Contraception and Pregnancy in Patients with Rheumatic Disease

4. Systemic Lupus Erthematosus

Sara Wasserman¹ and Megan E. B. Clowse¹

(1)

Division of Rheumatology and Immunology, Duke University Hospital, 3535 Trent Drive, Durham, NC 27710, USA

Megan E. B. Clowse

Email: megan.clowse@duke.edu

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a diagnosis made based on laboratory values, symptoms, and signs. To be diagnosed with SLE a woman must have at least 4 out of 11 positive American College of Rheumatology Criteria (see Table 4.1). Positive anti-nuclear antibody in the serum will be found in over 95 % of women with SLE. Smith antibodies, anti-dsDNA antibodies, anti-Ro/SSA, and anti-La/SSB can aid in a diagnosis of SLE, but are not necessary. Patients who meet some, but not 4 or more criteria are sometimes given a diagnosis of undifferentiated connective tissue disease (UCTD) which is a disease that usually has a milder course and only rarely progresses to SLE. To make a diagnosis of SLE, one should consult with a rheumatologist.

Table 4.1

1997 Updated American college of Rheumatology Criteria Classification for SLE

Malar rash	Over malar eminences, spares the nasolabial folds
Discoid rash	Erythematous raised patches with follicular plugging. Leaves a scar
Photosensitivity	Skin rash as result of reaction to the sun
Oral ulcers	Usually painless
Arthritis	2 or more peripheral joints, morning stiffness
Serositis	Pericarditis or pleurisy
Renal disease	• Proteinuria > 3(+) or • 0.5 grams daily protein or cellular casts
Neurologic disease	Seizures or psychosis
Hematologic disease	• Hemolytic Anemia-with reticulocytosis or • ≥2 occasions of one of the following: • Lymphopenia (<4,000 mm3) or • Leukopenia (<1,500 mm3) or • Thrombocytopenia (<100,000/mm3)
Antibodies	• Anti-DNA • Anti-Smith • Anti-phospholipid Antibodies: a) Abnormal level of IgG or IgM anticardiolipin antibodies b) A positive test of lupus anticoagulant c) False positive RPR testing
Positive ANA

Preconception Counseling

The importance of preconception counseling should not be underestimated as it is a critical time to establish a women’s pregnancy risk, adjust medications, and discuss pregnancy treatment options. It is generally recommended that a woman be monitored for 6 months prior to attempting conception as significant lupus activity within 6 months of conception was associated with a fourfold increase in pregnancy loss rate in the Hopkins Lupus Cohort [1]. A thorough history and physical should be performed to help stratify pregnancy risk, focusing on prior lupus nephritis and recent lupus activity. In addition, initial lab testing should be completed including screening for lupus activity, antiphospholipid antibodies, and anti-Ro/SS-A and anti-La/SS-B antibodies associated with neonatal lupus. Medications used to treat SLE as well as other medications should be thoroughly reviewed and all teratogens should be discontinued or substituted for other medications.

Impact of SLE on Pregnancy Outcome

Pregnancy Loss

The rate of miscarriage and stillbirth in lupus pregnancies is higher than that of the general population. A large retrospective case–control study comparing women with lupus to their healthy friends and relatives demonstrated a rate of pregnancy loss of 21 % in those with lupus compared to a rate of 8–14 % in the friends and relatives [2]. Pregnancy loss rates ranging between 15 and 30 % have been reported in different lupus cohorts [3–6]. While the risk of miscarriage does not differ much from that of the general population, it is the stillbirth rate (>20 weeks gestation) that is significantly elevated in the lupus population around 5 % [7]. One of the greatest risk factors for pregnancy loss is high lupus disease activity and thus avoiding pregnancy during periods of high disease activity or within 6 months of periods of high disease activity is important and can help avoid complications [7]. There was a threefold increase in pregnancy loss in those with high activity lupus in the first and second trimesters in a prospective study looking at the Hopkins Lupus cohort over 16 years [7].

In addition, antiphospholipid syndrome is a significant risk factor for pregnancy loss and thus aspirin and low-molecular-weight heparin is recommended to aggressively modify this risk factor when present [8] (management of obstetric antiphospholipid syndrome is discussed in detail in Chap. 2). Other risk factors for pregnancy loss include proteinuria, thrombocytopenia, lupus nephritis, and hypertension [9].

Preterm Birth

Another complication that frequently occurs in lupus pregnancies is preterm birth, which is defined as delivery before 37 weeks gestation. The rate of premature delivery in women with lupus was 21 % in a case–control population-based study, sixfold higher than that seen in healthy controls [10]. Preterm birth rates suggested by different cohorts range from 14 % to over 50 % [3, 5, 11–13]. In some cases, early deliveries are medically necessary and induction of labor is performed to avoid fetal and maternal complications, such as preeclampsia or fetal distress. However, some preterm births are spontaneous and a proportion are due to preterm premature rupture of membranes (PPROM) [14, 15]. PPROM was found to be higher in the SLE population than in a control population [15]. In the general population, PPROM is often related to antepartum infections such as chorioamnionitis and endometritis whereas the etiology of increased incidence of PPROM in women with lupus is currently unclear.

Other risk factors for premature birth include antiphospholipid syndrome, hypertension, increased lupus activity during pregnancy and conception, and prednisone use during pregnancy [5, 7, 14, 16]. In the Hopkins Cohort, two thirds of women with high activity lupus based on the physician’s estimate of lupus activity delivered prematurely, while only one third of those with low lupus activity did [7]. Again this lends support for aggressive risk reduction to avoid pregnancy complications.

Small for Gestational Age

Small for gestational age (SGA) is defined as birth weight less than the tenth percentile for gestational age and low birth weight is defined as birth weight less than 2,500 g. Fetal growth restriction is a major cause of morbidity and mortality. In a report published by the Center for Disease Control for 2009, the low birth weight rate of the general population in the USA was estimated to be 8.16 % [17]. There has been disagreement between different studies on the rate of low birth weight and SGA in different lupus cohorts. Some studies show rates of 5–10 % [4, 5], similar to the normal population, while others demonstrate an increased risk with rates of SGA above 30 % in lupus pregnancies [16, 18]. Thus evidence for increased risk of SGA in lupus is somewhat controversial. Some risk factors that have been associated with low birth weight rate include C4 hypocomplementemia, hypertension during pregnancy, and renal disease [16, 18].

Neonatal Lupus

Another neonatal complication that can be encountered is neonatal lupus. Neonatal lupus is a clinical spectrum of disease seen in infants whose mothers have anti-Ro/SSA or anti-La/SSB antibodies. It most commonly manifests with cardiac or dermatologic manifestations. The risk of congenital heart block is 2 % [19] in offspring of mothers with anti-Ro/SSA and/or anti-La/SSB antibodies, and often leads to the need for pacemaker. The rash resembles that of subacute cutaneous lupus, and those with only skin involvement have an excellent prognosis. A recent case–control study suggests hydroxychloroquine may be protective in lowering the risk of cardiac manifestations in infants born to mothers with anti-Ro/SSA antibodies [20]. (The topic of neonatal lupus and information on the long-term outcome for children of women with lupus is discussed in detail elsewhere in this volume, in Chaps. 13 and 15).

Preeclampsia

Hypertensive conditions, including preeclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts) pose a significant risk to SLE women during their pregnancies. Proteinuria (more than 300 mg protein in the urine in 24 h) and hypertension (blood pressure greater than 140/90) that occur usually after 20 weeks of gestation define preeclampsia. Severe preeclampsia manifests with any of the following; hypertension (blood pressure greater than 160/110), proteinuria (more than 5 g in 24 h), oliguria, renal failure, pulmonary edema, elevated liver function tests, epigastric pain, thrombocytopenia, visual or cerebral disturbances, and hemolytic anemia. With the addition of grand mal seizure, preeclampsia becomes eclampsia. Since the maternal risks subside after delivery of the fetus and placenta, delivery is regarded as the most definitive treatment [21].

Women with SLE unfortunately are at an increased risk for preeclampsia during pregnancy. Ten to 30 % of pregnancies were complicated by preeclampsia and hypertension in prior SLE cohorts which is several fold higher than the rate seen in other women [22]. The risk is heightened in those with pre-pregnancy hypertension, renal insufficiency, and lupus nephritis. In addition, greater than 10 mg daily prednisone during pregnancy significantly increases the risk of hypertension and preeclampsia [23].

Distinguishing a flare of lupus nephritis from that of preeclampsia can be a dilemma. They both present with hypertension and proteinuria during pregnancy. However, making this distinction is important as management is different for the two conditions. For preeclampsia and eclampsia, delivery is indicated whereas for SLE nephritis, there is a need for immunosuppressive therapy. Some helpful methods to aid in differentiating between them are outlined in Table 4.2. For one, preeclampsia very rarely occurs before 20 weeks of gestation and lupus nephritis can occur at any time during pregnancy. Some clinical features that help point toward lupus nephritis as opposed to preeclampsia include active urinary sediment with white blood cells, red blood cells and casts in addition to SLE activity in other organs such as rash, arthritis, and oral ulcers. A patient with proteinuria with a rising anti-dsDNA and falling complement is more likely to be having an SLE nephritis flare. In contrast, complement in pregnancy often rises and can rise or stay stable in preeclampsia [24, 25]. Some clues in support of a diagnosis of preeclampsia include serum uric acid elevation and decreased urine calcium excretion (<195 mg/24 h urine collection) [26]. Unfortunately, abnormal liver function tests, thrombocytopenia, and hemolytic anemia can occur in both conditions and are not helpful in discriminating between these conditions. Sometimes, it is not possible to discern between the conditions and treatment for both may be necessary.

Table 4.2

Distinguishing factors for active lupus, preeclampsia, and HELLP syndrome

Signs and symptoms	Active SLE	Preeclampsia	HELLP syndrome
Timing in pregnancy	Any trimester	Third trimester	Third trimester
Blood pressure	Normal or high	Greater than 140/90	Normal or high
Proteinuria	Normal or elevated	Greater than 300 mg/24 h	Normal or elevated
Active urine sediment (casts, RBCs, WBCs)	Yes	Usually negative	Usually negative
Serum creatinine	Stable or rising	Stable	Stable
Platelets	Low or normal	Normal	Low, less than 100,000
Hemolysis	Maybe	No	Microangiopathic hemolytic anemia
Anti-dsDNA antibody	May be elevated	Negative or stable	Negative or stable
Complement: C3, C4	May be low	Usually normal	Unknown
Liver function testing	Normal or high	Normal	Transaminases elevated greater than 1,000
Uric acid	Normal or high	High	High
Urine calcium	Normal or high	Low	Unknown
SLE symptoms: arthritis, rash, oral ulcers	Present	Absent	Absent
CNS dysfunction	Sometimes present	Headache may be present	Not usually

The precise etiology and mechanism of preeclampsia has not been fully elucidated and remains under investigation. It is hypothesized that abnormal placental development leads to preeclampsia, specifically limited invasion of the trophoblast into the uterus and its spiral arteries which leads to diminished placental perfusion. This is thought to result from abnormal angiogenesis, oxidative stress, and immunological alterations [27, 28].

Due to the fact that excessive production of thromboxane, a platelet-derived vasoconstrictor and platelet activator, has been demonstrated in preeclampsia, daily low-dose aspirin may help with prevention. In 2007, a Cochrane Review [29] was published which included 59 trials and a total of 37,560 women and evaluated the use of aspirin in pregnancy. This study demonstrated that for women who were high risk for preeclampsia, daily low-dose aspirin is associated with a 25 % risk reduction. There were risk reductions of 8 and 14 % for preterm birth and fetal or neonatal death, respectively, when daily low-dose aspirin was used during pregnancy [29]. While none of the trials specifically looked at women with autoimmune disease, because women with SLE are particularly at high risk for preeclampsia, 81 mg daily aspirin should be considered for all women with lupus during pregnancy.

Maternal Complications

Maternal Mortality

The maternal mortality rate may be as much as 20-fold higher than the non-SLE population with a rate of 325 deaths per 100,000 lupus pregnancies [22]. However, pregnancy probably does not add to the mortality risk of women with SLE as the nonpregnant SLE annual death rate is between 790 and 3,208 deaths per 100,000 patient years which is two to tenfold higher than that of the pregnant SLE death rate. Maternal deaths have been documented in the literature in patients who had active lupus nephritis, uncontrolled hypertension, HELLP syndrome, preeclampsia, thrombosis with pulmonary embolism, severe SLE exacerbation, and pregnancy associated cardiomyopathy [3, 6, 22, 30]. Women with SLE and pulmonary hypertension, prior cerebrovascular event, or myocardial infarction are at increased risk for pregnancy mortality and should consider avoiding pregnancy.

Lupus Manifestations and Flares During Pregnancy

Approximately 30–70 % of women with lupus will experience a lupus flare during pregnancy [5, 8, 16, 31]. The rate of flares during pregnancy varies between different studies, which is likely a result of studying different patient populations and using varying definitions for flare. Whether pregnancy is a risk factor for increased lupus flare is controversial as some studies show increased flares during pregnancy, others decreased and some the same [3, 16, 23, 32, 33]. Flares occur in all trimesters and in the postpartum without a clear preference to time. Fortunately, most flares during pregnancy are mild to moderate with manifestations of arthritis, constitutional and cutaneous symptoms [3, 8], as shown in Table 4.3. Up to 30 % of women with SLE will experience more severe flares during pregnancy including thrombocytopenia or nephritis [3, 14] (see Table 4.3). These more severe flares can put a pregnancy in jeopardy and increase the risk of preeclampsia, premature birth, and even pregnancy loss. The rate of pregnancy loss in those with thrombocytopenia in the first trimester was 43 %, compared with a rate of 13 % in those without in a cohort study [9]. Conception at times of active disease should be avoided as it has poor prognostic implications for the health of the newborn and mother.

Table 4.3

Types of lupus activity during pregnancy

	Cortes-Hernandez et al. [16] (n = 39)	Carmona et al. [5] (n = 15)	Georgiou et al. [3] (n = 59)
Arthritis	27 (69 %)	3 (20 %)	48 (81 %)
Skin lesions	13 (33 %)	8(53 %)	55 (93 %)
Lupus nephritis	4 (10 %)	2 (13 %)	6 (10 %)
Fever	3(8 %)	a	28 (47 %)
Serositis	1 (3 %)	3 (20 %)	5 (8 %)
Hepatitis	1 (3 %)	a	a
CNS involvement	a	a	2 (3 %)
Hemolytic anemia	4 (10 %)	a	Hematologic involvement: 6 (10 %)
Thrombocytopenia	1(3 %)	5 (36.3 %)

^aData not provided

High lupus activity within 6 months of conception is a predictor for a significant SLE flare during pregnancy [14]. In a cohort study, 58 % of women with active lupus prior to pregnancy experienced high lupus activity during pregnancy, whereas only 8 % with inactive lupus prior to pregnancy did [7]. Also women with history of frequent and significant flares are more likely to have high lupus activity during pregnancy [16]. Since high lupus activity during pregnancy increases risk of poor outcomes like preeclampsia, fetal loss, and prematurity, educating patients to avoid conception close to times of high lupus activity is a preventative measure. In addition, the use of contraception in patients with high disease activity should be addressed.

Discontinuation of needed immunosuppressive therapy and particularly discontinuation of hydroxychloroquine can also increase the risk of lupus flares during pregnancy [16, 34]. In a study looking at hydroxychloroquine in the Hopkins Lupus Cohort, 30 % of the patients who remained on hydroxychloroquine during pregnancy had flares in comparison with 55 % who discontinued the drug during pregnancy [34]. In addition, women who continued hydroxychloroquine were on a lower average prednisone dose [34, 35]. Higher prednisone dosage is associated with premature birth. Studies have shown no adverse effects of hydroxychloroquine on the fetus or the pregnancy [36]. For these reasons, it is recommended that hydroxychloroquine be continued during pregnancy to manage disease activity.

A successful lupus pregnancy involves careful planning in terms of conception timing and modification of immunosuppressive therapy. Immunosuppression, when needed, is preferable to SLE activity. For women with significant history of organ involvement and disease activity, particularly those with a history of lupus nephritis or thrombocytopenia, discontinuing immunosuppressive therapy for pregnancy is not recommended. This in itself can lead to disease flares and poor pregnancy outcomes. Whenever possible, teratogenic medications like cyclophosphamide and mycophenolate mofetil should be discontinued at least 3–6 months prior to conception and switched to an alternative immunosuppressive medication, such as azathioprine or cyclosporine. Azathioprine has been documented to be safe in pregnancy with little teratogenicity in studies of transplant and inflammatory bowel disease populations in the setting of pregnancy [37]. Similarly cyclosporine has also been studied in pregnant transplant patients and the observed rate in newborns of congenital malformations did not differ significantly from that seen in the general population [37]. It is recommended that cyclosporine be maintained at the lowest effective dose. In those with active lupus who risk preterm birth, pregnancy loss and preeclampsia, the advantage of continuing immunosuppression such as hydroxychloroquine, cyclosporine, and azathioprine, which have all demonstrated no or minimal teratogenicity, should not be underestimated.

Lupus Nephritis

The prevalence of lupus nephritis flares during pregnancy in different lupus cohorts has ranged from 16–36 % [11, 12, 33, 38]. The wide range of incidence can be accounted for by the variation in definitions for nephritis and heterogeneity in patient populations. Whether renal flares have a higher prevalence in pregnant lupus patients than in nonpregnant lupus patients is controversial and studies have had conflicting results [23, 32, 39]. This again may be a result of no standard definition for renal lupus disease amongst different studies.

While lupus nephritis can be devastating to the pregnancy, in the majority of cases it does not result in end stage renal disease or hemodialysis-dependent renal failure. Due to both the maternal and the pregnancy risk of active lupus nephritis, it must be treated during pregnancy.

Several studies have suggested that active renal disease at the time of conception and within 6 months prior to pregnancy are significant predictors for pregnancy complications and adverse outcomes [39, 40] (see Table 4.4). In a retrospective study which included women with SLE and active nephritis and those with SLE who did not have nephritis, preterm delivery happened more frequently at a rate of 52 % in those with renal disease and only 19 % in those without renal disease [40]. Fetal loss was also more frequent in the group with active nephritis at a rate of 35 % compared to 9 % in those who did not have nephritis [40]. Women with active lupus nephritis in pregnancy have higher rates of hypertension, preeclampsia, and stroke [40]. Due to the great risk that active renal disease has on a pregnancy, it is ideal to wait for at least 6 months of quiescence before conception.

Table 4.4

Pregnancy outcomes in women with prior lupus nephropathy (LN) and pregnant women with SLE without nephropathy

	Saavedra et al. [41]			Bramham et al. [42]			Wagner et al. [40]
	Prior LN (n = 35)	No prior LN (n = 60)	P value	Prior LN (n = 43)	No prior LN (n = 64)	P value	Prior LN, but quiescent (n = 20)	Prior LN and active (n = 23)	No prior renal disease (n = 47)	P value
Rate of renal flare	16 (45.7 %)	4 (6.6 %)	0.00001	6 (14 %)	1 (1.5 %)	a	a	a	a	N/A
Rate of all flares	19 (54.2 %)	15 (25 %)	0.004	14 (36 %)	25 (40 %)	a	a	a	a	N/A
Preeclampsia	8 (22.8 %)	8 (13.3 %)	0.2	12 (28 %)	10 (16 %)	a	7 (35 %)b	13 (57 %)b	5 (11 %)b	<0.001
Preterm birth	17 (48.5 %)	24 (40 %)	0.4	13 (30 %)	7 (11 %)	0.029	6 (30 %)	12 (52 %)	9(19 %)	0.007
Pregnancy loss	7 (20 %)	6 (10 %)	<0.05	0	1 (1.6 %)	a	5 (25 %)	8 (35 %)	4 (9 %)	0.031
Low birth weight (<2,500 g)	10 (28.5 %)	21 (35 %)	0.06	14 (33 %)	14 (22 %)	a	1 (5 %)	1 (4 %)	2 (4 %)	0.98

^aNot reported

^bMaternal complications including preeclampsia, hypertension, eclampsia, stroke, HELLP syndrome, and maternal death

The rate of relapse of renal disease during pregnancy in women with a prior history of lupus nephritis is about 30 % [16, 33]. Women who do not have active nephritis during pregnancy, but rather a history of nephritis, still have a significant increase in pregnancy complications. In a meta-analysis, 16.3 % of pregnant patients with a history of nephritis had gestational hypertension and 7.6 % experienced preeclampsia, a statistically significant increase over background rates of these disorders [43]. Pregnancies in patients with previous nephritis also had higher rates of fetal loss than women without history of renal disease [16].

Thrombosis

Pregnancy itself is a hypercoaguable state and increases even a healthy woman’s risk of thromboembolism about fourfold [44]. In addition, independent of antiphospholipid syndrome, SLE patients have a significantly increased risk of thrombosis, even outside of pregnancy. Thus when a lupus patient is pregnant her risk of thromboembolism increases to an even greater degree. In a large retrospective study in California, which included all women with deliveries during a 2-year period, the rate of DVT during pregnancy was sevenfold higher in those with lupus as compared to the other women [10]. In another nationwide retrospective study which looked at all pregnancy-related admissions from 2000 to 2003, the risk of venous thromboembolism during pregnancy was five to eightfold higher in those with SLE as compared to other women. In the same study, the risk of stroke during pregnancy was 6.5-fold higher in those with SLE as compared to other women [22].

It is important to evaluate a woman’s risk of thromboembolism early on in pregnancy. Antiphospholipid syndrome is caused by autoantibodies and manifests with symptoms of venous or arterial thrombosis and pregnancy loss. This syndrome occurs both in the presence and in the absence of lupus or another autoimmune disease. Up to 40 % lupus patients will have antiphoshpolipid antibodies, but only 15 % will have symptoms, thrombosis and have antiphosholipid syndrome [45, 46]. For more information on antiphospholipid syndrome during pregnancy, please refer to Chap. 6. Some thrombotic risk factors, such as antiphospholipid syndrome or history of other hypercoaguable disorder, are modifiable. SLE patients with prior history of antiphospholipid syndrome manifesting as thrombosus should be put on full-dose therapeutic low-molecular-weight heparin during pregnancy. Alternatively, those SLE patients with history of antiphospholipid syndrome with obstetrical complications but no prior clotting events can be treated with prophylactic low-molecular-weight heparin during pregnancy. SLE patients without associated APS or other clotting disorders do not need to be treated with heparin during pregnancy.

Diabetes and Hypertension

Studies have demonstrated a fourfold increase in the prevalence of hypertensive disorders in SLE patients who are pregnant as compared to healthy pregnant controls [10]. Risk factors for gestational hypertension include renal disease and a former diagnosis of hypertension [47]. Both diabetes and hypertension diagnosed prior to pregnancy are more common in women with SLE than in healthy controls [22, 48], most likely because treatment with corticosteroids can increase the risk of both these disorders. While studies have not shown a statistically significant increase in incidence in gestational diabetes in SLE pregnancies [22, 49], it is certainly a concern nonetheless, especially in those on corticosteroids during pregnancy [23].

Cesarean Section Deliveries

Higher rates of women with lupus have Cesarean section deliveries when compared to the general population [22, 23]. Greater than a third of women with lupus are delivered by C-Section, a rate higher than is typical. [5, 13, 22, 23]. The indications for Cesarean section in lupus pregnancies are the same as those in the general population; however, since complications necessitating C-section such as preeclampsia and gestational hypertension affect lupus pregnancies more often than those of healthy women, there are more C-sections performed in lupus pregnancies. In one retrospective study in Canada, more women with a preterm delivery were either induced or had a C-section in the face of hypertension, HELLP syndrome, fetal distress, or preeclampsia than those who delivered at term [4]. Other indications in the literature seen for delivery by C-section include placenta previa, breech, cephalo-pelvic disproportion, and failed induction. Nonetheless, nothing precludes a woman with lupus who has an uncomplicated pregnancy from delivering by standard vaginal delivery. In fact, most women with lupus undergo successful vaginal delivery.

Diagnostic Investigations and Monitoring

Laboratory Testing

Full lab testing prior to pregnancy helps to establish a baseline and risk stratify a woman with lupus (see Table 4.5). Laboratory testing to assess lupus activity is important to monitor at the onset and throughout pregnancy. This assessment includes complement levels, anti-dsDNA titer, complete blood counts, urinalysis, and kidney function. Complement (C3 and C4) which frequently increases during healthy pregnancy may fall with increased lupus activity. The anti-dsDNA antibody can be positive in up to half of lupus pregnancies and may be associated with increased lupus activity, particularly in the kidneys. The complete blood count should be monitored to assess for hemolytic anemia and thrombocytopenia due to lupus activity. Leukopenia and especially lymphopenia is common in lupus and does not necessarily reflect disease activity. Lupus nephritis frequently starts asymptomatically, so monitoring for this with a complete urinalysis and serum creatinine is very important. Lupus nephritis generally presents with proteinuria, red and white cells in the urine, and granular casts. Serum creatinine typically decreases during pregnancy due to increased renal blood flow, so a patient without a decline in creatinine should be very closely monitored for developing or worsening nephritis.

Table 4.5

Laboratory testing during lupus pregnancy

	Screening at initiation of pregnancy	Monitoring for lupus activity	To discriminate between preeclampsia and lupus flare
Complete blood count with differential	X	X	X
Chemistries with liver and kidney function	X	X	X
Anti-dsDNA antibodies	X	X	X
Complement levels: C3 and C4	X	X	X
Complete urinalysis	X	X	X
Urine protein:creatinine ratio	X	X	X
24 h urine for protein and creatinine		If urine protein:creatinine increased or serum creatinine elevated
Anti-cardiolipin antibodiesa	X
Lupus anticoagulant: dilute Russell viper venom time and sensitive PTTa	X
B2-glycoprotein 1 antibodya	X
Anti-Ro (SSA) and anti-La (SSB) antibodies	X
24 h urine for calcium			X
Uric acid level			X

^aIf tests positive, repeat in 6–8 weeks to confirm antiphospholipid syndrome positivity

At the initial pregnancy visit, assessment of antiphospholipid antibody status should be obtained, including anti-cardiolipin antibodies, lupus anticoagulant antibodies, and anti-beta2-glycoprotein-1 antibodies. The interpretation of the labs, however, can be challenging in women without a prior pregnancy and this is discussed in detail in Chap. 6. Also the risk of neonatal lupus should be assessed during the initial visit by checking anti-Ro/SSA and anti-La/SSB antibodies.

Fetal Monitoring and Surveillance

All women with lupus should consider having a maternal–fetal medicine consultation to help guide obstetrical management throughout the pregnancy.

Beyond the usual pregnancy screening followed in all pregnancies, pregnancies in women with lupus can benefit from increased monitoring in the third trimester. The goal of this screening is to identify possible placental insufficiency that would prompt an early delivery to improve long-term outcomes. Periodic ultrasounds should be performed to assess amniotic fluid quantity and fetal growth. This is usually started once or twice weekly around 28–32 weeks gestation. Some methods used to assess for hypoxemia include non-stress test, biophysical profile, and umbilical artery Doppler velocimetry wave form analysis. In the USA, the most commonly used method is the “modified” biophysical profile. This involves a non-stress test and amniotic fluid measurement twice weekly. Abnormal results in fetal surveillance testing should cause contemplation of either medication intervention or prompt delivery.

Treatment

General Principles of Treatment for All Pregnant Women with SLE

When considering treatment of lupus during pregnancy, it is important to consider and balance the risks of medication to the developing fetus and the benefits of the medication in controlling lupus activity. The prevention of active SLE is of primary importance. Considering that many medications have minimal risks, immunosuppression when needed is preferable to SLE activity. Please refer to Chap. 14 for further information about the medications discussed in this section. See Table 4.6 for an overview guide to lupus treatment during pregnancy.

Table 4.6

Treatment options in lupus pregnancy based on lupus activity

Lupus activity	Corticosteroid	Immunomodulator
No lupus activity	None	Hydroxychloroquine
Mild lupus activity	Low-dose prednisone (<10 mg)	Hydroxychloroquine
Moderate lupus activity	Moderate-dose prednisone (10–40 mg)	Hydroxychloroquine and azathioprine or cyclosporine
Severe lupus activity	High-dose prednisone (1 mg/kg/day) and/or pulse-dose methylprednisolone (1 g/day)	Hydroxychloroquine and azathioprine or cyclosporine IVIG Cyclophosphamide if the life or organs of the mother are threatened in the second or third trimesters

All women should be started on a prenatal multivitamin preferably prior to pregnancy or as soon as possible during it. The vitamin should contain at least 800 μg folic acid and 27 mg of iron.

All of a woman’s medications should be reviewed thoroughly ideally prior to conception. Women on azathioprine and hydroxychloroquine should continue these medications. The risk of discontinuing these medications and having the disease flare outweighs the minimal risk of the medications themselves. Methotrexate, mycophenolate mofetil, and cyclophosphamide should be stopped at least 3 months prior to pregnancy as all are teratogenic and should be changed to safer medications like azathioprine or cyclosporine. The transition from mycophenolate mofetil to azathioprine or cyclosporine can be challenging and is usually safest if they are crossed over several months to avoid a lupus flare. Pregnancy should be delayed until the patient has been stabilized for at least 3 months on the new medication to avoid an unexpected flare during pregnancy.

Pregnancy outcomes can be improved with 81 mg aspirin. As discussed earlier in the chapter, low-dose daily aspirin has been associated with a decrease in preeclampsia, preterm birth, and fetal and neonatal death [29]. Nonsteroidal anti-inflammatory medications (NSAIDS) should be generally avoided during the first trimester of pregnancy as they are associated with problems with embryo implantation and miscarriage and also during the third trimester as they promote premature closure of the ductus arteriosus and prolonged labor. The risk of oligohydramnios induced by NSAIDs remains throughout all trimesters of gestation as NSAIDs have effects on fetal renal function and can cause a reduction in amniotic fluid [37].

No Lupus Activity

Women with lupus require no specific treatment during pregnancy in the absence of signs or symptoms of active SLE. In the past, prophylactic corticosteroids were standard practice, but this is no longer recommended due to increased rates of diabetes, hypertension, and preterm delivery [5]. Women who are already taking hydroxychloroquine should continue it throughout pregnancy, even if lupus activity has been quiescent for any period of time prior to conception. On the other hand, the rare patient with years of quiet activity without hydroxychloroquine probably does not need to start this drug for pregnancy. Women with positive anti-Ro/SS-A or anti-La/SS-B antibodies, regardless of symptoms, may benefit from hydroxychloroquine because this might decrease the risk for cardiac neonatal lupus [50].

Mild Lupus Activity

Hydroxychloroquine is the cornerstone therapy to treat mild lupus flares in pregnancy. For more symptoms that impact quality of life, low-dose corticosteroids can be used during pregnancy. The preferred corticosteroids to use during pregnancy are prednisone and prednisolone, as less than 10 % will cross the maternal–fetal membranes [37]. Mild lupus activity—rashes, mouth ulcers, mild alopecia, and mild arthritis—will not generally have a negative impact on pregnancy outcomes. Therefore, the risks of corticosteroids need to be balanced with the impact of lupus on the woman’s quality of life. The use of steroids does not come without risks and the dose should be kept as low as possible. Steroids are associated with gestational hypertension, diabetes, and premature birth [23]. Exposure to corticosteroids in any form and dose in the first trimester may be associated with an increase in the risk of cleft lip or palate, but the absolute risk of this still remained low at 3 per 1,000 infants with steroid exposure [51]. In addition, very infrequent use of NSAIDs in the late first and second trimester to treat mild symptoms of arthritis, pain and serositis is considered safe although it is important to remember that the risk of oligohydramnios induced by NSAIDs does exist throughout all trimesters.

Moderate Lupus Activity

Azathioprine and higher doses of prednisone can be used for those with moderate lupus activity that is not controlled with the previously mentioned medications. In women who require an immunosuppressant before pregnancy to control moderate to severe lupus activity, azathioprine is a good choice and should be continued throughout pregnancy. In addition, women on other more teratogenic medications, like methotrexate or mycophenolate mofetil, may be switched to azathioprine prior to pregnancy. Cyclosporine has primarily been studied in the transplant population during pregnancy and there has been no increase in neonatal deaths or recurring patterns of congenital anomalies [52]. The rate of congenital malformations did not exceed the 3 % reported in the general population [37]. There have been a few case reports in SLE patients that support its safe use during a lupus pregnancy [53, 54].

While mycophenolate mofetil is a very effective drug for active lupus, it has been associated with a high pregnancy loss rate and a fetal anomaly rate of 25 %. [52] For these reasons, it should not be continued during pregnancy.

Methotrexate is also teratogenic and should be avoided during pregnancy. Ideally it should be discontinued at least 3 months prior to a planned pregnancy and folic acid should be supplemented.

Belimumab has limited data in pregnancy and has been listed as pregnancy class C likely due to the fact that B cell and immunoglobulin levels decreased in infant monkeys exposed in utero. In studies performed in monkeys, no increase in pregnancy loss or congenital malformations was noted, though there was a high degree of transplacental transfer [55]. Unintended pregnancies that occurred during the phase 2 and 3 drug trials of belimumab make up the current human data. There were 83 reported belimumab exposed pregnancies with known outcomes. Of these 83 pregnancies; 24 % were elective terminations, 27.7 % were miscarraiges and 42 % were live births. There were 3 reported congenital malformations (3.6 % rate) amongst these belimumab exposed pregnancies; however one was caused by a chromosomal translocation also found in the mother [56]. Based on current data, no recommendations or conclusions regarding the use of belimumab in pregnancy can be made. Hopefully with growth of the registry, the safety of the drug will be better understood.

Severe Lupus Activity

When organ threatening lupus arises during pregnancy, it puts maternal and fetal health in danger. In these situations, pulse dose steroids in a regimen of 1 g intravenous methylprednisolone daily over three consecutive days is necessary especially in cases of severe organ activity such as in CNS or renal disease. This has the benefit of controlling disease activity rapidly. There are no studies on the administration of high-dose steroids and the fetal effects and thus the risk of this therapy remains unknown.

In addition, IVIG may be used, particularly for renal or hematologic disease [57]. While data on IVIG is limited, the literature has reported no adverse effects on the fetus [37]. A small study which included 12 patients who received IVIG during pregnancy demonstrated a significant decrease in SLE activity and symptoms and positive fetal outcomes after IVIG administration [58].

While we like to avoid cyclophosphamide during pregnancy because of the risk of teratogenicity and pregnancy loss, sometimes it is required as a last resort when disease activity is putting the life of the mother at risk. Data on pregnancy outcomes following cyclophosphamide are limited, but most pregnancies exposed to the drug for lupus activity end in a pregnancy loss [59]. There is uncertainty about whether it is the cyclophosphamide or the severe lupus activity in these women that was the cause of their pregnancy losses. Interestingly, there have been no reports of fetal loss or congenital abnormalities in pregnant women who have gotten cyclophosphamide for treatment of breast cancer in the second or third trimesters [60]. When cyclophosphamide is warranted during pregnancy, healthcare professionals must discuss frankly with the mother the high risk of fetal demise associated with this medication.

Conclusion

Pregnancy in a woman with lupus has the potential for many risks and complications; however, most pregnancies result in the delivery of a healthy baby. The main barrier to pregnancy success is high activity lupus. Therefore, the risk of poor outcome can be mitigated by avoiding conception during periods of lupus flare, continuing immunomodulation during pregnancy, and monitoring for and treating lupus flare during pregnancy. Women with SLE are best served by following with a medical team consisting of a high risk obstetrician and a rheumatologist throughout pregnancy. Fortunately, many women during pregnancy remain in good health and have successful deliveries of healthy infants.

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