Collagen Vascular Diseases in Pregnancy

Key Abbreviations

Anti-β2–glycoprotein I antibody aβ2-GP-I

Anticardiolipin antibody aCL

American College of Obstetricians and Gynecologists ACOG

American College of Rheumatology ACR

Antinuclear antibody ANA

Antiphospholipid antibody aPL

Antiphospholipid syndrome APS

Azathioprine AZA

Catastrophic antiphospholipid syndrome CAPS

Congenital heart block CHB

C-reactive protein CRP

Deep venous thrombosis DVT

Erythrocyte sedimentation rate ESR

Estimated glomerular filtration rate EGFR

Hydroxychloroquine HCQ

Intrauterine growth restriction IUGR

Intravenous immunoglobulin IVIG

Lupus anticoagulant LAC

Low-molecular-weight heparin LMWH

Lupus nephritis LN

Major histocompatibility complex MHC

Mycophenolate mofetil MMF

Methotrexate MTX

Neonatal lupus erythematosus NLE

Nonsteroidal antiinflammatory drug NSAID

Normal sinus rhythm NSR

Preterm birth PTB

Rheumatoid arthritis RA

Recurrent early miscarriage REM

Rheumatoid factor RF

Small for gestational age SGA

Systemic lupus erythematosus SLE

Sjögren syndrome SS

Systemic sclerosis SSc

Tumor necrosis factor alpha TNF-α

Regulatory T cell T REG

Unfractionated heparin UFH

Systemic Lupus Erythematosus

Epidemiology and Etiology

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disorder that can affect multiple organ systems, including the skin, joints, kidneys, central nervous system, heart, lungs, and liver.

SLE is more prevalent among women than men, and most women who are affected by the disease manifest it at some point during their reproductive years. Not infrequently, an initial diagnosis is made during the course of an evaluation for pregnancy complications or during pregnancy or the postpartum period. Significant racial differences are apparent in disease prevalence: black women have a prevalence of 405 per 100,000 compared with a prevalence of 164 per 100,000 among white women.

Genetic predisposition appears to be an important contributing factor to the development of SLE in that 5% to 12% of relatives of SLE patients also have the disease. The concordance for SLE is high (~25%) among monozygotic twins. Rare genetic factors such as deficiencies in complement components and mutations in the TREX1 gene, which encodes a DNA-degrading enzyme—as well as more common single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC)—are associated with the development of SLE. Although an individual may be genetically predisposed to develop SLE, the cause appears to be multifactorial. Studies have identified various exposures—such as to the Epstein-Barr virus, ultraviolet (UV) light, and silica dust—as having associations with SLE. Emerging research suggests that such exposures may mediate the development of SLE through epigenetic changes that cause sustained alterations in gene expression.

Consistent with the higher prevalence of SLE among women, hormonal factors appear to play an important role. Early menarche, oral contraceptives, and postmenopausal hormone replacement have all been associated with an increased risk for SLE.

Clinical Manifestations

The clinical course of SLE is characterized by periods of disease “flares” interspersed with periods of remission. The most common presenting symptoms of SLE include arthralgias, fatigue, malaise, weight change, Raynaud phenomenon, fever, photosensitive rash, and alopecia. Constitutional symptoms will be present in nearly all women at some point in their disease course. More than 90% of individuals with SLE will experience arthralgias, which are typically migratory and most commonly involve the proximal interphalangeal and metacar­pophalangeal joints, wrists, and knees. The arthralgias of SLE typically improve as the day progresses. Most patients also have skin manifestations at some point in the course of the disease, and the classic presentation is a malar “butterfly” rash that worsens with sun exposure. For women who present in the postpartum period, some SLE symptoms—such as fatigue and hair loss—may be easily overlooked. More severe but less common manifestations include discoid lupus (inflammatory skin lesions that result in scarring), lupus nephritis (LN), pleurisy, pericarditis, and seizures or psychosis.


The American College of Rheumatology (ACR) has devised a set of diagnostic criteria for SLE. These criteria were most recently revised in 1997 ( Table 46-1 ) and are highly sensitive and specific for SLE. To be diagnosed with SLE, a patient must have at least four of the 11 clinical and laboratory criteria, either serially or simultaneously. It should be emphasized, however, that some women with features of SLE might not meet the strict diagnostic criteria but can still be at risk for pregnancy complications. These women may benefit from increased surveillance and even treatment.

TABLE 46-1


Malar rash Fixed erythema, flat or raised, over the malar eminences that tends to spare the nasolabial folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Oral ulcers Oral or nasopharyngeal ulceration, usually painless
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

  • Pleuritis (convincing history of pleuritic pain, rubbing heard by a physician, or evidence of pleural effusion)

  • Pericarditis documented by ECG or rub or evidence of effusion


  • Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation is not performed

  • Cellular casts: Red cell, hemoglobin, granular, tubular, or mixed


  • Seizures in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

  • Psychosis in the absence of drugs or metabolic derangements


  • Hemolytic anemia with reticulocytosis

  • Leukopenia <4000/mm 3 on two or more occasions

  • Lymphopenia <1500/mm 3 on two or more occasions

  • Thrombocytopenia <100,000/mm 3 in the absence of drugs


  • Anti-DNA: Antibody to native DNA in abnormal titer

  • Anti-Sm: Presence of antibody to Sm nuclear antigen

  • Positive finding of antiphospholipid antibodies based on * (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis for 6 months

Antinuclear antibody An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

For the purposes of enrollment in clinical studies, a person is defined as having systemic lupus erythematosus (SLE) if four or more of the 11 criteria are present, serially or simultaneously.

ANA, antinuclear antibody; ECG, electrocardiograph; Ig, immunoglobulin.

* Testing for antiphospholipid antibodies should also include IgG and IgM anti-β2–glycoprotein I antibodies.

Because nearly all individuals with SLE will have a positive antinuclear antibody (ANA) titer, this is a reasonable initial screening test for women with suggestive symptoms. If the ANA test is negative, a diagnosis of SLE is highly unlikely. However, an elevated ANA titer is not specific for SLE because it can also be seen in other autoimmune conditions such as Sjögren syndrome, scleroderma, and rheumatoid arthritis (RA). Anti–double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies are more highly specific for SLE, albeit less sensitive. Anti-dsDNA titers are frequently elevated in the setting of a disease flare, whereas Anti-Sm antibodies are detected in 30% to 40% of individuals with SLE and are associated with LN. Antiribonucleoprotein (anti-RNP) antibodies are associated with myositis and Raynaud phenomenon. Patients with either SLE or Sjögren syndrome may also have anti-Ro/SSA and anti-La/SSB antibodies, which are particularly relevant to the obstetric patient because of the association with neonatal lupus erythematosus (NLE) and congenital heart block (CHB).

Lupus Flare in Pregnancy

Studies on the risk of SLE flare in pregnancy have yielded inconsistent results. In the 1960s and 1970s, studies suggested a significant risk for disease flare in pregnancy with accompanying high rates of adverse maternal and fetal/neonatal outcomes. However, more recent studies indicate that pregnancy may not significantly increase the risk of an SLE flare. If flares do occur in pregnancy, they are generally not severe and are relatively easily treated. The best predictor of the course of SLE during gestation is the state of disease activity at the onset of pregnancy . In one study, approximately one third of women who were in remission for at least 6 months prior to pregnancy suffered an SLE flare compared with two thirds of women with active disease at the beginning of pregnancy. Thus women with SLE should be counseled to delay pregnancy until their disease has been in remission for at least 6 months.

The detection of SLE flare in pregnancy requires frequent clinical assessment and astute clinical judgment. Flares in pregnancy most commonly manifest as fatigue, joint pain, rash, and proteinuria. Assessing anti-dsDNA titers and complement (C3 and C4) levels may provide additional evidence of disease flares in women with clinical symptoms. The routine assessment of anti-dsDNA and complement levels in asymptomatic women is of doubtful clinical utility.

Lupus Nephritis in Pregnancy

Renal manifestations are present in approximately half of all patients with SLE. Although LN may be suspected based on hematuria, proteinuria, and casts on urinalysis, confirmation of the diagnosis requires a renal biopsy. According to the International Society of Nephrology and the Renal Pathology Society, six classes of LN have been defined, with the most common and severe form being class IV, or diffuse LN. All patients with active diffuse LN have proteinuria and hematuria, and a significant subset of patients will progress to nephrotic syndrome, hypertension, and renal insufficiency. Women with LN, particularly active disease, are at especially increased risk for adverse pregnancy outcomes that include hypertensive disorders of pregnancy, disease flares, low birthweight infants, and indicated preterm delivery. Similar to SLE in general, the activity of LN during pregnancy is related to disease status at conception. In one study, an LN flare was seen in only 9% of cases in which the disease was in remission for at least 5 months prior to pregnancy, compared with 66% of cases in which disease was clinically active at conception. Women with baseline renal insufficiency are at greatest risk. Ideally, assessment of baseline renal status—serum creatinine and urine protein excretion—is done prior to planning a pregnancy. If the patient is already pregnant, assessment as early as feasible in the pregnancy is recommended. As a general rule, a serum creatinine of 1.4 to 1.9 mg/dL (estimated glomerular filtration rate [EGFR] ~30 to 59 mL/min/1.73 m 2 ) is a relative contraindication to pregnancy given the substantial risk of midterm pregnancy complications that might require preterm delivery. Most experts consider a serum creatinine of 2.0 mg/dL or greater (EGFR ~15 to 29 mL/min/1.73 m 2 ) to be an absolute contraindication to pregnancy, again because of the substantial risk of pregnancy complications requiring extreme preterm birth (PTB) and the threat to long-term renal function. Women with moderate and especially severe baseline renal insufficiency should be counseled regarding the small (5% to 10%) but real risk of an irreversible decline in renal function during pregnancy.

Women with LN often have increasing proteinuria across gestation, related in part to increased glomerular filtration. However, an isolated increase in proteinuria without new-onset or worsening hypertension or a significant rise in serum creatinine should not be an indication for preterm delivery. Furthermore, the American College of Obstetricians and Gynecologists (ACOG) no longer considers proteinuria a necessary diagnostic criterion for preeclampsia.

Distinguishing between a flare in SLE (and LN) and preeclampsia can pose a clinical dilemma. Both entities can present with hypertension and proteinuria. If the pregnancy is at or near term, delivery may be the most prudent strategy. Preeclampsia should resolve after delivery. However, if the pregnancy is still very preterm, distinguishing between a disease flare and preeclampsia is more critical. A SLE flare can usually be treated, such as with corticosteroids, to prolong the pregnancy and optimize neonatal outcomes. Because elevated anti-dsDNA titers and low complement levels are often seen in active SLE, assessing them may aid in distinguishing between a disease flare and preeclampsia. However, it should be emphasized that hypocomplementemia can also be seen in preeclampsia. Examination of the urine sediment may also provide useful information because hematuria and cellular casts often accompany an LN flare but are not characteristic of preeclampsia. Renal biopsy may be considered in difficult cases but is usually avoided during pregnancy unless management of the pregnancy is incumbent upon the results.

Women with severe LN are often treated with mycophenolate mofetil (MMF), a significant teratogen that is contraindicated in pregnancy. MMF is typically replaced by azathioprine (AZA) when a pregnancy is planned or soon after conception in an unplanned pregnancy. In one study, preconceptional replacement of MMF with AZA among women with inactive disease did not lead to an increase in LN flares in the 3 to 6 months prior to a confirmed pregnancy.

Pregnancy Complications

Women with SLE do not appear to be less fertile than women without SLE, but they are at increased risk for multiple adverse pregnancy outcomes that include pregnancy loss, PTB, preeclampsia, and intrauterine growth restriction (IUGR).

Pregnancy Loss

Studies from the 1960s and 1970s reported pregnancy loss rates as high as 50% among women with SLE. Although rates of pregnancy loss appear to have declined over the decades, probably related to improved treatment and surveillance, women with SLE are still at greater risk for pregnancy loss compared with women who do not have SLE. One study found that even women with disease remission at the onset of pregnancy had a risk of miscarriage or fetal death of 17% compared with 5% for women without SLE. A meta-analysis reported a spontaneous abortion rate of 16% and a stillbirth rate of 3.6% among women with SLE. The National Institutes of Health (NIH) sponsored Predictors of Pregnancy Outcome: Biomarker In Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE), a study that followed a cohort of women with inactive or mild-to-moderate SLE activity at conception. Because patients were enrolled in the late first or early second trimesters, early pregnancy loss was not assessed. However, the overall fetal death rate among these women was 4%, and the neonatal death rate was 1%.

Active disease at the onset of pregnancy confers an increased risk for pregnancy loss. Among a cohort of 267 pregnancies followed between 1987 and 2002, 77% resulted in a live birth among women with high-activity SLE compared with 88% among those with low-activity disease. In addition to disease activity, LN, hypertension, and antiphospholipid antibodies (aPLs) are all associated with an increased risk for pregnancy loss (see Chapter 27 ).

Intrauterine Growth Restriction

The increased risk for stillbirth among women with SLE is likely related to higher rates of placental insufficiency and IUGR (see Chapter 33 ), particularly among pregnancies complicated by active disease, hypertension, LN, and/or antiphospholipid syndrome (APS). Although the rate of IUGR among pregnancies complicated by SLE has been reported to be as high as 40%, modern treatments and improved pregnancy surveillance have probably decreased this rate . A study from the National Inpatient Sample analyzed over 16 million hospital admissions for childbirth and found that 5.6% of women with SLE carried a diagnosis of IUGR, compared with 1.5% among women without SLE (this difference was not statistically significant). In the PROMISSE study, 8% of infants of women with mild to moderate SLE were small for gestational age (SGA). Chronic, high-dose glucocorticoid treatment is also a risk factor for IUGR. Because of the increased risk for IUGR and stillbirth, it is standard practice to assess fetal growth intermittently with ultrasound after 20 weeks and to perform antenatal testing (nonstress tests or biophysical profiles) in the third trimester.

Preterm Birth

Women with SLE have an approximately threefold increased risk for PTB. In the PROMISSE study, 9% of pregnancies delivered before 36 weeks. Most of these PTBs are not spontaneous but are rather iatrogenic, the result of fetal or maternal indications (IUGR, preeclampsia, disease flare, deteriorating renal function, etc.). Women with active disease, aPLs, LN, and hypertension are at particular risk for PTB. In one study, a full-term delivery was achieved in only 26% of women with high-activity SLE compared with 61% of women with low-activity disease or remission. High-dose glucocorticoids have also been associated with an increased risk for preterm premature rupture of membranes.

Hypertensive Disorders of Pregnancy

Hypertensive disorders (gestational hypertension or preeclampsia) occur in 10% to 30% of pregnancies with SLE. The risk for preeclampsia is particularly increased in women with LN and/or chronic hypertension. Preeclampsia may develop in as many as two thirds of women with LN and is a frequent indication for iatrogenic PTB. It appears that preeclampsia is also more likely to develop at an earlier gestational age among women with a history of LN compared with those without such a history (37.5 weeks vs. 34.5 weeks in one study ). Daily low-dose aspirin (typically 81 mg in the United States) beginning early in pregnancy is recommended for women with SLE, partic­ularly those with renal manifestations, because evidence suggests this may modestly decrease the risk of developing preeclampsia.

As mentioned previously, it may be difficult in some cases to distinguish between an SLE flare and preeclampsia, and astute clinical judgment is required. Hospitalization for maternal and fetal monitoring, administration of antenatal steroids, and thoughtful determination of the need for delivery is frequently indicated in these cases.

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus is an acquired autoimmune condition related to the transplacental transfer of anti-Ro/SSA and anti-La/SSB antibodies. NLE most commonly presents as an erythematous, scaling, plaquelike rash that begins in the early neonatal period and may persist for 1 to 2 months. Less common manifestations of NLE include hematologic abnormalities (leukopenia, hemolytic anemia, thrombocytopenia) and hepatosplenomegaly. Fortunately, the incidence of NLE is low. Among all pregnant women with SLE, the risk of NLE is less than 5%. Of those women with SLE who test positive for anti-Ro/SSA and anti-La/SSB antibodies, at most 15% to 20% will have an affected newborn. Many mothers of newborns with NLE will not carry a current diagnosis of SLE. However, a significant number of these women will develop symptomatic autoimmune disease, often Sjögren syndrome, in the future. They should therefore be counseled to seek medical evaluation if symptoms of SLE or Sjögren syndrome develop.

The most serious manifestation of NLE is complete heart block. It is most frequently diagnosed at a routine prenatal visit when a fixed fetal bradycardia of 50 to 80 beats/min is detected. CHB is most commonly diagnosed between 16 and 24 weeks’ gestation, and it is rarely diagnosed in the third trimester. It is caused by the binding of antibodies to antigens in fetal cardiac tissue with subsequent damage to the cardiac conduction system and, ultimately, complete atrioventricular (AV) dissociation. Some cases progress to endocardial fibroelastosis, which can result in cardiac failure that leads to fetal hydrops and fetal death. Among women with anti-Ro/SSA and anti-La/SSB antibodies, the risk for CHB in the fetus is only 1% to 2%. However, women with a prior affected child have a recurrence risk for CHB of 15% to 20% in subsequent pregnancies. Fetal genetic factors, such as certain human leukocyte antigen (HLA) polymorphisms, may modify susceptibility to the development of CHB. Although many clinicians routinely test pregnant women with SLE for anti-Ro/SSA and anti-La/SSB antibodies, this practice is not without controversy given that CHB is infrequent, antenatal treatment to alter outcome is of uncertain efficacy, and a positive test result may cause unnecessary maternal anxiety.

Complete CHB is irreversible and is associated with an overall mortality rate of at least 20% (5% stillborn). The majority of survivors require a pacemaker. In one series of 102 cases, a prenatal diagnosis of CHB was associated with a 43% risk of mortality in the first two decades of life. Among a registry of 325 offspring with cardiac manifestations of NLE, predictors of a stillbirth or postnatal death included hydrops, endocardial fibroelastosis, earlier diagnosis, and a lower ventricular rate. In addition, the case fatality rate was significantly higher among minorities (32.1% for blacks compared with 14.3% for whites).

Management of Pregnancies Complicated by Systemic Lupus Erythematosus

Because SLE commonly affects women at some point during their reproductive years, the clinician should be familiar with the high-risk nature of these pregnancies and the altered management and increased surveillance required. Ideally, women with SLE would present for a preconceptional visit such that disease remission could be ensured, medications reviewed, and counseling performed.

Table 46-2 outlines recommendations for the management of pregnancies complicated by SLE. Key components include the assessment of disease activity and renal manifestations, surveillance for preeclampsia, surveillance of fetal growth, and antenatal testing. Co-management with a rheumatologist is particularly important for women with severe manifestations or active disease. Furthermore, some women experience a disease flare in the postpartum period; therefore the obstetrician should carefully assess disease activity at postpartum visits, and follow-up with rheumatology in the 1 to 3 months following delivery is usually recommended.

TABLE 46-2


Baseline assessment

  • Antiphospholipid antibodies: Lupus anticoagulant, anticardiolipin IgG/IgM, and anti-β2–glycoprotein I IgG/IgM

  • Review current medications and risks

  • Consider testing for anti-Ro/SSA and anti-La/SSB antibodies (controversial)

Lupus nephritis

  • Serum creatinine every 4 to 6 weeks

  • Baseline urine protein assessment (24-hour urine collection or spot protein/creatinine ratio)

  • Urine culture each trimester *

  • Increased surveillance for signs and symptoms of preeclampsia

Intrauterine growth restriction (IUGR)

  • Monthly ultrasonographic assessment of fetal growth after 24 to 28 weeks


  • NST/AFI or BPP beginning at 32 weeks unless indicated earlier (e.g., due to IUGR)

  • Delivery by 39 weeks unless indicated earlier (e.g., due to IUGR, preeclampsia, worsening renal function)

Chronic steroid therapy

  • Early and repeated screening for gestational diabetes

  • Stress-dose steroids at delivery, particularly for women on more than 20 mg/day of prednisone for more than 3 weeks

Antiphospholipid antibodies

  • Daily low-dose aspirin

  • Consideration of prophylactic or therapeutic heparin, depending on laboratory results and clinical history (see section on antiphospholipid syndrome )

Lupus flare

  • Continuation, or possibly initiation, of hydroxychloroquine

  • Postpartum monitoring for increased disease activity

AFI, amniotic fluid index; BPP, biophysical profile; IG, immunoglobulin; IUGR, intrauterine growth restriction; NST, nonstress test.

* Sulfa antibiotics may exacerbate lupus symptoms in some patients. Consider other antibiotics for the treatment of urinary tract infections.

Intravenous hydrocortisone 100 mg every 8 hours for 2 to 3 doses is one regimen.

Management of Congenital Heart Block

Given that complete CHB is irreversible and that the prognosis is grave, efforts have focused on trying to predict and prevent the development of CHB. Some experts have proposed serial fetal echocardiograms with Doppler monitoring of the PR interval or kinetocardiography in women with anti-Ro/SSA and anti-La/SSB antibodies, particularly in those with a prior fetus affected by CHB. However, these practices are controversial, and no formal guidelines for the type and frequency of monitoring have been established. Neither fetal Doppler PR interval monitoring nor kinetocardiography have been associated with proven benefit, in part because progression to CHB can occur rapidly and without discernable progression through first- and second-degree block. In spite of this, many experts—including expert rheumatologists and pediatric cardiologists—recommend serial PR interval monitoring of the fetus in a woman with anti-SSA/Ro and anti-SSB/La antibodies. In our experience, the inclinations of the local pediatric cardiology team play a dominant role in deciding upon the nature and frequency of such monitoring.

Even with early detection of cardiac conduction abnormalities or new-onset CHB, no credible evidence suggests that medical interventions alter outcomes. Current treatment recommendations are based on expert opinion and relatively small studies, all nonrandomized. Several case series have described use of fluorinated steroids such as dexamethasone for the treatment of either cardiac conduction abnormalities or new-onset CHB. The PR Interval and Dexamethasone Evaluation (PRIDE) study enrolled 40 women with anti-Ro/SSA antibodies and a fetus with any degree of heart block diagnosed echocardiographically. Thirty women were treated with dexamethasone and 10 declined treatment. No cases of CHB reverted, treated or untreated. Among six treated fetuses with second-degree block, three remained in second-degree block, two reverted to normal sinus rhythm (NSR), and one progressed to complete block. Two treated fetuses had first-degree block, and both reverted to NSR after initiation of dexamethasone. However, the one untreated fetus with first-degree block was in NSR at birth. Although case selection in this nonrandomized study likely played a role, no perinatal deaths were reported in the nontreated group compared with deaths (20%) in the dexamethasone group. Treatment with steroids was associated with more preterm and SGA infants; the potential adverse effects of steroids must thus be weighed against the limited data that support a benefit in cases of early cardiac conduction abnormalities.

Although experts generally agree that steroid treatment should not be expected to reverse CHB, at least one group of investigators has concluded that steroid treatment might reverse or improve hydrops, reduce morbidity, and improve 1-year survival. Others disagree. In addition to steroid treatment, β-stimulation—such as with terbutaline, ritodrine, or salbutamol—has been administered in some cases of a very low fetal heart rate (<55 beats/min) in an attempt to increase the heart rate and prevent hydrops. Once again, data to support this treatment strategy are very limited. Table 46-3 outlines management strategies for CHB.

TABLE 46-3


Anti-Ro/SSA, anti-La/SSB antibodies, no previously affected child

  • Risk of CHB is 1%-2%, routine monitoring of the fetal PR interval is usually not recommended (controversial)

Anti-Ro/SSA, anti-La/SSB antibodies, previously affected child

  • Risk of CHB is 15%-20%

  • Give hydroxychloroquine beginning in the first trimester (400 mg/day)

  • Consider serial monitoring of the fetal PR interval (controversial) with weekly pulsed Doppler echocardiography *

First-degree heart block

  • Patient may revert to normal sinus rhythm; monitor for progression

  • Consider dexamethasone treatment at 4 mg/day (controversial)

Second-degree heart block

  • Monitor for progression

  • Consider dexamethasone treatment at 4 mg/day upon diagnosis

  • Discontinue dexamethasone if condition progresses to complete block except with evidence of hydrops

  • Given potential adverse effects, consider discontinuation of dexamethasone if heart block reverts

First-degree (complete) heart block

  • Monitor for hydrops

  • Give dexamethasone if hydrops develops

  • Consider oral terbutaline (2.5-7.5 mg every 4-6 hr) for an FHR <55 beats/min

CHB, congenital heart block; FHR, fetal heart rate.

* Highest risk period for development of CHB is between 18 and 24 weeks’ gestation.

Fetal echocardiography is recommended to rule out structural heart disease.

Caution is warranted with chronic terbutaline therapy because of reported serious maternal adverse events. Terbutaline should especially be avoided in women with diabetes, hypertension, hyperthyroidism, seizures, or a history of arrhythmias.

Strategies to prevent conduction abnormalities altogether would certainly seem attractive, and three preventive treatments have been considered. Glucocorticoids are not recommended as preventative treatment for women at high risk of CHB due to lack of proven benefit and because most fetuses will not develop CHB. Furthermore, chronic glucocorticoid therapy is associated with some maternal and fetal risks, including potential programming effects on offsprings’ hypothalamic-pituitary-adrenal axis and neurodevelopment (see Chapter 5 ).

Two multicenter prospective observational studies have evaluated intravenous immunoglobulin (IVIG) as a preventative agent. The two studies enrolled a total of 44 women at high risk for CHB. The results do not indicate that IVIG is effective at preventing the development of CHB, and it should not be used for this purpose outside of approved research protocols.

More recent data suggest a potential benefit of hydroxychloroquine (HCQ) in decreasing the risk of NLE cardiac complications among high-risk women. In a historic cohort of 257 pregnancies in women with anti-Ro/SSA antibodies and a previous child affected with CHB, HCQ use beginning in the first trimester was associated with significantly decreased odds of cardiac NLE (0.23; 95% confidence interval [CI], 0.06 to 0.92), defined as second- or third- degree block or isolated cardiomyopathy. Given the low risk for fetal harm (see the section on medications) and potential benefit, initiation of HCQ in the first trimester should be considered among women positive for anti-Ro/SSA antibodies who have had a prior affected child.

Drug Used to Treat Systemic Lupus Erythematosus and Pregnancy Considerations

It should be noted that as of June of 2015, the U.S. Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Final Rule requires that the pregnancy safety letter categories of A, B, C, D, and X be removed from drug labels and replaced by a risk summary, clinical considerations, and available data. The goal of this change is to better assist health care providers in assessing the benefits versus risks of medications in pregnancy. This rule also requires that labels be updated when the information is outdated.

Drugs with Acceptable Risk Profiles in Pregnancy (See Chapter 8 )


Past concerns regarding HCQ being associated with fetal ocular toxicity and ototoxicity (FDA category C) have not been confirmed by studies published within the past 15 years. One study of 114 HCQ-exposed pregnancies, most in the first trimester, compared with 455 unexposed pregnancies found no significant difference in the rate of congenital anomalies. Moreover, the continuation of HCQ during pregnancy may be beneficial; one retrospective analysis showed that women who remained on HCQ had less severe SLE flares and thus required lower doses of glucocorticoids. Evidence also suggests that HCQ may prevent CHB in at-risk fetuses. Given the possible benefits and the apparent lack of harm, many experts now recommend that women on HCQ who become pregnant continue the medication during pregnancy. It is also a favored agent for the treatment of SLE flares in pregnancy, and HCQ is compatible with breastfeeding.


SLE flares in pregnancy are most commonly treated with glucocorticoids. Nonfluorinated steroids, such as prednisone and methylprednisolone (both FDA category C) are preferred in pregnancy because the placenta metabolizes these agents to an inactive metabolite, which results in limited fetal exposure. Some studies have reported a small increased risk of cleft lip and palate with first-trimester glucocorticoid use, but other studies have not confirmed these findings. If the risk for orofacial clefts is increased, this increase appears to be small. Prolonged use of glucocorticoids is associated with an increased risk for maternal bone loss, gestational diabetes, hypertension and preeclampsia, and adrenal suppression. The use of prednisone in moderate to high doses may be associated with preterm rupture of membranes (PROM) and fetal growth restriction. Women taking glucocorticoids should be screened early for gestational diabetes, and the test should be repeated at the usual 24 to 28 weeks if normal. Those on 20 mg/day or more of prednisone for at least 3 weeks are at greatest risk of adrenal suppression and should receive stress-dose steroids during labor and delivery. One stress-dose regimen is 100 mg of intravenous (IV) hydrocortisone every 8 to 12 hours for two to three doses. The risk of adrenal suppression for women taking 5 mg or less per day of prednisone is very small, and stress-dose steroids are not indicated. For women who take more than 5 mg and less than 20 mg per day, many clinicians still administer stress-dose steroids, although simply continuing women on their daily steroid dose is probably adequate. In general, prednisone is compatible with breastfeeding, although for women who take more than 20 mg per day, it may be prudent to delay feeding for 4 hours after the dose.

Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are considered first-line treatment for autoimmune disease symptoms such as arthralgias or arthritis. First trimester NSAID exposure was not associated with an increase in the rate of congenital malformations or a decrease in infant survival in several large population-based studies. It is controversial as to whether first- and early second-trimester use of NSAIDs is associated with an increased risk of spontaneous abortion. Third-trimester NSAID use may cause premature closure of the fetal ductus arteriosus, particularly after 30 weeks’ gestation, and oligohydramnios. For these reasons, NSAIDs are FDA category C before 30 weeks and category D thereafter. NSAIDs should be used judiciously in the late first and second trimesters of pregnancy and should be generally avoided after 28 to 30 weeks. The single exception is low-dose aspirin, which can be taken safely throughout pregnancy. Daily low-dose aspirin may provide modest risk reduction for the development of preeclampsia among high-risk women. Data are limited regarding cyclooxygenase 2 (COX-2) inhibitors such as celecoxib in pregnancy, and it is recommended that these agents be avoided. NSAIDs are compatible with breastfeeding.


Azathioprine (FDA category D) is used in the prevention of transplant rejection and in the treatment of SLE and LN. Although teratogenicity has been documented in animal studies, the human placenta lacks the enzyme that metabolizes AZA to its active metabolite, 6-mercaptopurine. As a result, very little active drug reaches the fetal circulation. Human studies have not found an increased risk for teratogenicity. Some studies have found increased rates of IUGR, PTB, and impaired neonatal immunity with AZA use in pregnancy. However, it is difficult to determine whether these outcomes are related to AZA use or the underlying disease. AZA, often in combination with glucocorticoids, is thus the preferred treatment for severe or active SLE in pregnancy. Most experts consider AZA to be compatible with breastfeeding, although long-term follow-up of exposed infants is limited. Avoiding feeding for 4 to 6 hours after a dose will markedly decrease the amount of drug in breastmilk.

Cyclosporine A

Cyclosporine A (FDA category C) is a calcineurin inhibitor sometimes used in the treatment of LN or severe arthritis. The drug is an immunosuppressive that inhibits the production and release of interleukin 2 (IL-2). Animal studies have demonstrated very low transplacental transfer of cyclosporine. Human studies are conflicting, but probably very little drug enters the fetal circulation. Data obtained primarily from organ transplant patients indicate a very low risk of teratogenicity, but the risk for PTB and SGA infants may be increased. The drug may also cause a rise in maternal creatinine. Women on cyclosporine are generally discouraged from breastfeeding, although data are limited regarding adverse outcomes.

Drugs with Uncertain or Higher Risk Profiles in Pregnancy


Cyclophosphamide (FDA category D) is an alkylating agent used in the treatment of LN and vasculitis. This drug is teratogenic and should not be used at all in the first trimester . Use of cyclophosphamide may be considered in the second and third trimesters in the rare patient with very severe and progressive disease manifestations. Cyclophosphamide is not compatible with breastfeeding .

Drugs Contraindicated in Pregnancy

Mycophenolate Mofetil

Mycophenolate mofetil (FDA category D) is an inhibitor of purine biosynthesis and is used in the treatment of LN. MMF is absolutely contraindicated in pregnancy due its abortifacient and teratogenic properties. MMF is associated with an increased risk for cleft lip and palate, micrognathia, microtia, and abnormalities of the ear canals. Women should avoid pregnancy until they have been off MMF for at least 6 weeks. No data are available regarding MMF use and breastfeeding, and it is considered contraindicated.

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Mar 31, 2019 | Posted by in OBSTETRICS | Comments Off on Collagen Vascular Diseases in Pregnancy
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