P- Reviewers: Andonopoulos AP, Tanaka H S- Editor: Song XX L- Editor: A E- Editor: Ma S
Published online Nov 12, 2013. doi: 10.5499/wjr.v3.i3.32
Revised: September 30, 2013
Accepted: November 1, 2013
Published online: November 12, 2013
Systemic lupus erythematosus (SLE) typically affects women in their childbearing age, who have the same fertility rates as the healthy population. The effect of pregnancy on the disease and the effect of SLE on pregnancy and the fetus are highly important issues for the attending physician. Whether lupus flares are more frequent during pregnancy remains controversial. Among the possible effects of SLE on pregnancy are a greater number of abortions, fetal loss, pre-term deliveries and perinatal mortality. The newborn may be affected by the onset of neonatal lupus erythematosus (neonatal LE), either as a skin or blood disease, or by the presence of congenital heart block. The frequent association between SLE and antiphospholipid syndrome represents another risk situation for the mother and the product of conception. Multiples drugs used in SLE patients should be evaluated. Those with teratogenic potential should be withdrawn before pregnancy, and when necessary, appropriate medications should be indicated to treat the mother without compromising the safety of the baby. In conclusion, pregnancies in lupus patients represent a challenge for the physician and must be closely followed up and treated if necessary, during all trimesters and in the puerperium period, to improve outcome.
Core tip: Systemic lupus erythematosus (SLE) typically affects women in their childbearing age. The effect of pregnancy on the disease and the effect of SLE on pregnancy and the fetus are highly important issues for the attending physician. The newborn may be affected by the onset of neonatal lupus erythematosus, either as a skin or blood disease, or by the presence of congenital heart block. The frequent association between SLE and antiphospholipid syndrome represents another risk situation. Optimization of pharmacological therapy before and during pregnancy should be done in order to reduce adverse events to the mother and the baby.
- Citation: Cavallasca JA, Costa CA, Maliandi MDR, Musuruana JL. Hot topics in lupus pregnancy. World J Rheumatol 2013; 3(3): 32-39
- URL: https://www.wjgnet.com/2220-3214/full/v3/i3/32.htm
- DOI: https://dx.doi.org/10.5499/wjr.v3.i3.32
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that typically affects women in their childbearing age. The peak incidence of SLE occurs between the ages of 15 and 40 years, with an estimated female to male incidence of 9:1. Multiple reports have researched the impact of pregnancy on SLE with dissimilar results. While some authors hold that pregnancy is not a cause of disease exacerbations other researchers have found exacerbations in 74% of cases. There is no consensus on the management of pregnancy in SLE patients; therefore pregnancy is a challenge for lupus patients and their physicians.
Although pregnancy in SLE currently has favorable outcomes for the majority of women, the potential for maternal and fetal complications still exists. Next we summarize the latest bibliographical data of SLE and pregnancy.
Women with SLE have normal fertility, even if disease is active. However, fertility may be reduced in the presence of impaired renal function. Cyclophosphamide has previously been associated with ovarian failure. However, it has now been demonstrated that cumulative dose of cyclophosphamide on patients over 32 is the most important predictor of anovulation. On the other hand, the use of azathioprine, cyclosporine and methotrexate is not associated with ovarian failure.
Patients with SLE should be encouraged to delay pregnancy until their disease is inactive for at least 6 mo, to avoid major complications and fetus exposure to potentially teratogenic medications.
|Severe pulmonary hypertension (estimated systolic PAP > 50 mmHg or symptomatic)|
|Severe restrictive lung disease (FVC < 1 L)|
|Chronic renal failure (Cr > 2.8 mg/dL)|
|Previous severe preeclampsia or HELLP syndrome despite therapy with aspirin and heparin|
|Stroke within the previous 6 mo|
|Severe lupus ﬂare within the previous 6 mo|
Barrier methods are the most common form of contraception in these patients. However, they are not the most appropriate choice because they have a relatively high rate of failure compared to, the significantly lower failure rate of hormonal contraceptives. Oral contraceptives are safe for about two thirds of SLE patients, according to OC-SELENA trial which demonstrated that oral contraceptives do not appreciably increase the risk of a severe flare as compared with placebo. The exception would be unstable lupus, hypercoagulability due to antiphospholipid antibodies or to nephrotic syndrome or past history of thrombosis. Although estrogen containing contraceptives are contraindicated for this risk group, other contraceptive methods can be recommended. Progestin-only methods, including the levonorgestrel-containing intrauterine devices (IUD) do not increase the risk of thrombosis in the general population.
The lowest failure rates are achieved with IUD, a method that offers effective, reversible contraception without increasing vascular risk. Besides, this method is considered safe for all women with SLE. Previous concerns about an increased risk of infection in immunocompromised patients appear unfounded.
The influence of pregnancy on disease activity in women with SLE is variable. This variability may be due to the differences in study populations, the number of patients included in the series, the methodological differences in the study design, the existence or lack of a control group, and the definition of flare that is being used. In, general flares during pregnancy were observed in 40%-60% of patients in all trimesters and in the puerperium period and they were usually mild. Severe flares may occur in 15%-30% of the cases dependent on disease activity 6 to 12 mo prior to conception[10,11]. Several studies to date provide a consensus: pregnancy outcome is optimal when disease is in complete clinical remission for 6-12 mo[12,13]. Pregnancy should therefore be planned when SLE is in remission.
Disease flare can occur at any time during pregnancy and puerperium without any clear pattern. Minor organ manifestations are common, however major organs manifestations can also occur; the main risk is glomerulonephritis. Some clinical and laboratory features of normal pregnancy can simulate lupus activity (Table 2).
|Lupus flare||Normal pregnancy|
|Clinical features||Malar rash||Palmar and facial erythema|
|Inflammatory arthritis||Arthralgia/Joint effusions|
|Laboratory features||ESR increased||ESR increased|
|Anemia||Anemia due to hemodilution|
|Complement levels drop||Complement levels increased|
|dsDNA antibodies rising||dsDNA antibodies stable|
|Proteinuria ≥ 300 mg/dL||Proteinuria ≤ 300 mg/dL|
In the last 2 decades, several lupus activity scales have been adapted for pregnancy: Systemic Lupus Erythematosus in Pregnancy Activity Index (SLEPDAI), Modified Lupus Activity Measurement (m-SLAM) and Lupus Activity Index in Pregnancy (LAI-P). All of them take into account the influence of pregnancy on clinical manifestation and common biochemical tests. LAI-P also accounts for specific manifestations of Antiphospholipid Syndrome in order not to score them as due to SLE activity. SLEPDAI and LAI-P have a sensitivity of 93% and a specificity of 98%. However, daily assessment and management of individual pregnant women with lupus still relies on the clinical skills of attending physicians[15-18].
Historically, lupus pregnancy was associated with a high rate of obstetric and fetal complications. These include spontaneous abortion, late miscarriage, intrauterine growth retardation, preterm delivery and prematurity (Table 3). With the widespread use of careful monitoring and treatment schedules of these patients many improvements in both fetal and maternal pregnancy outcomes have occurred. The rates of fetal loss has declined significantly in pregnancies in patients with SLE, from 43% before 1975 to 17% in recent years, live birth rates of 85%-90% have been reported in recent studies.
|Intrauterine growth retardation|
Predictors of fetal loss include: active disease, lupus nephritis, presence of antiphospholipid antibodies (aPL), thrombocytopenia, proteinuria and hypertension. In our series there were 61 live births, including one twin birth (85%), six still birth (8%) and 5 spontaneous abortions (7%).
Preterm delivery is frequent and the strong predictors of preterm birth are lupus activity, hypertension and corticosteroid use.
In this study, forty six percent of 72 pregnancies ended in preterm deliveries. Significantly more women in the preterm delivery group were taking ≥ 10 mg/d of prednisone compared to the full term delivery group.
Intrauterine growth retardation (IUGR) is reported in 10%-30% of pregnancies in patients with SLE. The risk is higher in presence of active disease and lupus nephritis.
Lupus pregnancy is associated with an increased risk of pre-eclampsia especially in the setting of lupus nephritis. Pre-eclampsia and eclampsia can both mimic lupus by presenting as edema, thrombocytopenia, hyperuricemia, anemia, hypertension, proteinuria, hematuria and seizures in eclampsia.
Pre-eclampsia is more common in patients with antiphospholipid syndrome, lupus nephritis, diabetes mellitus or past pre-eclampsia.
Investigations of serum complements C3, anti DNA antibodies and urinary sediment can help to differentiate between both diseases (Table 4). In our study we have seen gestational hypertension in 15 pregnancies (21%) and preeclampsia in 8 pregnancies (11%). No eclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurred.
|Pre eclampsia||Lupus nephritis|
|Backgrounds||Chronic hypertension, antiphospholipid syndrome, diabetes mellitus, past preeclampsia|
|Hypertension||Onset after 20 wk||Onset before 20 wk|
|Urinary sediment||Inactive||Active (red cells, white cells and cellular casts)|
|Anti DNA antibodies||Stable||↑↑|
|Uric acid levels||↑|
|Urinary calcium excretion||↓|
Approximately 50% of SLE patients will develop renal compromise that may carry complication to the mother and/or fetus. High rates of pre-eclampsia are common in women with lupus nephritis ranging from 9% to 35%, specially in women diagnosed with lupus nephritis during pregnancy, unplanned pregnancies or with active disease before pregnancy. Furthermore, the activity of lupus nephritis (LN) at conception has a high impact on premature birth and fetal losses, which range between 25%-57% in women with active LN vs 8%-12.5% in those with stable renal disease. Others potential pregnancy complications in patients with renal involvement are pre term delivery[27,28] and intrauterine growth retardation.
The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating aPL: lupus anticoagulant (LA), anticardiolipin antibodies (ACL) and/or anti-B2 glycoprotein I antibodies (anti-B2 GPI) in medium to high titers.
|Classification criteria of APS in pregnancy|
|One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (1) eclampsia or severe preeclampsia defined according to standard definitions, or (2) recognized features of placental insufficiency-, or (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.|
|Others obstetric manifestations of APS|
|Increased risks of intrauterine growth retardation|
|Risk of thrombosis in the mother|
The treatment of pregnancies in women who are positive for aPL, depends on the presence of concomitant risk factors. In women positive for aPL but with no prior thrombotic event or pregnancy loss, low dose aspirin is recommended throughout the pregnancy. In those with aPL positivity and with recurrent early losses or one or more late fetal loss, without history of systemic thrombosis, aspirin in combination with prophylactic doses of heparin is indicated during pregnancy. Patients with prior systemic thrombosis in the presence of aPL should receive full therapeutic doses of heparin during pregnancy.
Low-molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less adverse effects and easy monitoring. It requires more frequent dosing and twice-daily administration for all doses and it should be transitioned to unfractionated heparin near term to ensure fast reversal of anticoagulation at the time of delivery. Heparin treatment should be continued for 6 wk after delivery. Corticosteroids, in combination with aspirin, were shown to have similar efficacy to heparin, but with higher maternal morbidity. IVIg was evaluated in two randomized trials and it was less efficient than the aspirin and heparin combination treatment in prevention of recurrent loss. Some women are refractory to aspirin and heparin combination and continue to have recurrent losses despite treatment. No consensus exists for the management of this group of patients. The addition of corticosteroids, IVIg, and plasmapheresis has been tried, but data are limited.
Neonatal lupus erythematosus (NLE) is a condition represented by cutaneous, cardiac, hepatic, hematologic, neurologic and splenic abnormalities, observed in newborn infants whose mothers have autoantibodies against Ro/SSA, La/SSB and, less frequently, U1-RNP.
These autoantibodies cross the placenta and cause neonatal lupus in 1% of newborns, and subsequent children have a 25% risk if the mother has had a previously affected baby.
All lupus patients contemplating pregnancy should have an anti-Ro/SSA, anti-La/SSB status determined, these antibodies are present in 30%-50% of SLE patients. The majority of the affected babies suffer a transient and often mild lupoid rash characterized as annular erythematous or polycystic plaques on the scalp, neck or face, typically periorbital; they resemble the lesions of subacute cutaneous lupus erythematosus. These lesions last for weeks or months and then resolve spontaneously consequent to the disappearance of maternal antibodies in the neonatal circulation.
Hepatobiliary involvement in NLE includes elevation of liver enzymes and/or conjugated hyperbilirubinemia. Some babies may have hepato-splenomegaly and less frequently, cholestatic hepatitis and hepatic failure.
Hemolytic anemia, thrombocytopenia and neutropenia may occur in the first 2 wk of life and they usually are asymptomatic. Hematologic symptoms disappear by the end of the second month. Other abnormalities like aseptic meningitis, myelopathy, hydrocephalus and macrocephaly have rarely been described.
The most common and well recognized cardiac manifestation of NLE is congenital heart block (CHB) that occurs in only 2% of infants born to mothers with anti-Ro/SSA or anti-La/SSB antibodies. The risk of CHB increases in infants born to mothers with a previous child having CHB and occurs in nearly 20% of the subsequent pregnancies.
This cardiac manifestation is irreversible and has significant mortality (approximately 20% in the neonatal period), and morbidity with more than 60% of the cases requiring permanent pacemakers and 10% developing severe cardiomyopathy.
The first fetal echocardiogram should be performed at 16 wk of gestation and then weekly for high risk infants (prior fetus with CHB) or every 2 wk in lower risk settings.
The goal of this monitoring would be to identify a biomarker of reversible injury such as PR interval prolongation > 150 ms, moderate/severe tricuspid regurgitation, and/or atrial echodensity.
Prenatal maintenance therapy with betamethasone or dexamethasone given to the mother starting early in pregnancy (before 16 wk’ gestation), might reduce the risk of developing antibody-mediated congenital heart block in the offspring.
In contrast, recent data confirm the irreversibility of third degree block and progression of second to third degree block despite the use of dexamethasone. A potential benefit of this drug in reversing first or second degree block was observed in rare cases.
Moreover, in regard to the role of Toll- like receptors in the pathogenesis of cardiac-NLE, two studies, a case -control study and a multinational historical cohort study, suggest that hydroxychloroquine use in a mother with anti-SSA/Ro antibodies and a previous child with cardiac-NLE may reduce the risk of cardiac NLE recurrence in a subsequent pregnancy[39,40].
In our study, there was only one infant with CHB in an anti-Ro/SSA positive mother. Although intrauterine dexamethasone was administered, the infant did not survive.
SLE in women in their reproductive years may need potentially teratogenic drugs during pregnancy, puerperium and in the breastfeeding period, to control maternal disease and to ensure successful pregnancy outcome.
Because only those drugs considered safe can be studied in pregnant or lactating women, the number of controlled studies is small. Information on the safety of these drugs during these periods is derived only from experimental and preclinical studies (Table 6).
|Corticosteroids||Prednisolone, Dexamethasone, Betamethasone, Pulses methylprednisolone|
|Non-steroidal anti-inflammatory drugs and analgesics||NSAIDs (until week 32)||COX-2 inhibitors|
Cox-1 and Cox-2 are involved in ovulation and implantation. Several case reports and small series have described transient infertility after treatment with suppress duplicate non steroidal antiinflammatory drugs (NSAID), such as indomethacin, diclofenac, piroxicam and naproxen. Also, some studies in animals and humans have shown that these drugs can inhibit the rupture of the luteinized follicle.
Non-selective Cox inhibitors are not teratogenic and can be continued during the first and second trimesters, but all NSAID (except aspirin add at less than 100 mg/d) after the 20th gestational week can cause constriction of the ductus arteriosus and impair fetal renal function. Consequently, they should be withdrawn at gestational week 32.
In relation to low dose aspirin (LDA) there is no consensus on when to stop it before delivery. Some advice cessation of the treatment one week before a planned delivery with epidural anesthesi. Other experts do not stop LDA in patients with APS.
Most NSAID are excreted in very small quantities into breast milk. The American Academy of Pediatrics considers ibuprofen, indomethacin, diclofenac, piroxicam, naproxen, mefenamic acid, tolmetin, and flufenamic acid to be compatible with breastfeeding.
At present there are no reliable data on selective Cox-2 inhibitors so they should be avoided in pregnancy.
11-β hydroxi steroid dehydrogenase in the placenta deactivates prednisone and prednisolone. On the other hand fluorinated corticosteroids (betamethasone and dexamethasone), are less well metabolized by the placenta and should be avoided unless there is a need to induce fetal lung maturation or in an effort to treat in utero fetal heart block.
All corticosteroids increase the risk of premature rupture of membranes, hypertension, pre-eclampsia, diabetes mellitus and infection. Ideally, treatment should not exceed the recommended maximum dose of 15 mg a day.
An increased risk for clef palate has been associated with corticosteroid use during first trimester, although the risk is low.
Due to the side effects, prophylactic use of corticosteroids during pregnancy is not recommended.
Stress doses of hydrocortisone at delivery are recommended in patients on corticosteroids long term therapy.
Breast feeding is allowed with low to moderate doses of corticosteroids.
Hydroxychloroquine (HCQ) crosses the placenta with no significant difference in the mean concentration in maternal and cord blood. Discontinuation of this drug leads to increased risk of disease activity. The half-life of HCQ is approximately 2-3 mo, therefore pregnancies in which this drug was stopped just prior to or after conception will still have exposure to it.
Other articles did not find an increase in congenital malformations or cardiac conduction disturbances in children exposed antenatally to this drug.
A recent multinational study showed that HCQ use in mothers with positive anti-SSA/Ro antibodies and a previous child with cardiac neonatal lupus may reduce the risk of cardiac neonatal lupus in a new pregnancy.
Breastfeeding is permitted with this drug.
Methotrexate is contraindicated during pregnancy and in the breastfeeding period. There are known risks of fetal abnormalities in humans associated with methotrexate use. Therefore, all women of childbearing potential should be strongly counseled and advised to use reliable forms of contraception while taking methotrexate. If a woman inadvertently becomes pregnant, she should discontinue the medication immediately and be counseled concerning the risks of congenital abnormalities. Reports based on human cases describe a methotrexate embryopathy that includes growth deficiency, abnormalities in central nervous system, microcephaly, hypoplasia of skull bones, craniosynostosis, short limbs, hypodactyly, and syndactyly.
Therefore, this drug must be withdrawn three months before a planned pregnancy. Although the amount of methotrexate excreted in breast milk is low, it is unknown how this may affect a young infant and, therefore, methotrexate is considered to be unsafe during lactation[43,44].
Cyclophosphamide (CYC) is gonadotoxic in both women and men. Cryopreservation of sperm and sperm banking is the method of choice in men. Preservation of gonadal function in women is best done with a gonadotrophin-releasing hormone agonist. Its use in the first trimester of pregnancy is associated with fetal malformations and growth retardation, and suppression of fetal hematopoiesis if it is used during the second and third trimester.
This drug is excreted into breast milk. Suppression of hematopoiesis in breastfed infants has been reported, so it is contraindicated during breast feeding period. As MTX, it must be withdrawn 3 mo before a planned pregnancy.
Azathioprine (AZA) does not adversely affect the fertility of both women and men. It can be used during pregnancy at a daily dose not exceeding 2 mg/kg per day because higher doses have risk of depressed hematopoiesis in infants.
Nursing is not recommended by the American Academy of Pediatrics.
Successful use of Cyclosporin A (CsA) in pregnancy has been reported mainly in transplant recipients. It can be used in pregnancy at the lowest effective dose, with close control of maternal blood pressure and renal function during therapy. Breastfeeding is not recommend because small amounts of CsA are excreted in breast milk.
Mycophenolate mofetil (MMF) is contraindicated during pregnancy. It is associated with craniofacial malformations, ocular anomalies, limbs abnormalities and renal, cardiovascular and nervous system malformations. The drug should be stopped at least 12 wk before a planned pregnancy. Breastfeeding is not allowed.
Leflunomide is contraindicated during pregnancy and breastfeeding. It should be discontinued 2 years before conception or a washout procedure with cholestyramine should be used.
There is an increased risk of gestational diabetes and hypertension in women taking tacrolimus. It may be maintained during pregnancy at the lowest possible dose. Nursing is possible.
It can be used in pregnancy and in the breastfeeding period, no fetal adverse effects have been reported.
Rituximab crosses the placenta. It is not clear whether preconceptional or first trimester exposure to rituximab would expose the fetus to any risk. However, second and third trimester exposure causes B-cell depletion in the fetus with unknown long-term effects in the child. With a maximal elimination half-life of 36 d, discontinuation of rituximab for a period five times the half-life (6 mo) before conception may be adequate to not expose the baby to deleterious effects.
At present there are no data about the safety of Belimumab use during pregnancy.
Low-molecular-weight heparin (LMWH) and unfractionated heparin are safe in pregnancy and are considered in pregnant patients with lupus nephritis with serum albumin ≤ 30 g/L or with proteinuria ≥ 3g/24 h.
Arterial hypertension can develop during pregnancy, or a known history of hypertension pre-pregnancy can be present in a SLE patient with renal involvement.
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are popular for the treatment of hypertension in SLE patients and are widely used because they antiproteinuric effects. However, ACE inhibitors and ARBs should be stopped immediately after pregnancy is confirmed because these medications are associated with renal agenesis and fetal demise.
All antihypertensive agents cross the placental barrier and are present in varying concentrations in the fetal circulation.
Methyldopa is the first line agent for treating hypertension in pregnancy. It has been the most frequently assessed antihypertensive in randomized trials and has the longest safety track record.
Beta Adrenergic Blockers, as Labetalol or Metoprolol, should be used when monotherapy with Methyldopa is insufficient or when women are unable to tolerate Methyldopa.
Calcium channel blockers, such as nifedipine or isradipine are second line agents; they can be administered in hypertensive emergencies or in hypertension caused by pre-eclampsia.
Besides, nifedipine may be considered in patients with severe Raynaud phenomenon.
Diuretics should be avoided for treatment of hypertension because they may decrease placental blood ﬂow.
Post partum hypertension is common. Blood pressure typically rises after delivery over the first five days. Most antihypertensive agents used in routine practice are compatible with breastfeeding, but safety data for doxazosin, amlodipine, and ARBs are lacking.
Methyldopa should be avoided post partum because of the risk of postnatal depression.
The first line agent is labetalol, plus nifedipine or an ACE inhibitor if another agent is required. Diuretics are usually avoided if the woman wishes to breastfeed because of increased thirst[47,48].
Pregnancy in a lupus patient continues to be a mayor challenge for the physician and it should be considered as a high-risk situation. However, if it is planned when the disease is stable and under close supervision by a multidisciplinary team, we could expect a good outcome for the mother and her baby.
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