Connective tissue disease in pregnancy
======================================

* Oier Ateka-Barrutia
* Catherine Nelson-Piercy

## Abstract

Connective tissue diseases (CTD) include a variety of chronic multisystem disorders with a high percentage of autoimmune conditions. Many of these conditions affect women of childbearing age and, therefore, pregnancy poses an important challenge for doctors looking after such women. Knowledge of medication safety, the effect of pregnancy on such diseases and vice versa, together with preconception counselling and multidisciplinary team care, are the basic pillars needed to provide the best obstetric and medical care to these women. In this review, we discuss the management of the most common autoimmune CTD before, during and after pregnancy, along with the most relevant issues regarding appropriate medication.

Key Words
*   Pregnancy
*   connective tissue disease
*   management
*   pre-pregnancy counselling
*   medications

## Introduction

The changes in hormonal profiles found in pregnancy induce important immunomodulatory changes, with direct consequences on immune-mediated connective tissue diseases (CTD). Fertility in women with CTD is generally not affected, although patients with chronic kidney disease (CKD stage 3–5, with an estimated glomerular filtration rate (eEGR) of <50 ml/min), amenorrhoea because of previous high cumulative doses of cyclophosphamide and/or active disease might have reduced fertility.1 Therefore, knowledge of the management of CTD in pregnancy is important for doctors looking after women of childbearing age with CTD.

Women who are keen to undergo assisted reproductive techniques should be counselled about the increased risk of disease flare (particularly women with systemic lupus erythematosus (SLE) and thromboembolic events. Identification of high-risk patients (Box 1), pre-cycle counselling, and adequate thromboprophylaxis, plan of management and surveillance are mandatory.2

  
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## Systemic lupus erythematosus

### Effect of pregnancy on SLE

SLE flares during pregnancy have been related to irreversible organ damage.3 However, whether pregnancy increases the risk of lupus flare is still unresolved,4 although the puerperium might be a period of particular high risk. The risk of flare appears to be dependent on the disease activity 6–12 months before conception, because women with quiescent lupus over this period have less risk of flare during pregnancy, and vice versa.5 Active lupus nephritis (LN) at conception, and even in remission, confers a higher risk of flare during pregnancy6. Pregnancy does not seem to endanger long-term renal function, although, generally, the higher the baseline creatinine, the greater the risk of deterioration.6 Lupus flares during pregnancy and postpartum are usually non-severe (ie articular, dermatological and mild haematological), although severe flares with major organ involvement can occur. Given the multiple protective effects of hydroxychloroquine (HCQ),7 all women should be encouraged to continue to take HCQ throughout pregnancy and postpartum.

Distinguishing pregnancy-related signs and symptoms from certain lupus features can sometimes be difficult (Table 1). In pregnancy, erythrocyte sedimentation rate (ESR) and serum C3 and C4 levels usually increase; therefore, they are not considered valid markers of disease activity, but relative variation rather than absolute levels might be helpful. In patients with permanent proteinuria, this can increase throughout pregnancy because of increased renal blood flow, without indicating active nephritis.8 Up to a doubling of proteinuria from the baseline level in early pregnancy is to be expected.

View this table:
[Table 1.](http://www.rcpjournals.org/content/13/6/580/T1)

Table 1. 
Differences between pre-eclampsia and lupus nephritis.

### Effect of SLE on pregnancy

Patients with SLE are at high risk of multiple medical (a two- to fourfold increased risk of pre-eclampsia and thrombosis compared with the general population) and obstetric complications (preterm delivery 25%; fetal growth restriction 6–35%; and a two- to sixfold risk of fetal loss compared with controls) during pregnancy, particularly in those with chronic hypertension, renal impairment and women taking high-dose oral steroids.4 Conversely, patients with cutaneous lupus erythematosus only, or those with SLE in remission without major organ involvement, appear to have pregnancy outcomes comparable to those of the healthy population.

Disease activity 6 months before conception, hypertension, CKD, non-reversible organ damage, hypocomplementaemia and secondary antiphospholipid syndrome (APS) have also been recognised as risk factors for poor pregnancy outcomes.5

## Rheumatoid arthritis and other chronic inflammatory arthritides

In total, 48–66% of women with rheumatoid arthritis (RA) experience improvement in pregnancy, with approximately 20% becoming quiescent by the third trimester.9 However, women with positive rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) appear to be less likely to improve during pregnancy.10 Most women with psoriatic arthritis (PsA) generally improve or even remit during pregnancy, whereas the symptoms of most women with ankylosing spondylitis (AS) remain unaltered or worsen during pregnancy.11

Post-partum flares occur within the first 4 months in most patients with chronic inflammatory arthritides.10 Hypertensive disorders might be more frequent in women with RA and are often related to preterm deliveries and growth-restricted babies.12

## Systemic sclerosis

Pregnancy does not seem to affect disease activity in most (63–72%) women with systemic sclerosis (SSc). One-third will either experience an improvement or worsening of symptoms during pregnancy. SSc can be associated with an increased risk of developing hypertensive disorders in pregnancy, including pre-eclampsia.13

Clinically, symptoms of Raynaud's phenomenon generally improve because of the physiological vasodilation of pregnancy, whereas gastrooesophageal reflux disease symptoms worsen. Skin involvement usually remains stable or improves, but can worsen postpartum. Recent onset of scleroderma symptoms (<4 years), diffuse cutaneous involvement, or anti-Scl-70 (anti-topoisomerase-I) or anti-RNA-polymerase-III antibodies are associated with increased risk of active and aggressive disease compared with those women with longstanding SSc or with anti-centromere antibodies.13

Renal crises do not occur more frequently in pregnancy. In the unlikely even of a renal crisis, management must be with angiotensin-converting enzyme inhibitors (ACEI) despite the risks to the baby, because it is lifesaving treatment for the mother13.

SSc is associated with increased risk of preterm delivery (14–29%), intrauterine growth restriction, longer hospitalisation and, in women with long-standing diffuse scleroderma, miscarriage. Women with limited scleroderma generally have better pregnancy outcomes compared with those with diffuse disease. Corticosteroids for fetal lung maturation should not be given because they can precipitate a renal crisis.13

## Antiphospholipid antibodies and antiphospholipid syndrome

Antiphospholipid antibodies (aPL) are found not only in patients with SLE (30–40%), but also in patients with other CTDs, and in the general population (1–5%), and represent one of the major risk factors for poor obstetric outcome.14 Women with lupus anticoagulant (LA) and those with thrombotic antiphospholipid syndrome (APS) have the worst obstetric outcomes.15 A detailed discussion of APS in pregnancy is outside the remit of this review and readers are directed to a recent review on this topic.14

## Neonatal lupus syndrome

Anti-Ro and/or anti-La antibodies can be found in patients with SLE, Sjögren's syndrome, RA, SSc and healthy asymptomatic carriers. These antibodies cross the placenta by active transport between the 16th and 30th weeks of gestation, and can cause several clinical syndromes in the fetus and neonate, known as Neonatal lupus syndrome (NNLS.16

Cutaneous neonatal lupus is the most common manifestation, and the risk of an affected child among anti-Ro and/or -La-positive mothers is approximately 5%. It generally presents within the first 2 weeks of life as erythematous geographical lesions in light-exposed areas that resemble those seen in subacute cutaneous lupus. The rash usually disappears within 3–6 months without residual scarring.16

Congenital heart block (CHB) is the most severe form of NNLS and affects approximately 2% of babies born to anti-Ro and/or -La-positive mothers. This risk increases to 18% if the mother has already had a child affected by CHB, and up to 50% if she has had two affected children.16 CHB normally develops at 16–24 weeks of gestation. The risk of perinatal death among affected children is 10–20%, and most surviving children need a permanent pacemaker.17 Current recommendations include serial fetal echocardiograms between 16 and 30 weeks for pregnant women with these antibodies.16 In humans, neither steroid nor intravenous immunoglobulin (IVIG) treatment have been shown to reverse CHB once established. However, in mothers with SLE with anti-Ro and or -La antibodies, exposure to HCQ during pregnancy might decrease the risk of fetal CHB.18

## Vasculitis

Overall, it appears that, if women embark on pregnancy with vasculitis in remission, their risk of complications is low. Unlike the ESR, serum C-reactive protein (CRP) remains a reliable marker for disease activity during pregnancy.

Takayasu's arteritis (TA) generally does not worsen during pregnancy, but the most important factor for poor outcomes seems to be the development of hypertension and pre-eclampsia. Patients with aortic valve disease or stenosis of the aorta and/or its principal branches should receive comprehensive cardiovascular assessment before and throughout pregnancy.19,20

Remissions are achieved in a large proportion of women with Behçet's disease (BD). However, flare rates of between 25% and 65% have been reported, where the main manifestations were mucocutaneous, articular and ocular manifestations. However, the risk for the main obstetric complications appears not to be increased in women with BD.20,21

## Medications during pregnancy and breastfeeding

Table 2 highlights the safety of the drugs most used for CTD during pregnancy and breastfeeding. Although traditionally avoided during pregnancy, non-steroid anti-inflammatory drugs (NSAIDs) are generally safe drugs to use during pregnancy if they are used in short, limited courses. Although they are not teratogenic, they can be associated with renal and cardiac failure, hypertension, and fluid overload in the mother, and oligohydramnios and renal impairment in the fetus if used for long periods. They should be withheld towards the end of pregnancy (>30–32 weeks) because of an increased risk of early closure of the baby's ductus arteriosus, and increased risk of maternal bleeding and of asthma in the child.22 Colchicine use during pregnancy appears to be safe. In addition, the safety profile of HCQ has been widely researched, with no reported fetal neurosensory toxicity or malformations.22

View this table:
[Table 2.](http://www.rcpjournals.org/content/13/6/580/T2)

Table 2. 
Safety of drugs that are most used for connective tissue diseases during pregnancy and breastfeeding.

A minimum proportion of non-fluorinated corticosteroids cross the placenta or appear in breast milk (5–20% of total dose). Given their adverse effects, minimum maintenance doses (prednisone <7.5 mg/day), combined with steroid-sparing agents are recommended. Stress doses of hydrocortisone at delivery are recommended in patients taking long-term therapy.22

Among immunosuppressive drugs, azathioprine (AZA), sulfasalazine (SSZ), cyclosporine (CS) and tacrolimus (FK-506) are considered safe during pregnancy and breastfeeding.22,23 If pregnancy is being considered, mycophenolate mofetil (MMF), methotrexate (MTX), leflunomide (LFM) or cyclophosphamide (CYC) should be switched to safe alternatives (usually AZA) at least 3 months before conception, to monitor new flares or adverse effects from the change in drug regimen.22 Women taking SSZ or those who have unplanned pregnancies while taking MTX should take high-dose folic acid (5 mg/day) from 3 months before conception until at least the end of the first trimester, to prevent neural tube defects.

Several groups have demonstrated no increased risk of malformations in fetuses exposed to anti-tumour necrosis factor drugs.24 Such drugs are poorly excreted in breast milk and, hence, breastfeeding is considered to be safe. However, fatal disseminated Bacillus Calmette–Guérin (BCG) has been reported in babies of mothers who received biologics during pregnancy and it is imperative that women are advised to avoid live vaccines for their neonates.

With regards to rituximab, two recent retrospective series identified 240 exposed pregnancies with controversial results. Until more robust data are available, women should be counselled against pregnancy for 6–12 months after rituximab exposure because of the risk of neonatal B-cell depletion.25 Neonates who were exposed to this biological during the second or third trimester should receive close white blood cell and infection surveillance.22

Warfarin and other vitamin K antagonists are teratogenic during organogenesis (6–10 weeks of gestation) and they should be avoided during this period.22 Current recommendations include switching to low-molecular-weight heparin (LMWH) as soon as pregnancy is confirmed.26

Mild flares during pregnancy can be treated with HCQ and/or low-dose oral steroids (or occasionally NSAIDs during the first two trimesters). For moderate or severe disease, the use of methylprednisolone pulses or high-dose oral steroids followed by rapid reduction of oral steroids to low maintenance doses, combined with safe immunosuppressants, biologic agents and/or IVIG might be necessary. More severe cases might require a risk–benefit assessment and prioritisation of the mother's welfare over fetal concerns and, therefore, the use of stronger agents, such as MMF, CYC or rituximab (RTX).

## Pregnancy management plan

Pre-pregnancy counselling, risk assessment and stratification, a multidisciplinary approach, tailored antenatal and postnatal management plans, an experienced high-level neonatal unit, and early recognition of flares and complications (either medical and/or obstetric), are essential cornerstones for optimising the chance of successful outcomes for both mother and fetus.

The preconception visit should include a detailed summary of previous obstetric and medical history, current disease activity, last flare date, chronic organ damage, recent serological profile (RF, anti-CCP, aPL, anti-Ro/La, anti-double-stranded (ds)DNA, complement), baseline blood pressure, urine analysis and renal function. Likewise, the risk of pre-eclampsia, gestational diabetes and venous thromboembolism (VTE) should be estimated and appropriate management discussed. Harmful or unsafe medication should be stopped or changed to safer alternatives before pregnancy. Concomitant prophylactic calcium and vitamin D supplements should be prescribed to women receiving corticosteroids, who are at high risk for osteoporosis or vitamin D deficiency.4 Uterine artery Doppler is recommended at approximately 22–24 weeks of gestation, because of its high negative predictive value for pre-eclampsia and/or IUGR.

Patients with SLE (especially lupus nephritis), RA, SSc, undifferentiated CTD (UCTD), and/or aPL have a higher risk of developing pre-eclampsia compared with the general population. Low-dose aspirin (LDA) (75 mg/day) started before 16 weeks of gestation significantly reduces the risk of perinatal death, pre-eclampsia and its complications in women at higher risk,27,28 and its maximum effect is probably achieved when it is taken during the afternoon or at bedtime.29 In addition, all women with aPL should take LDA to decrease their risk of miscarriage and late obstetric complications.30 In high-risk patients and in those with a low calcium diet, the intake of at least 1 g of calcium daily has been shown to dramatically reduce the risk of pre-eclampsia and preterm delivery.31

## Postpartum

Because of a high risk of disease flare and thrombosis, close surveillance for 2–3 months after delivery is important. All women should have an assessment of their VTE risk and receive thromboprophylaxis postpartum accordingly.26 Counselling on contraception is important for women with CTD because planned pregnancy is associated with fewer complications and higher pregnancy success rates.

*   © 2013 Royal College of Physicians

## References

1.  Silva CA, Bonfa E, Ostensen M. Maintenance of fertility in patients with rheumatic diseases needing anti-inflammatory and immunosuppressive drugs. Arthritis Care Res 2010;62:1682–90.
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1002/acr.20323&link_type=DOI) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000285327000002&link_type=ISI) 

2.  Bellver J, Pellicer A. Ovarian stimulation for ovulation induction and in vitro fertilization in patients with systemic lupus erythematosus and antiphospholipid syndrome. Fertil Steril 2009;92:1803–10. doi:10.1016/j.fertnstert.2009.06.033 doi:10.1016/j.fertnstert.2009.06.033
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/j.fertnstert.2009.06.033&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=19632675&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000272752600001&link_type=ISI) 

3.  Andrade RM, McGwin Jr G, Alarcon GS, et al. Predictors of post-partum damage accrual in systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (XXXVIII). Rheumatology 2006;45:1380–4. doi:10.1093/rheumatology/kel222 doi:10.1093/rheumatology/kel222
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6InJoZXVtYXRvbG9neSI7czo1OiJyZXNpZCI7czoxMDoiNDUvMTEvMTM4MCI7czo0OiJhdG9tIjtzOjI3OiIvY2xpbm1lZGljaW5lLzEzLzYvNTgwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.  Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: integrating clues from the bench and bedside. Eur J Clin Invest 2011;41:672–8. doi:10.1111/j.1365-2362.2010.02443.x doi:10.1111/j.1365-2362.2010.02443.x
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1111/j.1365-2362.2010.02443.x&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=21158850&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

5.  Clowse ME, Witter FR, Magder LC, Petri M. The impact of increased lupus activity on obstetrical outcomes. Arthritis Rheum 2005;52:514–22. doi:10.1002/art.20864 doi:10.1002/art.20864
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1002/art.20864&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=15692988&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000226910100018&link_type=ISI) 

6.  Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009;24:519–25. doi:10.1093/ndt/gfn348 doi:10.1093/ndt/gfn348
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoibmR0IjtzOjU6InJlc2lkIjtzOjg6IjI0LzIvNTE5IjtzOjQ6ImF0b20iO3M6Mjc6Ii9jbGlubWVkaWNpbmUvMTMvNi81ODAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

7.  Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8. doi:10.1136/ard.2008.101766 doi:10.1136/ard.2008.101766
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6ImFubnJoZXVtZGlzIjtzOjU6InJlc2lkIjtzOjg6IjY5LzAxLzIwIjtzOjQ6ImF0b20iO3M6Mjc6Ii9jbGlubWVkaWNpbmUvMTMvNi81ODAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

8.  Bramham K, Hunt BJ, Germain S, et al. Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J Rheumatol 2011;38:1906–13. doi:10.3899/jrheum.100997 doi:10.3899/jrheum.100997
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoianJoZXVtIjtzOjU6InJlc2lkIjtzOjk6IjM4LzkvMTkwNiI7czo0OiJhdG9tIjtzOjI3OiIvY2xpbm1lZGljaW5lLzEzLzYvNTgwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

9.  de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum 2008;59:1241–8. doi:10.1002/art.24003 doi:10.1002/art.24003
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1002/art.24003&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=18759316&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000259669700007&link_type=ISI) 

10. de Man YA, Bakker-Jonges LE, 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 2010;69:420–3. doi:10.1136/ard.2008.104331 doi:10.1136/ard.2008.104331
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6ImFubnJoZXVtZGlzIjtzOjU6InJlc2lkIjtzOjg6IjY5LzIvNDIwIjtzOjQ6ImF0b20iO3M6Mjc6Ii9jbGlubWVkaWNpbmUvMTMvNi81ODAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

11. Ostensen M. The effect of pregnancy on ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis. Am J Reprod Immunol 1992;28:235–7. doi:10.1111/j.1600-0897.1992.tb00801.x doi:10.1111/j.1600-0897.1992.tb00801.x
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1111/j.1600-0897.1992.tb00801.x&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=1285888&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

12. Lin HC, Chen SF, Chen YH. Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-based study. Ann Rheum Dis 2010;69:715–7. doi:10.1136/ard.2008.105262 doi:10.1136/ard.2008.105262
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6ImFubnJoZXVtZGlzIjtzOjU6InJlc2lkIjtzOjg6IjY5LzQvNzE1IjtzOjQ6ImF0b20iO3M6Mjc6Ii9jbGlubWVkaWNpbmUvMTMvNi81ODAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

13. Steen VD. Pregnancy in scleroderma. Rheum Dis Clin N Am 2007;33:345–58, vii.
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/j.rdc.2007.03.001&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=17499711&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000247200000009&link_type=ISI) 

14. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010;376:1498–509. doi:10.1016/S0140-6736(10)60709-X doi:10.1016/S0140-6736(10)60709-X
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/S0140-6736(10)60709-X&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=20822807&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000284248500033&link_type=ISI) 

15. Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64:2311–8. doi:10.1002/art.34402 doi:10.1002/art.34402
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1002/art.34402&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=22275304&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000305742800027&link_type=ISI) 

16. Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin N Am 2007;33:267–85. doi:10.1016/j.rdc.2007.02.005 doi:10.1016/j.rdc.2007.02.005
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/j.rdc.2007.02.005&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=17499707&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000247200000005&link_type=ISI) 

17. Eliasson H, Sonesson SE, Sharland G, et al. Isolated atrioventricular block in the fetus: a retrospective, multinational, multicentre study of 175 patients. Circulation 2011;124:1919–26. doi:10.1161/CIRCULATIONAHA.111.041970 doi:10.1161/CIRCULATIONAHA.111.041970
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjExOiIxMjQvMTgvMTkxOSI7czo0OiJhdG9tIjtzOjI3OiIvY2xpbm1lZGljaW5lLzEzLzYvNTgwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

18. Izmirly PM, Costedoat-Chalumeau N, Pisoni C, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro associated cardiac manifestations of neonatal lupus. Circulation 2012;126:76–82. doi:10.1161/CIRCULATIONAHA.111.089268 doi:10.1161/CIRCULATIONAHA.111.089268
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjg6IjEyNi8xLzc2IjtzOjQ6ImF0b20iO3M6Mjc6Ii9jbGlubWVkaWNpbmUvMTMvNi81ODAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

19. Seo P. Pregnancy and vasculitis. Rheum Dis Clin N Am 2007;33:299–317. doi:10.1016/j.rdc.2007.02.001 doi:10.1016/j.rdc.2007.02.001
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/j.rdc.2007.02.001&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=17499709&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000247200000007&link_type=ISI) 

20. Gatto M, Iaccarino L, Canova M, et al. Pregnancy and vasculitis: a systematic review. Autoimmun Rev 2012;11:A447–59. doi:10.1016/j.autrev.2011.11.019 doi:10.1016/j.autrev.2011.11.019
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1016/j.autrev.2011.11.019&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=22155197&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

21. Martineau M, Haskard DO, Nelson-Piercy C. Behçet's syndrome in pregnancy. Obstet Med 2010;3:2–7.
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BvYm0iO3M6NToicmVzaWQiO3M6NToiMy8xLzIiO3M6NDoiYXRvbSI7czoyNzoiL2NsaW5tZWRpY2luZS8xMy82LzU4MC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

22. Østensen M, Khamashta MA, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209–27.
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1186/ar1957&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=16712713&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

23. Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C. Breastfeeding and tacrolimus. Serial monitoring in breast and bottle fed infants. Clin J Am Soc Nephrol 2013;8:563–7. doi:10.2215/CJN.06400612 doi:10.2215/CJN.06400612
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiY2xpbmphc24iO3M6NToicmVzaWQiO3M6NzoiOC80LzU2MyI7czo0OiJhdG9tIjtzOjI3OiIvY2xpbm1lZGljaW5lLzEzLzYvNTgwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

24. Marchioni RM, Lichtenstein GR. Tumor necrosis factor-a inhibitor therapy and fetal risk: a systematic review. World J Gastroenterol 2013;19:2591–602. doi:10.3748/wjg.v19.i17.2591 doi:10.3748/wjg.v19.i17.2591
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.3748/wjg.v19.i17.2591&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=23674866&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000318601300002&link_type=ISI) 

25. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117:1499–506. doi:10.1182/blood-2010-07-295444 doi:10.1182/blood-2010-07-295444
    
    [Abstract/FREE Full Text](http://www.rcpjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czoxMDoiMTE3LzUvMTQ5OSI7czo0OiJhdG9tIjtzOjI3OiIvY2xpbm1lZGljaW5lLzEzLzYvNTgwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

26. Royal College of Obstetrician and Gynaecologists. Thrombosis and embolism during pregnancy and the puerperium, reducing the risk (green-top 37a). London: RCOG, 2009.
    
    

27. Roberge S, Giguere Y, Villa P, et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol 2012;29:551–6. doi:10.1097/01.ogx.0000425641.72994.b5 doi:10.1097/01.ogx.0000425641.72994.b5
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1097/01.ogx.0000425641.72994.b5&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=22495898&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

28. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynaecol 2013;41:491–9. doi:10.1002/uog.12421 doi:10.1002/uog.12421
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1002/uog.12421&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=23362106&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 
    
    [Web of Science](http://www.rcpjournals.org/lookup/external-ref?access_num=000318115300005&link_type=ISI) 

29. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int. 2013;30:260–79. doi:10.3109/07420528.2012.717455 doi:10.3109/07420528.2012.717455
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.3109/07420528.2012.717455&link_type=DOI) 
    
    [PubMed](http://www.rcpjournals.org/lookup/external-ref?access_num=23004922&link_type=MED&atom=%2Fclinmedicine%2F13%2F6%2F580.atom) 

30. Soh MC, Pasupathy D, Gray G, Nelson-Piercy C. Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. J Rheumatol 2013;52:1642–7. doi:10.1093/rheumatology/ket173 doi:10.1093/rheumatology/ket173
    
    [CrossRef](http://www.rcpjournals.org/lookup/external-ref?access_num=10.1093/rheumatology/ket173&link_type=DOI) 

31. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010;(8):CD001059.

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