Special note, this is an academic article. Fertility in women of childbearing age with SLE is a complex and specific issue. It is important that you follow the advice of the rheumatologist you see for an individualized treatment plan tailored to your specific situation!!!
Systemic lupus erythematosus (SLE) is prevalent in women of childbearing age, and pregnancy is a major concern for many women with SLE, and pregnancy is a major component of education for SLE patients. With the increasing understanding of SLE disease and the improvement of multidisciplinary prenatal management, SLE is no longer an absolute contraindication to pregnancy.
According to the U.S. SLE Pregnancy Registry, of the approximately 4500 pregnancies in the United States each year, 1/3 end in cesarean delivery, 33% are preterm, more than 20% are complicated by eclampsia, and 30% are complicated by IUGR (intrauterine delayed fetal development).
Pregnancy in SLE has a negative impact on pregnancy outcome, and pregnancy also has an impact on the evolution of SLE, which can be ensured by choosing the right timing and individualizing the drug therapy during pregnancy under close prenatal monitoring.
The following are four aspects of SLE and pregnancy: 1) the impact of SLE on pregnancy; 2) the impact of pregnancy on SLE patients; 3) the management of pregnancy with SLE; and 4) the rational use of drugs during pregnancy and lactation in pregnancy with SLE.
I. Effects of SLE on pregnancy
1. Fertility
SLE disease itself has no effect on the fertility rate of female patients. However, some factors associated with the disease may still reduce the fertility rate of SLE patients. Active disease or high-dose glucocorticoids may lead to menstrual disorders and anovulatory cycles; amenorrhea may occur in patients with end-stage renal failure due to lupus nephritis; and the use of immunosuppressive drugs such as cyclophosphamide may lead to ovarian failure. Patients with SLE who are stable and do not require high doses of hormones or immunosuppressive drugs have the same chance of conceiving as normal women.
2. Pregnancy outcome
SLE has a negative impact on pregnancy outcome, mainly in the form of miscarriage, stillbirth, preterm delivery and intrauterine delayed fetal development (IUGR) in SLE patients than in normal controls. The database of CSTAR (Chinese SLE Research Collaborative Group) in China shows that the incidence of adverse pregnancy in SLE patients in China is about 9%. Large-scale clinical studies abroad found that the incidence of stillbirth and preterm delivery (preterm delivery within 28 weeks of gestation) was three times higher in patients with moderately to severely active SLE during pregnancy than in patients with mildly active or inactive SLE during pregnancy, and the incidence of late preterm delivery (preterm delivery after 28 weeks of gestation) and low neonatal weight was twice as high in the former as in the latter; the incidence of fetal loss (including The rate of fetal loss (including miscarriage and stillbirth) ranged from 12% to 40%. The variation in this range may be related to the degree of disease activity, the presence of combined lupus nephritis or positive antiphospholipid (aPL) antibodies in the different reported study subjects.
The following factors were significantly associated with spontaneous abortion: (1), positive aPL antibodies (aCL antibodies, LA, anti-β2 glycoprotein antibodies); (2), C3 hypocomplementemia; (3), recurrence and exacerbation of SLE during pregnancy.
The following factors were significantly associated with stillbirth: (1) positive anti-β2 glycoprotein antibodies; (2) C3 and C4 hypocomplementemia; (3) previous history of lupus nephritis; and (4) presence of hypertension at the time of pregnancy.
The activity of lupus nephritis has a significant impact on pregnancy outcome: fetal loss rate, 35-58% in the active lupus nephritis group and 9-11% in the quiescent lupus nephritis group. Therefore, active lupus nephritis should be considered a contraindication to SLE pregnancy.
The main pathological changes of aPL antibodies leading to adverse pregnancy outcome are massive placental infarction, meconium vasculopathy, meconium thrombosis, and perivillous fibrin-like changes. These placental changes are directly related to the hypercoagulable state of aPL-positive patients. aPL antibodies cause thrombosis by causing downregulation of PGI2 levels and upregulation of TAX2 levels, by resisting heparin/heparin-dependent antithrombin III activity, by inhibiting the protein C protein S pathway, by upregulating platelet endothelial cell adhesion molecule (PECAM-1) levels and by activating Platelets and vascular endothelial cells lead to a hypercoagulable state; aPL antibodies compete with placental anticoagulant protein I (PAP-1), a natural anticoagulant present in the placenta, for phospholipid subunits, thus interfering with the anticoagulant effect of these proteins and leading to thrombosis.
The incidence of preterm delivery is significantly higher in combined SLE in pregnancy (24%-58%), and recognized risk factors for preterm delivery include: lupus disease activity, presence of hypertension at the time of pregnancy, severe proteinuria, high titers of positive anti-dsDNA antibodies, and C3 hypocomplementemia.Cortes-Hernandez et al. reported a 31% incidence of IUGR, with significant correlates of hypertension, C3 and C4 hypocomplementemia, and Raynaud’s phenomenon.
In our pregnancy outcome survey of SLE population (105 patients, 111 pregnancies), those with active lupus had increased risk of miscarriage and stillbirth (17% vs 2%), increased preterm birth rate (53.2% vs 8.8%), increased fetal dysplasia (40% vs 5.6%), and greater risk of disease progression (56% vs 38%). Encouragingly, the incidence of adverse pregnancy outcomes due to SLE is decreasing each year through the combined efforts of rheumatologists and obstetricians and gynecologists.
3. Fetal outcomes
Neonatal lupus erythematosus (NLE) is one of the adverse fetal outcomes of concern, and early detection and treatment is key.
Neonatal lupus is a group of syndromes that include cutaneous lupus, mild hematologic abnormalities, and congenital heart block (CHB) and/or multisystem manifestations. The primary subjects affected are infants of mothers with anti-SSA/Ro (especially anti-52KD SSA) antibodies or anti-SSB/La (especially anti-48KD SSB) positive antibodies. The exact pathogenesis of neonatal lupus erythematosus (NLE) has not been fully elucidated. It is currently believed that autoantibodies, which are passed from mother to fetus via the placenta, play a major role in the pathogenesis of NLE. Anti-SSA antibodies or anti-SSB antibodies in the mother are most closely associated with NLE. These antibodies are IgG, which can enter the fetus through the placenta and are also commonly found in the skin tissue of NLE. Their appearance and disappearance in the affected child often coincides with the appearance and improvement of skin or other systemic symptoms (except CHB). Some studies have reported that anti-SSA and anti-SSB antibodies can be detected in the myocardium of NLE patients. These antibodies may damage the atrioventricular bundle and atrioventricular node in fetuses, and some autopsies have found that the atrioventricular node is replaced by scar tissue, which may explain why the CHB is permanently altered in NLE. Clinical manifestations of neonatal lupus erythematosus (NLE): Skin and/or heart damage are the most prominent clinical manifestations of NLE. In addition to the skin and heart, in a few cases the liver and blood can also be involved. However, with the exception of CHB, many non-cardiac clinical manifestations (e.g., skin and hematologic changes) disappear within 6-8 months of life as the infant clears the antibodies from the mother This does not cause permanent damage. The skin damage of NLE can occur at birth, but more often occurs within the first few weeks of life. Skin p occurs in sun-exposed areas, usually on the face and scalp, especially around the eyes; sun exposure is not always necessary, but sunlight can provoke or worsen the rash. The typical rash pattern is similar to that of subacute cutaneous lupus erythematosus (SCLE), presenting as annular erythematous or papular phosphoraceous lesions that tend to disappear within a few weeks or months; the most severe damage in NLE is in the heart, with a mortality rate of 20-30%, and CHB usually presenting as irreversible, complete AV block. The typical block occurs intrauterine and begins around mid to late pregnancy. In some cases, AV block begins as a first- or second-degree block and eventually progresses to a third-degree block; once a third-degree block is present, the lesion is irreversible. children with NLE may also present with bradycardia, suggesting involvement of the sinus node in addition to the AV node. In rare cases, dilated cardiomyopathy may be present in combination with third-degree block, with a chance of about 6%. The incidence of CHB in neonatal lupus erythematosus (NLE) is 0.005 % in the normal population, 7.2 % in newborns of SLE (anti-SSA-positive) mothers, 0.6 % in newborns of SLE (anti-SSA-negative) mothers, and 30 % in patients with SLE combined with anti-SSA-positive antibodies. For the diagnosis of neonatal lupus erythematosus (NLE), the American Rheumatism Association has proposed two diagnostic criteria for NLE: (1) typical symptoms of NLE: (1) typical subacute skin-like lupus erythematosus – annular erythematous, papular phosphoraceous lesions, sensitivity to light, mostly on the face, or lupus-like rash confirmed by skin biopsy pathology; (2) congenital heart conduction block (2) maternal or child with positive anti-SSA or anti- SSB antibodies positive. Neonatal lupus erythematosus (NLE) treatment: The damage of grade III CHB is permanent and no effective treatment is available; a pacemaker is required if bradycardia and low cardiac output are present. One study found that fetal CHB found at 16-24 weeks , can be treated by giving the mother oral dexamethasone 8mg/d and reducing the dose to 2mg/d after 2 weeks and maintaining the treatment until delivery, this treatment can reverse more than 60% of conduction block and is an effective treatment, but it can cause IUGR, adrenal suppression and learning ability after birth adverse effects such as diminished learning capacity after birth. In contrast, gammaglobulin or plasma exchange may have some effect, but the effect is not certain. The skin type and other organ damage are temporary, and most of them disappear within 6 months after birth without special treatment. Genetic counseling for neonatal lupus erythematosus (NLE): The chance of NLE in the fetus of a mother with positive anti-SSA and anti-SSB antibodies is about 1%; however, if the mother already has a child with NLE, the chance of delivering a child with NLE again is about 25%. Antenatal ultrasonography for neonatal lupus erythematosus (NLE) CHB: For anti-SSSA/SSB positive mothers, antenatal ultrasonography is expected to detect AV block early in the 16th to 24th week of pregnancy, during the window when maternal autoantibodies are able to cross the placenta and the fetus is in the developmental phase of the conduction system. Echocardiography and obstetrical checkups at least once a month after pregnancy are usually required for early detection of AV block and appropriate treatment. Prenatal intervention protocol for CHB in neonatal lupus erythematosus (NLE): When fetal echocardiography reveals a worsening fetal condition (e.g., heart failure or fetal edema), the mother should be treated with dexamethasone, which is used as a base drug at the beginning of CHB diagnosis because dexamethasone and betamethasone are not metabolized in the placenta and can be utilized in the fetus in an active form (if the fetus The use of dexamethasone (in combination with a beta-R agonist if the mean heart rate is consistently below 55 bpm) at the beginning of CHB diagnosis reduces the incidence of isolated complete AV block in the fetus and improves the prognosis, which is difficult to reverse once a definite complete fetal block has occurred.
The effect of pregnancy on SLE patients
Recurrence rate of SLE
The recurrence rate of SLE in pregnancy has been recently reported to be 13%-60%. Another prospective study concluded that the recurrence rate of SLE patients during pregnancy and postpartum is 65%, which is significantly higher than that of non-pregnant SLE patients (42%). More than 50% of SLE patients experience a relapse during pregnancy. It is generally accepted that the recurrence of SLE during pregnancy is mild to moderate, mainly manifested by fever, skin damage, mild hematologic abnormalities and arthritis.
However, in 15-30% of patients, severe renal disease may develop and continue to worsen even after the end of pregnancy. The timing of recurrence has been reported differently, with Cortes-Hernandez et al. suggesting that SLE tends to recur during pregnancy and the postpartum period, and Georgiou et al. reporting that SLE activity occurs more frequently in early pregnancy. recurrence of SLE can occur at any stage of pregnancy or even in the postpartum period, which is of great importance to enhance the prenatal and postpartum management of pregnant women with SLE. An increase in the number of SLE recurrences before pregnancy and an increase in the SLEDAI score are risk factors for predicting disease activity or recurrence during pregnancy. The reason for the inconsistent conclusions of many studies is the inconsistent criteria for evaluating SLE disease activity. ruiz-Irastorza et al. obtained the Lupus Activity in Pregnancy (LAI-P) scale based on the LAI scale and demonstrated its validity, and the LAI-P scale may serve as a uniform standard for evaluating SLE disease activity in pregnancy in the future. Another reason for the inconsistent findings of many studies is the difficulty in distinguishing the manifestations of SLE activity from the physiological changes of pregnancy: a series of physiological changes occur in pregnant women during pregnancy, some of which resemble the manifestations of SLE activity, such as thrombocytopenia, proteinuria, a small amount of joint effusion, and increased erythema of the face and palms during pregnancy, which may lead to over-evaluation of SLE activity in pregnancy. activity in pregnancy. A possible solution may still rely on a more specific and sensitive evaluation of lupus activity in pregnancy.
The main reasons for the lack of studies on the interaction between pregnancy and lupus nephritis are: the lower than normal fertility rate in patients with lupus nephritis due to ovarian failure and amenorrhea in patients with renal failure when treated with cyclophosphamide, and the unsuitability of pregnancy in women with a history of lupus nephritis. The recurrence rate of lupus nephritis in patients with lupus nephritis during pregnancy and after delivery is 8% to 60%. Pregnancy did not negatively affect renal function in patients with already diagnosed lupus nephritis as long as the patient was not in active disease at the time of pregnancy, which was significantly increased in pregnant women in the active lupus nephritis group. The deterioration of renal function (serum creatinine level) was used as a criterion to evaluate the recurrence of lupus nephritis, thus avoiding confusion with conditions such as physiological proteinuria in pregnancy.
Differentiation of pre-eclampsia from lupus nephritis activity. Pre-eclampsia is more similar to lupus nephritis activity due to its clinical presentation, and differentiation of these two conditions is of greater significance for diagnostic and therapeutic purposes.
It is also encouraging to note that the recurrence of SLE due to pregnancy is decreasing year by year with the joint efforts of rheumatologists and obstetricians and gynecologists.
Peri-pregnancy management of SLE patients
1. Contraception in SLE patients
Although SLE patients can marry at any time, the pregnancy must be planned and meet the permissible pregnancy conditions. Contraception must be used for those patients who do not meet the conditions that allow pregnancy and for those patients with moderately or severely active disease.
Forms of contraception.
The IUD, a safe and highly effective means of contraception for patients using only small doses of glucocorticoids and no other immunosuppressive drugs.
Oral contraceptives, which have been a contraindication for SLE patients in the past because of the fear that oral contraceptives could cause relapse of the disease, especially relapse of lupus nephritis and thrombosis in the city. However, the results of an international multicenter lupus study showed that oral contraceptives can treat ovarian cysts, which are more common in younger SLE patients, and glucocorticoid-induced osteoporosis, and that fewer relapses were observed in patients taking oral contraceptives than in those not taking them. Therefore, oral contraceptives are considered safe for patients with SLE, but it is essential to use contraceptives with an absolute predominance of progestin component. Oral contraceptives should not be used in patients with unstable SLE, patients with antiphospholipid syndrome (APS) or nephrotic syndrome, or patients with a history of hypercoagulability or thrombosis.
2. Timing of pregnancy
Pregnancy in patients with SLE should be selected when the disease is stable and inactive. Pregnancy can be considered in the following cases: ① the disease is stable for at least six months (preferably more than one year) after regular treatment; ② urine protein quantification <0.5g/24h; ③ the dose of glucocorticoids is below the equivalent dose of 15mg/d prednisone; ④ no immunosuppressive agents are used or have been stopped for at least six months (except hydroxychloroquine). Timing of pregnancy in patients with lupus nephritis: to meet both the above conditions and the conditions of nephropathy remission; remission of nephropathy: ① stable renal function, blood creatinine (Cr) ≤ 140 μmol/L, glomerular rate filtration (GFR) >50 mL/min; ② no abnormalities in urine sedimentation examination, urine protein <0.5 g/24h; ③ normal blood pressure; ④ normal C3 level and lasting for more than 6 months.
3. Follow-up management during pregnancy
If the patient’s condition permits pregnancy under the guidance of the physician, the patient will be followed up every 4 weeks for <12 weeks, every 2 weeks for 12-28 weeks, and every 1 week for >28 weeks; if the patient’s condition is unstable or/and the pregnancy is unplanned, the patient will first be assessed whether the pregnancy can be continued, and if the pregnancy can be continued (or the patient wishes), the patient will be followed up every 1 week to assess whether the pregnancy can be continued or should be terminated. At each follow-up visit, in addition to the clinical evaluation of the patient, the following laboratory tests are performed: blood pressure, routine blood count, urine count, liver and kidney function, blood glucose ESR CRP, complement C3 and C4, anti-ds-DNA antibody titers, aPL antibody titers, fetal echocardiography monitoring (generally required at least every two weeks after pregnancy, especially during the 16 to 24 week window) and SLEDAI score. These indicators detect the presence of active disease, and the decrease in serum complement levels, the increase in anti-ds-DNA antibody titers, and the increase in CRP also indicate an increased risk of preterm delivery of the fetus.
4. Timing of pregnancy termination
In severe cases, regardless of gestational age, termination of pregnancy is indicated to ensure the safety of the mother. This includes serious complications such as cardiac failure, extensive interstitial lung disease combined with pulmonary failure, severe hyperemesis, SLE nephropathy with urine protein >5g/24h, serum creatinine >150μmol/L, no improvement after active treatment, worsening of the condition, immunological examination, ACL abnormalities and hypocomplementemia affecting placental function, various auxiliary examinations showing decreased placental function and fetal maturity In cases with intrauterine manifestations of fetal hypoxia or FGR, which does not improve with treatment, with a late pregnancy score of 7 or more. The termination of pregnancy is decided according to the condition and obstetric indications, and SLE in pregnancy is not an absolute indication for cesarean section.
IV. Rational use of medication during pregnancy and lactation in SLE combined with pregnancy
Ideally, SLE patients should be pregnant in complete remission. However, the number of patients who are in complete remission and do not need medication is relatively small, and most patients still need to receive medication for SLE at the time of pregnancy. Clinicians should be alert to the potential side effects of antirheumatic drugs. Physiological changes in pregnancy (increased maternal blood volume, placental permeability to drugs) may result in altered kinetic properties of drugs in the body, but there are no guidelines for drug dose adjustment. In addition, the teratogenic effects of drugs are an issue that cannot be ignored.
Drug therapy in pregnant SLE patients should be individualized according to the characteristics of the patient’s SLE condition and the complications of pregnancy. Clinicians should provide patients with appropriate treatment plans after fully weighing the pros and cons. In patients with lupus nephritis, high-dose (80 mg/d) corticosteroid therapy before and several days after delivery may reduce the recurrence of postpartum lupus nephritis. The management of SLE pregnancies with antiphospholipid syndrome (APS) is mainly characterized by positive aPLs, thrombosis (arterial and venous) and/or habitual abortion. High titers of aPLs and previous pregnancy failure are good predictors of pregnancy failure in patients with SLE. The presence or absence of anemia, thrombocytopenia and activity of the primary disease must also be evaluated before deciding whether or not to become pregnant . Patients with positive antiphospholipid antibodies but without manifestations of antiphospholipid syndrome are recommended to be treated without specific therapy or to be treated with aspirin 100-160 mg/d until discontinuation before delivery. Treatment of pregnant women with SLE in combination with APS is determined by the patient’s past medical history: aspirin 100-160 mg/d is recommended for patients with a history of miscarriage without thromboembolism, and heparin (15000 U bid) or low molecular heparin (60 mg bid) is recommended for patients with a history of thromboembolism until discontinuation before delivery. Postpartum treatment should continue for 6-12 weeks after delivery because of the high risk of thrombosis in the first 3 months after delivery.
The FDA has proposed classification criteria for drugs used during pregnancy: Class A refers to a large number of strictly controlled trials without adverse effects on the fetus; Class B refers to animal tests suggesting risk without adverse effects observed in humans, or negative animal tests but lacking sufficient human observation data; Class C refers to a lack of human observation data and positive or absent animal tests; Class D refers to investigation data or post-marketing data indicating fetal Class X refers to animal tests, or human observations, or survey data, or post-marketing data indicating that the toxicity to the fetus significantly exceeds the benefit to the pregnant woman.
Glucocorticoid drugs (Class B to C)
Hydrocortisone and cortisone are able to pass through the placenta, but 11β-dehydrogenase in the placenta can convert hydrocortisone to inactive cortisone. Therefore, when hormonal therapy is necessary for the mother, choose prednisone, hydrocortisone or cortisone. Dexamethasone and betamethasone are able to pass through the placenta without being inactivated and in nearly equal concentrations between mother and fetus. They are classified as Class C drugs by the FDA and are chosen only when there is a fetal condition requiring hormone therapy. The use of hormones during pregnancy is relatively safe, but there are toxic side effects. High doses of hormones (equivalent to 1-2 mg/kg/d of prednisone) during the first trimester, when the fetal hard palate is forming, should be avoided. Long-term maintenance treatment with prednisone at 5-10 mg/d or higher increases the incidence of gestational diabetic hypertension, edema, sodium retention, premature rupture of the amniotic membrane, and osteoporosis. Treatment with an average of 10 mg prednisone per day does not increase the incidence of intrauterine growth retardation or birth defects. Delivery should be considered as a moderately stressful situation and 50-70 mg of hydrocortisone or 10-15 mg of methylprednisolone should be administered intravenously on the day of delivery, but should be reduced to the usual dose within 1-2 days. The hormone dosage can be increased when the stress is felt to be more severe or when the patient’s condition is significantly worse. Prednisone and prednisolone are secreted in small amounts with breast milk and can be used during lactation. However, when the dose is too high, exceeding prednisone 20 mg 1-2 times a day, it is best to lactate 4 hours after taking the drug.
Non-steroidal anti-inflammatory drugs (NSAIDS)
Can inhibit prostaglandin synthesis, inhibit or reduce contractions, and prolong pregnancy. Therefore certain NSAIDS, including indomethacin, can be used to treat preterm labor. Although most traditional NSAIDS are FDA Class B drugs, their use during pregnancy requires caution. NSAIDS such as indomethacin have been reported to cause hypohydramnios. NSAIDS can also inhibit platelet aggregation, causing fetal hemorrhage and postpartum hemorrhage. nSAIDS should not be used in the 7th – 9th trimester because they can promote premature closure of the fetal ductus arteriosus, leading to fetal pulmonary hypertension. cox-2 inhibitors may have the same side effects as other NSAIDS, and they are FDA classified as a Class C drug. All NSAIDS are discontinued 6-8 weeks before delivery, preferably at 32 weeks of gestation. most NSAIDS can be used during lactation but can cause increased risk of birth jaundice and kernicterus in newborn fetuses. When use is necessary, choose a drug with a widely recognized safety profile . There is a lack of information on the use of COX-2 inhibitors during lactation.
Hydroxychloroquine
The FDA classifies it as a Class C drug. Although hydroxychloroquine crosses the placenta, it has not demonstrated definite fetal toxicity at therapeutic doses for connective tissue disease (6.5 mg/kg). It is currently considered feasible to continue hydroxychloroquine during pregnancy to control disease activity, which may mitigate the risk of pregnancy exacerbation. However, it may not be beneficial to take hydroxychloroquine only at the beginning of pregnancy. Hydroxychloroquine is secreted in breast milk and the infant receives an average of 2% of the mother’s dose per kilogram of body weight per day through lactation, and despite the slow clearance of the drug in the infant and the potential for cumulative effects, most experts now agree that hydroxychloroquine is relatively safe for use during lactation.
Methotrexate (MTX)
Classified by the FDA as a Class X drug, MTX can cause a variety of fetal malformations, including craniosynostosis, limb malformations, central nervous system abnormalities such as anencephaly, hydrocephalus, and cerebrospinal meningeal bulge. The teratogenicity is more obvious when used in the first trimester of pregnancy. Because MTX is widely distributed in body tissues and can remain in the liver for 116 days, most experts recommend discontinuing MTX in the first 4 months of pregnancy and supplementing with folic acid until the end of pregnancy. MTX is secreted in breast milk and can accumulate in infant tissues and is contraindicated during lactation.
Leflunomide
Leflunomide is a competitive inhibitor of dihydroorotic dehydrogenase (DIDG). Although the half-life of leflunomide is only 14-15 days, its active product participates in a large enterohepatic circulation. This is well explained by the fact that leflunomide requires 2 years of discontinuation before it is not measurable in the blood. the FDA classifies it as a Class X drug. Animal studies have shown that it is embryotoxic and is contraindicated during pregnancy. Patients who wish to conceive and are already taking leflunomide should have their blood levels tested prior to conception if they are ≥0.02 mg/L and should take 11 days of cholestyramine (8 g tid); if they are below 0.02 mg/L, they should be retested at least twice at two week intervals for confirmation; if the blood level is still not low enough, they can take cholestyramine again. And the patient should go through at least three menstrual cycles before getting pregnant after the treatment of abciximide. If pregnancy occurs accidentally while taking Leflunomide, the fetus may be affected by the drug during the organogenesis phase, even if the drug is taken immediately upon detection. Leflunomide is also contraindicated during lactation.
Azathioprine
FDA classifies it as a Class D drug. Azathioprine can pass through the placenta, but the fetal liver lacks the enzyme hypoxanthate pyrophosphorylase and cannot convert azathioprine to an active product, so the fetus should not be affected. Some scholars previously recommended dose reduction at 32 weeks of gestation to prevent neonatal leukopenia and thrombocytopenia. However, more attention is currently being paid to the use of subtherapeutic doses. One study showed no clear adverse effects of azathioprine 100 mg/d in the offspring. Therefore, azathioprine may be used with caution in pregnant women if they do need it to control their disease activity. Azathioprine can be secreted into breast milk and is contraindicated during lactation.
Cyclophosphamide (CTX)
CTX can cause decreased fertility and amenorrhea. However, the toxicity of CTX to the ovaries may be related to the age at which a woman initially receives the intravenous drug, with a greater risk of amenorrhea in women over 31 years of age. The risk of ovarian hypofertility also increases with cumulative dose of CTX with little relation to the duration of treatment. the FDA classifies it as a class D drug. the risk of CTX causing congenital malformations is about 20%. CTX can be secreted into breast milk and is contraindicated during lactation.
Cyclosporine A
FDA classifies it as a Class C drug. Cyclosporine A crosses the placenta and can affect placental endothelin-1 and NO homeostasis. Patients treated with cyclosporine A after transplantation have been reported to deliver newborns of gestational age and without maternal hypertension or renal impairment. The National Transplant Registry has followed the offspring of female renal transplant recipients treated with cyclosporine A up to childbearing age and found no significant health problems. Cyclosporine A should be avoided during breastfeeding, although no adverse effects have been reported in infants. It should be noted that there is a large individual variation in the dose of drug received by infants through breast milk. One case was reported in which an infant received a therapeutic dose of the drug in blood, while the concentration in breast milk was relatively low.
Mycophenolate mofetil (MMF)
The FDA classifies it as a Class C drug. However, some animal studies have shown that mycophenolate esters are teratogenic when they do not cause maternal toxicity or when they are still within therapeutic doses. Some of the current case reports suggest that it should be avoided during pregnancy and discontinued at least 6 months prior to conception. Interestingly, there were no malformations in 42 infants whose fathers used MMF during pregnancy. MMF is secreted into breast milk and is contraindicated during lactation.
The 2008 European Society of Rheumatology (EULAR) Expert Consensus on Systemic Lupus Erythematosus (Ann Rheum Dis 2008;67:195) describes pregnancy and lupus as
Hydroxychloroquine is safe
Prednisolone, azathioprine, and low-dose aspirin inconclusive
Mycophenolate, CTX and MTX should be avoided
In conclusion: SLE combined with pregnancy does increase the risk of pregnancy in terms of pregnancy outcome; pregnancy also has a negative impact on the change in the condition of SLE; however, SLE is not an absolute contraindication to pregnancy, and most patients with SLE can achieve a satisfactory pregnancy outcome when they become stable and tend to be in remission, and when pregnancy is monitored closely by obstetrics, together with individualized maternal drug therapy by rheumatology The majority of patients can achieve a satisfactory pregnancy outcome with close obstetric monitoring and individualized pregnancy medication from rheumatology.