or manifest as fatigue, they do not have a statistically significant impact on pregnancy outcomes. They can, however, lead to significant discomfort and the use of higher doses of corticosteroids during pregnancy. Stopping immunosuppressants including mycophenolate mofetil or azathioprine because of pregnancy may lead to a flaring of SLE activity, particularly renal or hematologic, that could lead to significant pregnancy morbidity. For this reason, women who require these drugs to maintain quiet SLE activity before pregnancy will likely benefit from con-tinuing azathioprine during pregnancy (see further discus-sion in Medications in Pregnancy and Lactation later).

Lupus nephritis, whether active or quiescent during preg-nancy, affects pregnancy outcomes. Several prospective studies of lupus nephritis in pregnancy document that women with prior lupus nephritis have a higher rate of pregnancy loss, preterm birth, and preeclampsia than other women with and without SLE. Active lupus nephritis during pregnancy increases the pregnancy loss and preterm birth rates by twofold to threefold.13,14 Renal failure is a rare complication of active lupus nephritis in pregnancy.

Maternal death is 20-fold more common among SLE pregnancies than other pregnancies, but it is fortunately rare.8 When compared with the annual risk of death in all women with SLE (ranging between 0.5% and 1% of all women, depending on the study sample), the risk of death in pregnancy for women with SLE is lower (0.3%).8 This is likely because women with the most severe SLE, who are at the highest risk for death, avoid pregnancy. Reported causes of maternal death in women with SLE include thrombosis, in particular pulmonary embolism, and infection. Although risk factors for maternal death have not been studied due to the rarity of this event, patients at higher risk for death include those with prior major thrombosis; severe pulmo-nary hypertension, lung, or renal disease; and women requir-ing high-dose immunosuppression.

Several simple interventions can be employed to decrease the likelihood of fetal and maternal morbidity:

1. Time pregnancy to coincide with periods of disease quiescence. At least 6 months of quiet SLE is required to decrease the risk of disease flare and adverse preg-nancy outcomes. Accomplishing this requires discuss-ing and prescribing effective contraception to women with significant SLE activity to avoid conception. Active SLE does not impair fertility.

from the mother, through the placenta, and to the fetus. Later in pregnancies, these arteries are not able to expand to provide sufficient blood flow to the fetus, resulting in a cascade of endocrine, inflammatory, and endothelial changes that promotes maternal hypertension and proteinuria.9 In the general population, preeclampsia typically occurs in 5% to 8% of pregnancies and only 1/10 of these present before 34 weeks gestation. The risk for preeclampsia is increased if a woman has previously had preeclampsia, particularly if it occurred early in pregnancy and was severe (blood pres-sure over 160/110, proteinuria over 5 g/24 hr, or other severe organ manifestations). Also at risk are first pregnan-cies and pregnancies in women with obesity, diabetes, hypertension, age older than 40, and a family history of preeclampsia.9 Up to one quarter of pregnancies in women with SLE are complicated by either hypertension or pre-eclampsia.10 In a meta-analysis of SLE pregnancies, 7.4% reported preeclampsia, but the rate varied greatly between studies.7 Preeclampsia can be difficult to distinguish from active lupus nephritis. Other signs of SLE activity including arthritis, rash, low complement, or rising double-stranded deoxyribonucleic acid (dsDNA)-titer can help determine the etiology of hypertension and proteinuria. Treatment of these two conditions is different: immunosuppression for SLE and delivery for preeclampsia. In some situations, treat-ment for both is prudent and the ultimate determination of cause will be possible postpartum either through resolution of preeclampsia over the first month after delivery or renal biopsy for persistent disease.

Placental insufficiency, which leads to less blood and nutrient flow to the developing fetus, can lead to small babies. Definitions of this vary, but it can be measured both in utero via ultrasound and at birth by birth weight and is typically defined as a baby weighing less than the 10th percentile of expected weight for gestational age. In the meta-analysis of SLE pregnancies, 12.7% of babies were noted to be small. In an analysis of the Nationwide Inpa-tient Sample, which includes data for 20% of all deliveries in the United States, 5.6% of pregnancies in women with SLE were identified as intrauterine growth restricted, a rate that was 2.6-fold higher than for other pregnancies in the United States (P < .01).10 In the Hopkins Lupus Cohort, 23% of all live births weighed less than the 10th percentile for gestational age of delivery.11

Although up to 30% of women with SLE will have a flare during pregnancy, the majority of these are fairly mild and readily controlled.7,11 Several studies in the 1980s and 1990s tried to determine whether SLE worsens with pregnancy, but the conclusions were often conflicting. It seems that many patients will proceed through pregnancy without dif-ficulty, but an important minority will suffer significant disease activity that can harm both the pregnancy and the womans own health and survival.

Significant SLE activity is associated with increased pregnancy loss and preterm birth. The degree of SLE activ-ity is importantit appears that mild activity of the skin or joints will have minimal impact on pregnancy outcomes. Internal organ involvement including the kidneys, hemato-logic cell lines, serositis, and the central nervous system (CNS) is more highly associated with pregnancy morbidity. Women with highly active SLE around the time of concep-tion have an estimated 40% risk of pregnancy loss.11,12 This


family size. From these data, it appears that reduced numbers of children among women with RA may be related to choice rather than to reduced fertility or increased pregnancy loss.22 Reduced sexual activity due to functional limitations from the disease are a further, nonbiologic cause of lower birth rates due to reduced opportunity for conception.23

Although several disease-modifying antirheumatic drugs (DMARDs) may assert teratogenic effects on the fetus,24 and nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with temporal and reversible infertility,25 most chronic medications taken to manage inflammatory arthritides have no known adverse effect on hormonal, ovarian, or endometrial function. Several studies have found that estrogen-containing oral contraceptives yield a protective effect or mildly ameliorating effect on RA, and increased use of oral contraceptive pills among women with RA may further contribute to lower birth rates. These medication issues are easily overcome in women with RA who desire a pregnancy. However, it is much more difficult to formally study biologic infertility in this population. Few studies have been able to disentangle true inability to con-ceive a child from the myriad of other reasons for which women with RA may have fewer pregnancies. There has been a suggestion of reduced ovulatory function among women with RA in a small study of menstruating women,26 but this has yet to be followed up with larger studies. A recent population-based study from Norway has found that women with RA used assisted reproduction technolo-gies more than age-matched healthy women.27 Similar findings were seen in a case-control study of pregnant women in the Netherlands (17.8% RA patients used assisted reproductive techniques compared with 3% in healthy women).28

Pregnancy Outcomes

In the absence of exposure to potentially teratogenic medi-cations (including methotrexate, leflunomide, and myco-phenolate mofetil [MMF]), earlier observations showed that maternal-fetal outcomes did not appear to be changed by maternal RA.20 However, more recent studies have shown that there are, in fact, some differences in these outcomes comparing women with RA with the general population. Several recently published population-based studies have documented an increased risk of preterm birth (


Despite a wide range of disease activity during pregnancy, the majority of studies have shown that RA may worsen or flare in the postpartum period.34,36,37,41 In addition, a recent study has demonstrated an increase in the incidence of RA during the first 24 months following delivery compared with 25 to 48 weeks postpartum among premenopausal women in Norway,42 suggesting that either the incidence of RA peaks in the postpartum months or pregnancy may delay the onset of RA in susceptible individuals.

Ways to Improve Outcomes

Monitoring disease activity during pregnancy can be tricky because distinguishing underlying activity of RA from normal changes during pregnancy is often not clear. Both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are markers of systemic inflam-mation that are often used to follow disease activity in rheumatic disease. Unfortunately, both these levels can fluc-tuate in pregnancy with more dramatic increases seen in ESR rather than CRP.36 Therefore these levels must be interpreted with caution in women with RA. Furthermore, clinical changes of pregnancy such as fatigue, swelling (especially of the distal extremities), and carpal tunnel syn-drome are commonly seen in pregnancy. Careful examina-tion of the wrist and assessment of neurologic symptoms are important to distinguish carpal tunnel syndrome from RA flare.

Given the growing evidence that active disease during pregnancy is associated with increased risks of adverse fetal outcomes, it is important to achieve control of disease activ-ity before conception and during pregnancy whenever pos-sible. In the ideal situation, women with RA considering pregnancy should aim to achieve good control of disease after discontinuation of medications with teratogenic potential, using medications considered safer during preg-nancy if necessary to reduce inflammation. Determining the right medications for a pregnant patient can be challenging and requires an individualized approach. Certain medica-tions are strictly contraindicated during pregnancy and should always be avoided due to teratogenic potential: methotrexate and leflunomide. Additionally, these agents should be discontinued immediately on the discovery of pregnancy in a woman receiving these medications (leflu-nomide will require an additional washout with cholestyr-amine).43 If a disease-modifying agent is required to control chronically active disease during an anticipated or con-firmed pregnancy, plaquenil, sulfasalazine (SSZ), and/or azathioprine carry the fewest risks to the developing fetus

age, maternal smoking, maternal age, education, parity, and prednisone use.28 A second study, from the United Kingdom, found that women with active disease during the third tri-mester had lower birth weight than women with RA in remission; women with inactive RA had birth outcomes indistinguishable from healthy control women.29 Together, these data suggest that RA is associated with higher risks of preterm delivery and lower birth weight infants; however, this may be mitigated by achieving good control of disease activity during at least the third trimester of pregnancy.

Disease Outcomes

Since the initial report by Hench in 1938,33 it has been thought that RA disease activity improves during preg-nancy. In reviewing the majority of the data looking at disease activity during pregnancy, it appears that approxi-mately 75% of patients will have some degree of improve-ment.34,35 This may occur as early as the first trimester and continue through the end of pregnancy. The exact underly-ing immunologic mechanism as to why this occurs is unclear. However, more recent reports have suggested that this improvement is actually not as dramatic as was once per-ceived. De Man and colleagues looked prospectively at 84 patients with RA and determined improvement and dete-rioration by the DAS28 changes.36 For women who started the pregnancy with moderate disease activity, only 48% had a moderate improvement response. Those with low disease activity during the first trimester tended to remain stable. Only 27% of the patients as a whole were in remission by the third trimester. In comparison, Barrett37 and Nelson and colleagues35 in previous studies showed that 16% and 39%, respectively, were in remission during the third trimester (though different definitions of remission were used). Unfortunately, no clinical or laboratory predictors have been found to reliably predict the disease course during pregnancy. Conflicting reports have been published looking at the degree of maternal-fetal human leukocyte antigen (HLA) class II mismatch and maternal RA disease activ-ity.35,37-40 The majority of studies have confirmed that a higher degree of maternal-fetal HLA mismatch is associated with improved disease activity during pregnancy35,38,39; however, a study of 110 maternal-fetal pairs failed to find such an association.40 More recently, a prospective study of 118 pregnant women with RA from the Netherlands found that women who were seronegative for rheumatoid factor or anticyclic citrullinated peptide had a greater likelihood of improvement in disease activity during pregnancy.41 This has yet to be studied in other populations.

Table 39-1 Odds Ratios of Preterm Delivery and small for gestational Age infants among Women with Rheumatoid Arthritis Compared with Healthy Controls in Population-Based studies

Study Year LocationPreterm

Delivery (OR) 95% CI

Small for Gestational Age (OR) 95% CI

Wallenius42 2010 norway 1.85 1.09-3.13 1.6 1.00-2.56Chakravarty21 2006 united states 2.2 1.2-4.1Lin30 2010 Taiwan 1.17 0.98-1.40 1.2 1.05-1.38Reed31 2006 united states 1.78 1.21-2.60 1.51 0.94-2.43norgaard32 2010 sweden/Denmark 1.44 1.14-1.82 1.56 1.20-2.01

CI, confidence interval; OR, odds ratio.


weeks postpartum. Neonatal or fetal death after 22 weeks gestation occurred in 7% to 13% of pregnancies compli-cated by pulmonary hypertension, about one-third had intrauterine growth restriction, and more than 85% deliv-ered preterm.50 Medical treatment of pulmonary hyperten-sion may include prostacyclin, nitric oxide, and calcium channel blockers. Due to the high maternal and fetal mor-bidity and mortality, pulmonary hypertension is considered a contraindication to pregnancy.50

Scleroderma renal crisis, though rare in pregnancy (occurring in 2% to 3% of scleroderma pregnancies), can be catastrophic.47 It can be difficult to distinguish from preeclampsia, both presenting with hypertension, pro-teinuria, and in severe cases hemolysis and thrombocy-topenia. Women at particular risk for this complication include those with a prior history of it and those with recent onset of rapidly progressive diffuse disease. If the pregnancy is near term, delivery followed by aggressive ACE inhibitor therapy is indicated. If not near term, treatment with ACE inhibitors should be weighed. These drugs carry sig-nificant risk for permanent and fatal renal disease in the fetus but are also the essential treatment for scleroderma renal crisis.47

Gastroesophageal reflux disease often worsens in preg-nancy. Raynauds phenomenon, however, often improves due to decreased vascular resistance.47 Skin disease does not seem to change significantly in pregnancy.47 The peripheral edema of pregnancy may be particularly uncomfortable, however, for women with diffuse scleroderma.

An approach to improving pregnancy outcomes in women with scleroderma begins with careful preconception counseling and continues with close monitoring during pregnancy.

1. Women with pulmonary hypertension, a history of scleroderma renal crisis, or severe interstitial lung disease should be made aware of the significant risk to their life, health, and the survival of a pregnancy due to their disease.

2. Women without known pulmonary hypertension should undergo screening with an echocardiogram and pulmonary function testing before or early in pregnancy to identify previously subclinical disease.

3. Women taking ACE inhibitors or angiotensin-receptor blockers should discontinue these prior to pregnancy, if possible.

4. Due to the high risk of preterm birth and preeclamp-sia, a daily dose of low-dose aspirin should be considered.

5. Women with scleroderma should be followed closely in pregnancy by rheumatology and a high-risk obstet-rical team. In addition, cardiology or pulmonologists may need to be involved on the basis of the degree of cardiopulmonary disease.

6. Repeated screening for intrauterine growth restriction should be performed in the third trimester.

PSORIATIC ARTHRITIS

Psoriatic arthritis (PsA) is a chronic destructive autoim-mune arthropathy often associated with the presence of psoriasis. Psoriasis is a chronic inflammatory skin condition

and are generally considered relatively safe.44 However, these agents may have limited efficacy for moderate to severely active disease and may be insufficient to control disease during pregnancy. The use or continuation of antitumor necrosis factor (TNF) agents during pregnancy has been more controversial. Some studies have suggested an increased risk for congenital abnormalities, whereas others have not.45 Cumulatively, the data seem to show that expo-sure to anti-TNF agents in pregnancy does not seem to increase risk of miscarriage, preterm delivery, or congenital malformations.46 In cases of severe inflammatory disease before or during pregnancy, TNF inhibitors may be used with caution, provided that the mother is aware of and comfortable with the risk-to-benefit ratio.

For acute flares of disease, use of glucocorticosteroids is the best option because they have a rapid onset of action and can be titrated to the level of disease activity. There is vast experience with glucocorticoids during pregnancy for many indications. Prednisone is perhaps the most ideal choice for the treatment of maternal disease because a very small amount of active drug will enter the fetal circulation.44 In fact, some women may even require regular glucocorti-coid use if background DMARD therapy is ineffective. The goal should always be to minimize the dose as best as pos-sible and to prescribe adequate calcium and vitamin D supplementation during use. Isolated joints may be best managed through direct local injection of steroids, thus avoiding significant systemic exposure to the drug. Although intermittent NSAID use appears to be safe, there are some risks to regular use, particularly during the latter half of pregnancy because it can be associated with premature closure of the ductus arteriosus.44

SCLERODERMA

The hallmarks of scleroderma, vasculopathy and fibrosis, complicate surprisingly few numbers of pregnancies in women with this disease. Pregnancies are relatively rare in women with scleroderma, primarily because the onset of the disease is often after a woman has completed her family. About 200 pregnancies in women with scleroderma have been reported in the literature, however, with largely good results. The rate of miscarriage is about 15%, which is 50% higher than in the general population.47 Stillbirths, however, are rare. Preterm birth rates range from 25% to 40%, depen-dent on the degree of internal organ damage.47 Reports of preeclampsia are rare, but in a nationwide database of preg-nancies, 23% of the 504 with scleroderma had hypertensive complications, including preeclampsia.48

To maintain pregnancy, a womans body must make major hemodynamic changes including an increase in blood volume of 50%, increase in cardiac output, and decreased vascular resistance.49 These adaptations may be hindered by underlying vasculopathy in women with scleroderma. Pul-monary hypertension, in particular, can both limit preg-nancy success and put the woman at significant risk for death from hemodynamic collapse. Pregnancy in a woman with pulmonary hypertension carries a maternal mortality rate of 17% to 33% with deaths caused primarily by right ventricular failure or pulmonary embolism.50 The risk for death is greatest around the time of delivery and in the


incidence of AS in women of childbearing potential, data regarding pregnancy experiences in this population are sparse.

Pregnancy Outcomes

Unlike SLE and RA, underlying maternal AS does not appear to be associated with increased risks of maternal or fetal morbidity. A questionnaire-based study of 649 women with AS in North America and Europe57 was performed looking at pregnancy outcomes. It was found that 15.1% ended with miscarriage, a rate not dissimilar to the general population. The overwhelming majority (93.2%) of cases delivered at term, but 58% delivered by cesarean section with AS, rather than other pregnancy-related conditions, as the stated indication. Neonates were healthy with a mean birth weight of 3339 g. Studies looking at pregnancy and fetal outcomes appear to show no increase in premature labor, preeclampsia, or adverse fetal outcomes.

Disease Outcomes

Most women with AS who become pregnant either remain stable or may have some clinical worsening of symptoms during the course of pregnancy. In addition, at least half will have some aggravation of symptoms in the postpartum period as well.54,57-59 In Ostensen and Husbys questionnaire-based study of pregnancy in AS, disease activity during pregnancy was reported as unchanged in 33.2%, improved in 30.9% (which correlated with a history of peripheral arthritis), and worsened in 32.5% (which was mostly increased low back pain/hip pain after week 20). Sixty percent had a postpartum flare within 6 months after deliv-ery.57 In a smaller study of nine patients with AS followed prospectively during pregnancy with validated disease activ-ity measures (BASDAI scores, morning stiffness, patient global assessment), the majority had active disease during pregnancy, four had a decrease of 20% during pregnancy, and no remissions were found. Furthermore, women with AS had high pain scores throughout pregnancy when com-pared with women with RA, with resultant increased utili-zation of NSAIDs and paracetamol.60

Special considerations specific to AS should be consid-ered. Bone loss is a well-recognized feature in AS. Osteopo-rosis is common and is largely related to disease activity, whereas vertebral fractures appear to be related to duration of disease and structural severity of the disease.61 The preva-lence of vertebral fractures has been reported but variable.62 Cooper and colleagues reported an increased odds ratio of 7.7 (4.3 to 12.6).63 These fractures are often spontaneous, low-trauma fractures. Pregnancy can also lead to osteoporo-sis and/or bone density loss, which most often occurs in the lumbar spine in the peripartum period or within a few months after the birth of a child. Bone density loss related to pregnancy in combination with underlying bone density loss or loss of integrity due to AS may increase the risk of fracture even further and has been reported.64,65 This bone fragility should especially be considered during delivery when tremendous intrauterine pressure, most of which is transmitted to the perineum and lumbar spine, is created during active labor and pushing. If a patient has severe osteoporosis and/or poor spinal mobility, an elective

manifested by hypertrophic erythematosus plaques with overlying scale that can be quite disfiguring and functionally limiting for affected patients. Both psoriasis and PsA affect men and women equally; the average age of onset of psoria-sis is in the second and third decades with PsA often occur-ring approximately 10 years later among the 20% who will go on to develop PsA.51

Pregnancy and Disease Outcomes

Outcomes data for women with PsA are scarce52; however, preconception counseling for patients with these conditions is similar to those with RA. They should have a good under-standing of drug toxicities, side effects, and benefits of use as detailed earlier. In addition, it appears as though women can expect some degree of improvement in their arthritis symptoms during pregnancy. At least half of women show some resolution of their arthritis in case series reported to date.53,54 However, the degree of improvement has not yet been elucidated because more recent data reviewing preg-nant PsA cohorts have not occurred. Furthermore, most case series and reports of pregnancy in PsA have occurred before the use of biologics and the era of better disease control, so it is difficult to say with certainty if these women actually clinically improve during as opposed to before preg-nancy. As in RA, a postpartum flare often occurs within 3 months.53 Studies looking at pregnancy and fetal outcomes appear to show no increase in premature labor, preeclamp-sia, or adverse fetal outcomes.53,54


Management of the arthritis in PsA during pregnancy is similar to that of RA. NSAID use sparingly, corticosteroids at low dose, and DMARDs that are not fetal toxic such as SSZ may be good options. Plaquenil is generally not com-monly used in patients with PsA due to the thought that it may increase flares in skin disease. Similarly, corticosteroids may be relatively contraindicated in some patients with profound cutaneous disease. As with other conditions, it is important to discontinue potentially teratogenic medica-tions including methotrexate and leflunomide before con-ception. The use of TNF inhibitors may be considered in cases of severe disease where the benefits of improved control of disease outweigh potential risks associated with antenatal exposure.

ANKYLOSING SPONDYLITIS

Ankylosing spondylitis (AS) is a chronic autoimmune disease that most often affects the axial skeleton, as well as the hips and shoulders, that is often, but not always, associ-ated with the HLA-B27 allele. In contrast to most autoim-mune diseases, AS displays a male predominance in a ratio of 4 : 1. The overall prevalence of disease in Caucasian populations is approximately 0.03% to 0.1%.55 Prevalence estimates in women of childbearing age are not available, but the incidence in Rochester, Minnesota, is 3.6 to 6.4 cases per 100,000 person-years.56 Treatment options for AS are much more limited than for RA, and most therapies do not appear to abrogate the progressive spinal fusion that is characteristic of the disease. Because of the relatively low


and pulmonary embolism have been reported, but the majority of women appear to do well without progression of Takayasus arteritis during pregnancy. More than 80% of pregnancies resulted in the delivery of a healthy baby, though preterm delivery, either spontaneous or induced for preeclampsia, was common. Intrauterine fetal demise was reported in 8% of pregnancies, and intrauterine growth restriction (a marker of poor placental perfusion) occurred in almost 20% of pregnancies.71

Treatment of Takayasus arteritis during pregnancy depends on the current symptoms of the disease. If active inflammation is present, leading to arterial damage, treat-ment with corticosteroids or immunosuppressants with a low teratogenic risk may be reasonable. Among asymptom-atic women, these medications may not be necessary during pregnancy and should not be started prophylactically. Close monitoring of blood pressure is essential during pregnancy, and treatment with acceptable antihypertensives will likely promote good placental health and minimize maternal organ damage. Blood pressure can increase significantly during labor, exacerbated by maternal exertion. It is impor-tant to keep in mind that maternal blood pressure measure-ments may be inaccurate with an arm cuff if subclavian stenosis is present. In these cases, internal blood pressure monitoring and/or avoidance of labor via a scheduled cesar-ean section may be prudent.

Small Vessel Vasculitis

Granulomatosis with polyangiitis (formerly Wegeners gran-ulomatosis), microscopic polyangiitis, and Churg-Strauss vasculitis are all rare small vessel vasculitides with a peak onset after the reproductive years. In addition, the primary treatment for severe disease includes cyclophosphamide, which leaves many women infertile. For these reasons, there are few systematically collected data on pregnancies in these diseases. A recent review of 20 pregnancies in 12 women with systemic necrotizing vasculitis (including WG, CSS, PAN, and MPA) from several centers in France included 2 elective abortions, 4 miscarriages, and 14 live births, half of which were delivered preterm. Complications included iso-lated episodes of pancreatic artery microaneurysms, tran-sient cardiac failure, renal insufficiency from thrombotic microangiopathy, and severe pneumonia. Vasculitis remained quiescent in most pregnancies.72 Case reports of small vessel vasculitis in pregnancy are similar with rela-tively good pregnancy outcomes. Several report the onset of vasculitis during pregnancy.

The principles of treatment of these vasculitides are similar to other systemic rheumatologic disease: Increased disease activity is likely related to poor pregnancy outcomes, so maintenance of quiet disease is important. Continuation of low-dose prednisone and azathioprine seems prudent in women with recently active disease, but these medications do not need to be initiated prophylactically in women who have been in remission.

Behets Disease

Behets disease, which primarily manifests with oral and genital ulcers but can also involve ocular or CNS disease and arterial or venous thrombosis, is a rare disease with

cesarean section may be considered to reduce risks associ-ated with active labor.


Management of AS during pregnancy is similar to that of RA. However, data regarding the relationship between active disease and adverse pregnancy outcomes are scarce due to fewer numbers of pregnant patients who have been studied. NSAIDs should be used as needed to improve func-tion, but use should be limited or discontinued in the third trimester. Corticosteroids at low dose and DMARDs such as SSZ may be good options to treat peripheral disease but do not have much utility in treating axial symptoms. Use of anti-TNF therapy during pregnancy remains controver-sial at this point and should be used only with caution in the absence of more definitive data regarding pregnancy outcomes.

The mechanical variants that result in patients with AS are important to consider during delivery. AS often results in inflammation of and/or fusion of the pubic symphysis or sacroiliac (SI) joints. Hormones released during pregnancy such as relaxin cause the symphysis pubis and SI joints to soften and separate to some degree to prepare for the birth-ing process. For example, the nonpregnant gap of the pubic symphysis is 4 to 5 mm but in every pregnancy there will be an increase in 2 to 3 mm. If fusion interferes in adequate separation, it can create a mechanical obstacle during labor and delivery. In some cases, this may cause increased pain and/or lead to need for cesarean section delivery as opposed to vaginal birth. As noted earlier, Ostensen and colleagues reported that, compared with healthy women, caesarean section was more frequently performed in patients with AS and in 58% of the cases AS was the indication for cesarean delivery.57 Aside from potential difficulties with labor mechanics, these ligament and/or joint changes in the setting of underlying inflammation may worsen pain symp-toms and increase SI joint or pubic symphysis dysfunction (a disorder common in healthy pregnant women).

VASCULITIS

The data on pregnancy in women with vasculitis are limited to case reports and case series. Because of the dearth of reli-able scientific data, many of our assumptions about the treatment of vasculitis in pregnancy are based on the prin-ciples we have learned about pregnancy in other systemic autoimmune diseases. Based on this, we assume that having significant vasculitis activity, particularly in the kidneys or lungs, is associated with poor pregnancy outcomes.

Takayasus Arteritis

Takayasus arteritis, a large vessel vasculitis that leads to stenoses and aneurysms in the aorta and its branches, pri-marily affects young women. More than 150 pregnancies in women with Takayasus arteritis have been published, most coming from five case series.66-70 The primary complication seen in these pregnancies was hypertension (30% of preg-nancies) with almost 20% developing preeclampsia.71 Serious maternal complications including myocardial infarction, aortic aneurysm and rupture, renal insufficiency,


patients, this is usually achieved with the use of warfarin to a target international normalized ratio (INR) of 2.0 to 3.0. In some cases, recurrent thromboses recur despite therapeu-tic levels of warfarin and these patients may need to be managed with a higher target INR of 3.0 to 4.0, long-term therapy with heparin, or combination antithrombotic agents.76

When women with APS and thrombotic manifestations consider pregnancy, aggressive antithrombotic therapy with LMW heparin must be continued to reduce risks of recur-rent maternal thromboses during the increased hypercoagu-lable state of pregnancy and the postpartum period. In addition, studies have suggested that women with throm-botic manifestations have higher risks of adverse pregnancy outcomes than do women with only obstetric manifesta-tions of APS despite using the more aggressive antithrom-botic management protocol with low-dose aspirin and LMW heparin (daily heparin dosing for obstetric APS com-pared with twice-daily dosing for thrombotic APS patients).77 Overall, with appropriate antithrombotic prophylaxis and management, live-birth rates are greater than 70%.76 At this time, there is no role for prednisone or other immunosup-pressive treatment in the prevention of thrombotic or obstetric complications due to APS.

Antiphospholipid Syndrome with Obstetric Manifestations

Optimal management of pregnancy in women who meet obstetric criteria for APS has been the subject of several randomized clinical trials and meta-analyses; unfortunately, some controversy remains regarding the optimal treatment regimen.76 Two randomized controlled studies found a sig-nificant reduction in pregnancy loss in women treated with unfractionated heparin plus aspirin when compared with aspirin alone.78,79 Other trials, comparing LMW heparin plus aspirin to aspirin alone, did not find a difference in live-birth rates.80,81 Studies that have evaluated the differ-ence between LMW or unfractionated heparin (plus aspirin) have failed to find a difference in outcomes.82,83 A recent meta-analysis of heparin plus aspirin compared with aspirin alone has concluded that heparin (LMW or unfractionated) plus aspirin has a 30% increase in live-birth rate compared with aspirin alone.84 Experts generally agree that low-dose aspirin should be instituted in the preconceptional period, with the addition of once-daily subcutaneous heparin (LMW or unfractionated) on confirmation of pregnancy.76,77 Newer experimental evidence strongly suggests a critical role of tissue factor and activated complement in APS-mediated pregnancy loss.85 Inhibitors of these factors have yet to be studied in the clinical setting.

Antiphospholipid Antibodies or Lupus Anticoagulant without a History of Clinical or Obstetric Events

Although the presence of lupus anticoagulant or antiphos-pholipid antibodies is associated with increased risks of adverse pregnancy outcomes, there is currently no way to predict which asymptomatic seropositive women will go on to develop related obstetric complications in the absence of a prior history of a clinical event. Thus randomized

limited pregnancy data. Case series are contradictory about the course of disease activity, with some reporting improve-ment and others worsening during pregnancy. Pregnancy outcomes are largely good, but some women have increased numbers of miscarriages and episodes of hypertension.73 Pregnancy is a period of hypercoagulability, so prophylactic treatment with low-molecular-weight (LMW) heparin for women with a history of thrombosis is important.

ANTIPHOSPHOLIPID ANTIBODIES AND THE ANTIPHOSPHOLIPID ANTIBODY SYNDROME

The antiphospholipid antibody syndrome (APS) is dis-cussed in detail in Chapter 82. However, the APS, albeit primary or secondary in women with other autoimmune diseases, has important implications for women who are considering pregnancy. In some cases, the clinical manifes-tations of the syndrome are limited to the obstetric realm. The revised 2006 criteria for the APS include (1) laboratory criteria: lupus anticoagulant, anticardiolipin antibodies, or anti-2 glycoprotein I positive on two or more occasions at least 12 weeks apart; (2) vascular thromboses: at least one unequivocal episode of arterial, venous, or small vessel thrombosis; and (3) obstetric criteria: one or more unex-plained deaths of a morphologically healthy fetus after 10 weeks gestational age; one or more births before 34 weeks gestation because of preeclampsia or placental insufficiency; or three or more consecutive spontaneous abortions (before 10 weeks gestation) without chromosomal, anatomic, hor-monal, or other causes to explain pregnancy loss.74 The prevalence of lupus anticoagulant or antiphospholipid anti-bodies in the general population is unknown, but it is esti-mated that up to 8.5% of the general obstetric population has positive antibodies.75 However, it is important to recog-nize that the mere presence of antibodies/lupus anticoagu-lant does not in itself confer an increased risk of thromboses/obstetric complications, and actual clinical events are required to make a diagnosis of the actual syndrome. For example, only about 40% of SLE patients with positive titers for antiphospholipid antibodies will develop throm-botic events, even though SLE patients have a high preva-lence of antibodies.76 When thinking about pregnancy outcomes among women with antiphospholipid antibodies or the antiphospholipid antibody syndrome, it is helpful to divide women into three general categories: (1) women with APS and a history of arterial/venous thrombotic events; (2) women with APS with clinical manifestations limited to obstetric complications (no maternal thrombotic events); and (3) asymptomatic women found to have posi-tive tests for lupus anticoagulant and/or antiphospholipid antibodies (no history of adverse pregnancy outcomes or maternal thromboses).77

Antiphospholipid Antibody Syndrome with Thrombotic Manifestations

As is evident in the nonpregnant population of APS patients with a history of arterial or venous thromboses, there is a high rate of recurrent thromboses and lifelong anticoagu-lant therapy is the mainstay of treatment.76 In nonpregnant


similar study from a Danish birth registry found an increased risk for miscarriage, particularly for women who picked up a prescription for NSAIDs in the 6 weeks before the miscar-riage (odds ratio [OR], 3.0 to 6.99).87 Suppression of pros-taglandins by NSAIDs may lead to poor implantation or decreased placental perfusion, both of which can precipitate miscarriage. Avoidance of frequent NSAID use in the first trimester and around the time of conception may be prudent.86

Many studies have not found an association between NSAIDs and a higher rate of congenital malformation, preterm birth, or low birth weight.87 Several studies, however, have identified a possible link between NSAID use and congenital heart defects.88,89

In the second and third trimesters, NSAID use may decrease fetal renal perfusion, leading to decreased amniotic fluid production and oligohydramnios. This condition is typically reversible with cessation of the drug.

NSAIDs are contraindicated in the third trimester because they can prompt closure of the fetal ductus arterio-sus (DA), the channel through which blood bypasses the fetal lungs. In previous years, NSAIDs were used as tocolytic agents to halt premature labor, allowing several elegant studies demonstrating the impact of NSAID use at different points in the third trimester. With exposure before 27 weeks gestation, the DA is largely unaffected. Between 27 and 34 weeks, however, about half of the fetuses will have constriction of the DA, a finding that is evident within hours of NSAID dosing but reverses within several days.90 Preterm infants with third-trimester exposure to indometh-acin have a higher rate of necrotizing enterocolitis, intra-ventricular hemorrhage, and a mild decrease in renal function for several days of life.91

During lactation, the preferred NSAID is ibuprofen due to its relatively short half-life and low penetration into breast milk. For a woman taking 400 mg of ibuprofen every 6 hours, less than 1 mg of ibuprofen is excreted into the breast milk each day.92 This is far lower than the recom-mended maximum pediatric dose of 40 mg/kg per day.

Corticosteroids

Corticosteroids vary structurally and will affect the mother and fetus differently. Betamethasone and dexamethasone have fluorine at the 9-alpha position and are not well metabolized by the placenta. They will cross the placenta with direct effects on the fetus. Most other corticosteroids, however, are metabolized in the placenta by 11-beta-hydroxysteroid dehydrogenase to inactivated forms, leaving less than 10% of the active drug to reach the fetus.93 If the goal is to treat the mother, prednisone is the most ideal glucocorticoid because a small amount of active drug will enter the fetal circulation. If the goal is to treat the fetus, betamethasone and dexamethasone are better options and are commonly used in women at risk for preterm delivery to reduce the risk of respiratory distress and cerebral hemor-rhage in the preterm infant. Some recent reports suggest betamethasone may be preferred to dexamethasone because it may offer better long-term neurodevelopmental outcomes for the fetus.94,95

Corticosteroids carry the risk of elevated blood pressure, steroid-induced hyperglycemia, and osteopenia. These risks

controlled trials or risk-benefit analyses of primary prophy-laxis during pregnancy are not available. This can be par-ticularly troubling in primigravidas with known positive antibodies because outcomes of previous pregnancies cannot be used to predict the course of a current or future preg-nancy. In these cases, the risk of bleeding associated with use of heparin and aspirin is not offset by a theoretic improvement in pregnancy outcomes. Many practitioners elect to use low-dose aspirin alone in these situations, although there are no data to support this practice. In sub-jects with SLE and asymptomatic antiphospholipid antibod-ies, the use of HCQ before and during pregnancy may be considered because HCQ may have some antithrombotic properties by several different mechanisms.85 Again, no clinical data are available to support the routine use of HCQ in pregnant women for the purpose of reducing the risk of APS-related obstetric complications.

MEDICATIONS IN PREGNANCY AND LACTATION

The decision to use medications in pregnancy must always balance the risks and benefits to both mother and fetus. For some more systemic rheumatologic diseases, in particular SLE, the risk to the pregnancy of active SLE outweighs the risks of many medications. For other more limited diseases such as RA, the disease process has limited impact on the fetus, making medications more optional.

The U.S. Food and Drug Administration (FDA) rates each medication on the basis of its potential risk to the fetus (Table 39-2). Although this system can provide some general guidance, it is not a perfect system by which to treat a patient. For example, azathioprine and MMF are both FDA class D immunosuppressants, but current data indicate that azathioprine is probably far safer for a fetus than MMF. The FDA has plans to replace the current grading system with more objective data, but when this change will occur is unclear.

Breast-feeding is generally believed to be beneficial to both mother and infant in the best of circumstances. Some rheumatologic medications may transfer into breast milk to a degree that is potentially dangerous, whereas others have more limited transfer. Although current infor-mation on lactation and medications is included in this chapter (see Table 39-2), continually updated information is available from the Texas Tech University Infant Risk website at www.infantrisk.org/.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are classified by the FDA as C, with possible risks in the first and second trimesters, but D in the third trimes-ter with well-defined risks.

Some evidence indicates that frequent use of NSAIDs in the week of conception can increase the risk for miscarriage. In a case-control study based on pregnant women in the Kaiser hospital-system database, those taking NSAIDs around conception and in the first trimester had a 1.8-fold increase in miscarriage. That risk increased to a 5.6-fold risk for women taking the NSAID in the week of conception and to an 8.1-fold risk for those taking daily NSAIDs.86 A


should the findings be true, it should be noted that cleft palates occur at a rate of about 1/1000 in the general popula-tion and thus the risk with steroid use would increase this to 3/1000. This small increase in risk should be weighed against the need to treat active disease in the mother. There have also been rare isolated reports of neonatal cataracts and adrenal suppression in infants after corticosteroid use, which may be dose dependent.90

The pharmacokinetics of prednisolone, the active form of prednisone, has been studied in breast milk.97 Levels measured in the milk are typically less than 0.1% of the total prednisolone dose ingested by the mother, which when small to moderate doses are being used, is less than 10% of the infants endogenous cortisol production. Ost and col-leagues97 evaluated a patient taking up to 80 mg of daily

are pertinent in a pregnant woman because pregnancy requires tight blood pressure control and may induce insulin resistance (and often frank gestational diabetes), as well as osteopenia or osteoporosis of pregnancy. These issues can be exacerbated by steroids, so proper monitoring and calcium and vitamin D supplementation should be employed.

Nonfluorinated corticosteroids do not appear to put a fetus at risk for congenital abnormalities. The exception is a few reports of an increased risk of cleft lip and/or palate, a first-trimester risk. A meta-analysis looking at birth defects after maternal exposure to corticosteroids reported a 3.3 increase in the odds ratio of clefts after first-trimester expo-sure.96 Subsequent studies have been mixed, some showing similar results and some showing no difference. However,

Table 39-2 Frequently used Rheumatologic medications in Pregnancy and Lactation

DrugFDA Pregnancy Classification Teratogenic Risks Other Pregnancy Issues Lactation

nsAiDs C (first and second trimesters)

D (third trimester)

minimalPossible risk of gastroschisis

Decreased fetal renal blood flow causing oligohydramnios

Closure of the ductus arteriosus

Prolongation of labor

ibuprofen preferred for short half-life and limited transfer into breast milk

Prednisone C Possible increased risk of cleft palate with doses >20 mg daily

maternal hyperglycemia leading to macrosomia

Hydroxychloroquine C Low risk of ocular toxicity Decreases sLE flare; may decrease risk for cardiac neonatal sLE

AAP: compatible with lactation

sulfasalazine B minimal risk infant may have minimal immunosuppression

Compatible with lactation; theoretic risk for kernicterus: limit exposure for premature infants or those with jaundice

methotrexate X 5%-10% risk of anomaly with first-trimester exposure

increased risk of pregnancy loss; treat with increased folic acid

not advised

Leflunomide X High risk in animal studies; no known increased risk in human study

Cholestyramine not advised

Azathioprine D minimal risk infant may be immunosuppressed at delivery

not advised

mycophenolate mofetil

D increased risk of anomalies, particularly in the ear

increased miscarriage risk

not advised

Cyclophosphamide D increased risk with first- trimester exposure but not second or third trimester

increased miscarriage risk

not advised

TnF inhibitors B may not be increased; proposed associated with VACTERL association

may be allowable due to minimal transfer into breast milk and low absorption of immunoglobulins via the gi tract

Rituximab C no known risks of fetal malformations

Exposure just before conception or during pregnancy may lead to neonatal cytopenias

unknown

Tocilizumab C unknown may increase miscarriage risk

unknown

AAP, American Academy of Pediatrics; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, sys-temic lupus erythematosus; TNF, tumor necrosis factor; VACTERL, Vertebral abnormalities, Anal atresia, Cardiac abnormalities, Tracheoesophageal fistula and/or Esophageal atresia, Renal agenesis and dysplasia, and Limb.


considered an effective form of contraception. Abnormal or reduced spermatogenesis is due to the SSZ metabolite sulfapyridine.

In contrast to its effects on men, SSZ is among the more preferred DMARDs for pregnant women who require ongoing disease-modifying therapy. Much of the data regarding pregnancy outcomes with SSZ exposure is derived from the inflammatory bowel disease (IBD) literature. A recent meta-analysis of 2200 pregnant women with IBD (642 received SSZ or related agents) found no statistically significant differences for congenital anomalies (OR, 1.16; 95% confidence interval [CI], 0.76 to 1.77) or other adverse pregnancy outcomes.113 These data confirm several other reports of population-based studies published over the past several decades.114,115 Congenital abnormalities discussed in isolated case reports have not been seen in systematic population-based studies.

Two additional considerations are worth noting. The first is the theoretic risk that SSZ may cause folate deficiency as it inhibits dihydrofolate reductase and the cellular uptake of folate.116 Pregnant women require at least 800 g of folic acid replacement, which should be continued, and perhaps increased, during SSZ use. Folic acid deficiency has been linked to neural tube defects, which can occur as early as 5 weeks of pregnancy (just 3 weeks after conception), so this should be part of the preconception planning discussions. The second consideration is in regards to late-term use. A SSZ metabolite called sulfapyridine can cross the placenta, displace bilirubin from albumin, and possibly lead to neo-natal jaundice.117 Although there are no reports of this occurring after in utero exposure to SSZ, one may consider holding SSZ use during lactation in a preterm or jaundiced baby for 1 to 2 months.

Except in the setting of prematurity, hyperbilirubinemia, or other acute stresses, SSZ is considered safe during lacta-tion. Sulfapyridine levels in breast milk were found to be about 30% to 60% of those in the mothers serum,118 but should not pose risk for a healthy full-term infant.

Azathioprine

Azathioprine (AZA) carries an FDA classification of D, but it is widely viewed as one of the safest immunosuppressants available in pregnancy. While animal studies have identi-fied congenital anomalies after in utero exposure, several large human studies in women taking the drug for SLE, inflammatory bowel disease, or solid-organ transplants have documented no risk of congenital anomalies following exposure. The few reported congenital anomalies in preg-nancies exposed to AZA seem to be sporadic without a specific organ or pathogenic pattern. Pregnancies exposed to AZA, however, are at increased risk for preterm birth and growth retardation. Whether this is more related to the drug or the underlying maternal disease remains unclear.

AZA does cross the placenta, and infants are born with low levels of the drug and its metabolites. This leads to a theoretic risk for neonatal infection that has not been borne out in prospective studies.

For some women with systemic rheumatologic disease, the benefits of disease suppression outweigh the potential risks of AZA. Significant SLE activity, for example, is asso-ciated with up to a 40% risk of miscarriage and over a 60%

prednisolone and calculated that the prednisolone ingested from the milk would add, at most, 10% to the endogenous corticosteroid production of the infant, which may have little clinical significance. Peak steroid levels in breast milk occur about 2 hours after a dose is taken and rapidly decline.98 These small to moderate amounts of corticoste-roids do not appear to have adverse effects on the develop-ing infant; however, exposure may be minimized if nursing is done 3 to 4 hours after the dose is taken.

Hydroxychloroquine

HCQ crosses the placenta, and infants may be born with similar serum concentrations of the drug as the mother. The literature includes several reports of isolated women taking daily chloroquine during multiple pregnancies and having infants born with anomalies, most commonly ocular. This finding, however, has not been replicated in studies of HCQ. Researchers systematically evaluated almost 100 infants in several studies for ocular toxicity and did not find abnormalities.99-103 A recent study of 21 infants with in utero HCQ exposure found electroretinogram abnormalities in 6, with resolution in one after 7 months. Prior reports of six children and four children with in utero HCQ exposure did not find abnormalities with this testing.104,105 Further information about the lasting impact of HCQ on the retina of infants will be helpful. A study of cardiac conduction in exposed infants found no anomalies.106 Several larger studies have found no increase in fetal anomalies in infants exposed to daily dosing of HCQ for rheumatologic disease.106,107

The discontinuation of HCQ early in pregnancy is asso-ciated with SLE flare and decreased gestational age.106,107 An increase or decrease in preterm birth and pregnancy loss has not been statistically associated with HCQ use. A case-control study of cardiac neonatal lupus has found a protec-tive effect from HCQ. Although univariate analysis in this study found a 70% decrease in cardiac neonatal lupus with HCQ use, multivariate analysis did not maintain statistical significance for this finding.108 Prospective studies of HCQ for prevention of neonatal lupus would provide valuable clinical information for women with Ro/SSA antibodies.

HCQ does cross into breast milk but in limited quanti-ties.109,110 Analysis of two lactating women taking HCQ estimated that a fully breast-fed infant would ingest an esti-mated 0.2 mg/kg/day of HCQ, compared with maternal dosing of 6 mg/kg/day.104 The American Academy of Pedi-atrics has designated HCQ as compatible with breast-feeding with only minimal risk to the infant.111 For this reason, breast-feeding is generally allowed in women taking HCQ.

Sulfasalazine

Fertility in women does not appear to be affected by SSZ use; however, it can lead to reduced fertility in men due to oligospermia and reduced sperm motility. Fortunately, this is not an irreversible event; normal spermatogenesis should return approximately 2 months after cessation of the drug. Men who want to conceive a child with a partner should be counseled to discontinue the medication 3 months prior.112 It is also important to counsel men that, although fertility may be reduced, the use of SSZ is not


resulted in fetal anomalies, decreased birth weight, and increased mortality in the offspring after birth.22 On the basis of available animal data, the FDA has categorized leflunomide as category X; this indicates that clear associa-tions between the drug and fetal abnormalities have been identified and the risks of use in pregnant humans outweigh any potential benefits. In his article reviewing reproductive risks of leflunomide, Brent nicely outlines managing elimi-nation of leflunomide in a woman who has become preg-nant on leflunomide or desires pregnancy largely on the basis of manufacturer and FDA recommendations.123 The level believed to be safe in humans is 0.02 mg/L (i.e., 10 half-lives). If a woman treated with leflunomide wants to become pregnant, the medication should be stopped and cholestyramine administered to decrease the blood levels rapidly to this level. Cholestyramine, 8 g three times daily, reduces the half-life of the active metabolite from what has been found in early pharmacokinetics analysis to be up to 96 days to approximately 1 day. Therefore, a 10- to 11-day regimen of cholestyramine, 8 g three times daily, is recom-mended. This approach is certainly conservative but was suggested by the FDA and is the manufacturers recommen-dation. Plasma levels of the drug should be verified to be less than 0.02 mg/L by two separate tests performed 2 weeks apart. If levels still remain greater than 0.02 mg/L, then the regimen should continue to be administered and women should use effective contraception until levels are less than 0.02 mg/L. Based on the natural half-life of the drug (again, 96 days) it may take up to 2 years to reach plasma active metabolite levels of 0.02 mg/mL due to individual varia-tions; therefore levels should be checked (and if necessary cholestyramine administered) in any patient who has been treated with leflunomide in the previous 2 years. This prac-tice is also supported by a panel of 29 experts who partici-pated in a consensus workshop on antirheumatic drugs during pregnancy and lactation.90

Despite the dramatic fetal anomalies seen in rodents after leflunomide exposure, the available human data are more reassuring. Data from the OTIS Collaborative Research Group prospectively evaluated 64 women with RA treated with leflunomide (95% of which were treated with cholestyramine early in the pregnancy), 108 women with RA not treated with leflunomide, and 78 healthy preg-nant women. The rate of major structural defects in the exposed group was 5.4%, which was insignificant compared with both comparison groups (4.2% and 4.2%, respectively, P = .13). Although a small study group, these results are encouraging and suggest that these defects may be prevent-able with appropriate and early intervention.43 It is unknown how leflunomide exposure may affect a young infant, and lactation is considered to be unsafe until more data become available.

Mycophenolate Mofetil

MMF, a reversible inhibitor of inosine monophosphate, was FDA approved in 1995 for use in solid organ transplanta-tion. It is used with increasing frequency for the treatment of autoimmune conditions including lupus nephritis. MMF has been shown to be teratogenic in experimental animals, and increasing data through case reports and registry studies support its teratogenicity in humans.124-127 MMF readily

risk for preterm birth. Any potential harm from AZA use in pregnancy is dwarfed by these statistics. Two small studies of AZA use in SLE pregnancies show an association between AZA therapy and pregnancy loss that is strongly confounded by SLE activity.119,120 For SLE pregnancies in which SLE activity remains quiescent with AZA therapy, there is no increase in pregnancy loss or preterm birth.119

Although AZA does not appear to transfer into breast milk to a significant degree, breast-feeding while taking this medication is discouraged by the World Health Organiza-tion Working Group on Drugs and Human Lactation.121

Methotrexate (FDA Class X)

Methotrexate is a dihydrofolate reductase inhibitor that impairs purine metabolism, leading to abnormalities in ribo-nucleic acid and deoxyribonucleic acid synthesis. It is a known teratogen that can cause dysmorphic facial features, skull and limb abnormalities, and growth deficiency. In addition, developmental delay and mental retardation have been reported.122 The main toxicity appears to occur before 8 weeks gestation and can occur with high-dose methotrex-ate for cancer therapy or pregnancy termination, and in low-dose methotrexate it is used to treat rheumatologic disease. Although case reports include descriptions of sig-nificant anomalies, prospective and retrospective cohorts of pregnancies exposed to this drug do not demonstrate a high rate of anomalies. A collection of 97 pregnancies in women with rheumatologic disease exposed to methotrexate from 6 reports found a rate of anomaly of 7% of live births. Elec-tive termination was frequent (17%), and spontaneous mis-carriage was high (23% of pregnancies not terminated).122

All women taking methotrexate should be well informed about the risk for fetal anomalies and pregnancy loss associ-ated with the drug. A reminder that methotrexate is rou-tinely used to terminate ectopic pregnancies (at a dose about threefold the rheumatologic dose) can make this risk clearer. If a pregnancy is exposed to methotrexate, an increased dose of folic acid may be initiated; folinic acid therapy has been demonstrated to decrease the risk for fetal anomalies in some animal models.122 For women who have discontinued methotrexate at least 3 months before concep-tion, as is recommended, continuation of folic acid through pregnancy is recommended.

Given the relatively low rate of fetal anomalies identified in pregnancy cohorts, routine recommendation for preg-nancy termination is not required but should be offered to all women. Women who decide to continue pregnancy must understand the risks for both pregnancy loss and fetal abnor-malities. In wanted pregnancies, ultrasound screening for fetal anomalies should be encouraged with consideration of termination if these are identified. Unfortunately, ultra-sound may not be able to uncover all fetal anomalies, leaving some risk for anomaly despite normal evaluations.

Methotrexate has not been studied in lactation and is not recommended.

Leflunomide

It is known that leflunomide causes fetal anomalies in animals, primarily CNS and skeletal anomalies. When leflu-nomide was given to rats at only 1% of the human dose, it


One report of the FDA drug toxicity database hypo-thesizes that in utero TNF inhibitor exposure is associated with Vertebral abnormalities, Anal atresia, Cardiac abnor-malities, Tracheoesophageal fistula and/or Esophageal atresia, Renal agenesis and dysplasia, and Limb (VACTERL) association.132 VACTERL association is diagnosed when an infant is born with at least three major anomalies that are included in the previous definition. This hypothesis was prompted by the diagnosis of this association in an infant exposed to etanercept 50 mg twice a week throughout ges-tation for maternal PsA. In the FDA database, another 54 anomalies in 40 infants were identified. None of these infants met criteria for VACTERL association, but 56% of these anomalies fell into the categories included in the VACTERL diagnosis. Although this report brings to light potentially important data, it has several drawbacks when applied to clinical practice. Most importantly, the total number of pregnancies exposed to TNF inhibitors is unknown. In order to find an anomaly rate typical in the general population (3%), only 1200 pregnancies would require exposure to produce 40 infants with anomalies. In addition, the most common anomalies reported in the FDA database including cardiac and urogenital anomalies are also the most common seen in the general population. The more uncommon anomalies are only reported in one to two infants after TNF inhibitor exposure, leading to difficulty associating these with a specific cause.

Although immunoglobulins do not cross the placenta in the first half of pregnancy, the rate of immunoglobulin transfer increases linearly through the following weeks, leading to a large transfer in the weeks before term. At birth, the infant has a higher concentration of maternal antibod-ies than the mother.134 Based on this finding, it is hypoth-esized that TNF inhibitors do not cross the placenta before 16 weeks gestation but do cross in increasing concentra-tions as the pregnancy progresses. Infliximab has been docu-mented to cross the placenta in high levels close to term with infants exposed in utero having serum levels similar to the mother at delivery.135 The infant serum levels slowly decrease over the following weeks to months. Etanercept, on the other hand, may cross at lower levels. A single infant born after etanercept throughout pregnancy had a serum concentration under 4% of the maternal serum concentra-tion136 (Figure 39-3).

IgG immunoglobulins do not transfer into human breast milk, and they are not absorbed by the human infant gas-trointestinal tract. Six women taking infliximab during lac-tation have been documented to have no drug in their breast milk. Two women taking etanercept have been docu-mented to have minimal drug in their breast milk. Infants fully breast-fed by mothers taking both of these drugs have not had increasing serum TNF inhibitor concentrations.45

Rituximab

Rituximab is a chimeric (mouse/human) monoclonal anti-body directed against B cell surface antigen CD20 that is indicated for the treatment of B cell lymphoma and moderate to severe RA. In addition, it has been studied and is occasionally used off label for the treatment of other autoimmune diseases and hematologic disorders (SLE, multiple sclerosis, autoimmune cytopenias, thrombotic

crosses the placenta. Exposure to MMF during embryogen-esis leads to a possible increased rate of spontaneous abor-tions126 and an estimated 22% to 26% rate of congenital malformations.125,126 A distinctive MMF embryopathy has been identified as the EMFO tetrad: Ear (microtia and auditory canal atresia); Mouth (cleft lip and palate); Fingers (brachydactyly of fifth fingers and hypoplastic toenails; and Organs (cardiac, renal, CNS, diaphragmatic, and ocular).125 Based on these data, the FDA has recently included a black box warning on the package insert discussing terato-genicity as a concern with use of MMF in women of child-bearing potential.128 Use of reliable contraception is mandatory for women of childbearing potential. Women taking MMF who want to become pregnant should discon-tinue the drug at a minimum of 6 weeks before conception. In cases in which ongoing immunosuppression is required to maintain the mothers health, azathioprine is often con-sidered a safer alternative. There are no data on the excre-tion of MMF into breast milk or the effect if ingested by infants. Therefore lactation is also contraindicated while using MMF.

Cyclophosphamide

Cyclophosphamide (CYC) is an alkylating agent that alters DNA synthesis. It has an FDA pregnancy classification of D, indicating a significant and known risk with fetal expo-sure. First-trimester exposure to CYC carries a high risk for major congenital anomalies, particularly of the palate, limbs, and eyes, as well as miscarriage. The rate of these anomalies is unknown due to difficulties with prospective studies, but these malformations are not found in all live births after first-trimester exposure.

In the second and third trimesters, the risks for congeni-tal anomalies is far lower. While data is limited, pregnancies exposed because of maternal breast cancer in pregnancy have resulted in healthy, full-term infants. Among SLE pregnancies reported in the literature with mid to late tri-mester CYC exposure, two resulted in a fetal death and one in a successful preterm birth.129-131 In these cases, the mother was very ill preceding the CYC dosing, making it likely that the pregnancy loss would have occurred without the CYC treatment, as well. When a pregnant woman has a life-threatening flare of rheumatologic disease in the latter half of pregnancy, treatment with CYC can be entertained. The significant risk of pregnancy loss in this situation, with or without CYC therapy, should be discussed with the woman prior to dosing.

CYC transfers into breast milk and has been associated with cytopenias in nursing infants.131 For this reason, women taking CYC should not breast-feed.

Tumor Necrosis Factor

Due to a lack of fetal anomalies or adverse pregnancy out-comes found in animals exposed to TNF inhibitors, these all carry an FDA pregnancy classification of B. This does not mean, however, that they have been satisfactorily con-firmed as safe in human pregnancy. Limited prospective data on pregnancies exposed to TNF inhibitors suggest that there is not an increase in fetal anomalies, pregnancy loss, or preterm birth.46


concentration of rituximab in breast milk or its effects on breast-feeding infants.

Tocilizumab

The IL-6 inhibitor tocilizumab is an IgG antibody, so it likely crosses the placenta in the latter half of pregnancy. A preliminary report of pregnancy toxicity included 33 preg-nancies, largely to women enrolled in the drug studies per-formed for FDA approval of this drug. Of these, 48% were electively terminated and 9% had unknown outcomes. Of the remaining 16 pregnancies, 5 (31%) resulted in a spon-taneous abortion, 8 (50%) resulted in a full-term infant, 1 resulted in an infant death due to lung disease, and 1 was a gestational trophoblastic tumor.139 This suggests a higher rate of miscarriage than would be expected in RA pregnan-cies, but an assessment of further risks is not possible. No lactation information about this drug is available, so at this time it is not recommended.

selected References1. Whitacre CC, Reingold SC, OLooney PA: A gender gap in autoim-

munity, Science 283(5406):12771278, 1999.2. Mor G, Cardenas I: The immune system in pregnancy. A unique

complexity, Am J Reprod Immunol 63:425433, 2010.3. Saito S, Nakashima A, Shima T, Ito M: Th1/Th2/Th17 and regula-

tory T-cell paradigm in pregnancy, Am J Reprod Immunol 63:601610, 2010.

4. Petroff MG, Perchellet A: B7 family molecules as regulators of the maternal immune system in pregnancy, Am J Reprod Immunol 63:506509, 2010.

5. Trowsdale J, Betz A: Mothers little helpers: mechanisms of maternal-fetal tolerance, Nature Immunol 7:241246, 2006.

6. Petri M, Allbritton J: Fetal outcome of lupus pregnancy: a retrospec-tive case-control study of the Hopkins Lupus Cohort, J Rheumatol 20:650656, 1993.

7. Smyth A, Oliveira GH, Lahr BD, et al: A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis, Clin J Am Soc Nephrol 5:20602068, 2010.

8. Johnson MJ, Petri M, Witter FR, Repke JT: Evaluation of preterm delivery in a systemic lupus erythematosus pregnancy clinic, Obstet Gynecol 86:396399, 1995.

9. ACOG Committee on Practice BulletinsObstetrics: ACOG prac-tice bulletin. Diagnosis and management of preeclampsia and

thrombocytopenic purpura). Administration results in rapid and sustained depletion of peripherally circulating CD20+ B cells. Like other monoclonal antibodies, rituximab has an IgG construct and therefore crosses the placenta. Little IgG is seen in fetal circulation during the first trimester of preg-nancy. Levels slowly rise during the second trimester and reach maternal serum concentrations by approximately 26 weeks gestation. Maximum IgG transfer across the maternal-fetal interface occurs during the last 4 weeks of gestation, and fetal concentration often exceeds maternal concentra-tion at term delivery. Rituximab carries an FDA pregnancy classification of C. Several case reports of rituximab admin-istered during the second or third trimester of pregnancy for acute life-threatening maternal disease have been pub-lished. They have not found associations between antenatal rituximab exposure and adverse pregnancy outcomes or congenital malformations. More recently a study describing pregnancy outcomes following preconceptional or antenatal exposure to rituximab in the rituximab global safety data-base was published.137,138 Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death of unknown cause at 6 weeks. Eleven neonates had hematologic abnor-malities, none with corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, CMV hepati-tis, and chorioamnionitis); the rate of congenital malforma-tions was not different than the 3% to 4% expected in the general population. Two congenital malformations were identified: clubfoot in one twin and cardiac malformation in a singleton birth. In almost all cases, pregnancy was complicated by active maternal disease and concomitant use of potentially teratogenic medications (including com-bined chemotherapy with alkylating agents, methotrexate, MMF, and warfarin). The authors concluded that there was no apparent pattern of adverse outcomes (perinatal infec-tions, symptomatic cytopenias, or congenital malforma-tions) associated with rituximab exposure; however, patients should be followed closely if a pregnancy occurs within 6 months following rituximab administration or therapy is indicated to treat severe maternal disease during an estab-lished pregnancy. No data are available regarding the

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Figure 39-3 in utero tumor necrosis factor inhibitor exposure leads to transfer of the drug to the infant. A, infliximab 10 mg/kg was administered for severe Crohns disease five times in pregnancy with the last dose given 2 weeks before delivery. At 6 and 10 weeks postpartum (PP), the maternal and infant serum concentrations of infliximab were similar. Following a postpartum maternal dose of infliximab, the infant continued to have decreas-ing serum levels despite breast-feeding. B, Etanercept (25 mg subcutaneously twice a week) was administered throughout pregnancy and lactation to a woman with severe rheumatoid arthritis. At delivery, the infant had a serum level 3.5% of the maternal level. The infant level decreased over the following weeks despite breast-feeding.136


35. Nelson JL, Hughes KA, Smith AG, et al: Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis, N Engl J Med 329:466471, 1993.

36. de Man YA, Dolhain RJ, van de Geijn FE, et al: Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study, Arthritis Rheum 59:12411248, 2008.

37. Barrett JH: Does rheumatoid arthritis remit during pregnancy and relapse postpartum: results from a nationwide study in the United Kingdom performed prospectively from late pregnancy, Arthritis Rheum 42:12191227, 1999.

38. Zrour SH, Boumiza R, Sakly N, et al: The impact of pregnancy on rheumatoid arthritis outcome: the role of maternofetal HLA class II disparity, Joint Bone Spine 77(1):3640, 2010.

39. van der Horst-Bruinsma IE, de Vries RR, de Buck PD, et al: Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother, Ann Rheum Dis 57:286290, 1998.

40. Brennan P, Barrett J, Fiddler M, et al: Maternal-fetal HLA incompat-ibility and the course of inflammatory arthritis during pregnancy, J Rheumatol 27:28432848, 2000.

41. De Man YA, Bakker-Jonges LE, Dufour-van den Goorbergh CM, et al: Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy, Ann Rheum Dis 69:420423, 2010.

42. Wallenius M, Skomsvoll JF, Irgens LM, et al: Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry, Ann Rheum Dis 69:332336, 2010.

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44. stensen M, Lockshin M, Doria A, et al: Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs, Rheumatology (Oxford) 47(Suppl 3):iii28iii31, 2008.

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46. Vinet E, Pineau C, Gordon C, et al: Anti-TNF therapy and preg-nancy outcomes in women with inflammatory arthritis, Expert Rev Clin Immunol 5:2734, 2009.

47. Steen VD: Pregnancy in scleroderma, Rheum Dis Clin N Am 33:345358, 2007.

48. Chakravarty EF, Khanna D, Chung L: Pregnancy outcomes in sys-temic sclerosis, primary pulmonary hypertension, and sickle cell disease, Obstet Gynecol 111:927934