To help these patients have a successful pregnancy and delivery, this article addresses 5 common questions about pregnancy in lupus patients, from contraception to delivery.
Question 1: How do women with lupus in the active phase of the disease use contraception?
Condoms are the safest method of contraception for lupus patients, and both male and female condoms are safe and effective methods of contraception.
Use oral contraceptives with caution
Oral contraceptives have been reported in the literature to increase the risk of lupus and to contribute to the development of disease, especially LN, in patients with lupus. In addition, the incidence of thromboembolic disease is higher in lupus patients, especially in those with antiphospholipid antibodies, which are positive in about 50% of lupus patients, and oral contraceptives containing estrogen can increase the incidence of thromboembolic disease. Therefore, oral contraceptives should be used with caution in patients with lupus.
Lupus occurs mostly in adolescent and childbearing females, so it is speculated that sex hormones may play an important role in the pathogenesis of lupus. A national study (SELENA) in the United States evaluated the safety of estrogen in patients with lupus. 183 stable premenopausal lupus patients (except those with positive anticardiolipin antibodies or moderately elevated lupus anticoagulant titers) were randomized to an oral contraceptive group containing low doses of estrogen and a placebo group for a total of 1 year. The results showed that patients in the oral contraceptive group did not have increased lupus activity or severe lupus activity, while the placebo group had more LN activity. However, the results of the SELENA trial do not mean that oral contraceptives are available to all women with lupus. Oral contraceptives should be contraindicated in women with unstable disease, in a hypercoagulable state due to antiphospholipid antibodies, with nephrotic syndrome, or with a previous history of thrombosis.
Progestogen-only contraception should prevent osteoporosis
During the decades when oral contraceptives were banned, obstetricians, gynecologists and rheumatologists tried and gained some experience with single-progestin contraception in these patients. Studies in murine models have shown no adverse effect of progestins on lupus activity. However, women are less receptive to oral progesterone because of the problem of breakthrough bleeding.
Depo-progesterone is a long-acting progesterone that is easy to use (injections every 3 months), but long-term use carries an increased risk of osteoporosis, and the U.S. Food and Drug Administration (FDA) recommends that it should not be used for more than 2 years. When depo-progesterone has been used for more than 2 years in patients with lupus, then annual bone density examinations should be performed to monitor for bone loss and vitamin D and calcium supplements should be taken.
Less experience with IUDs Because older generation intrauterine devices (IUDs) can increase the risk of infection, there is limited experience with IUD use in patients with lupus.
For women with lupus who have only one sexual partner and are not using immunosuppressive agents other than low-dose prednisone, a newer generation IUD may be used. however, there are reports that patients can develop severe lupus activity after IUD placement and persistent disease activity that does not resolve until the IUD is removed.
Question 2: When is the best time to get pregnant in patients with lupus?
Pregnancy in patients with SLE should be selected when the disease is stable and inactive. Pregnancy can be considered in the following cases: ①The disease is stable for at least six months (preferably more than one year) after regular treatment;
② Urine protein quantification <0.5g/24h;
③Take glucocorticoid dose below 15mg/d prednisone equivalent dose;
④No immunosuppressive agents or have been discontinued for at least 6 months (except hydroxychloroquine).
Timing of pregnancy in patients with lupus nephritis: both the above conditions must be met and the conditions of nephropathy remission; remission of nephropathy.
①Stable renal function with blood creatinine ( Cr) ≤ 140 μmol/L and glomerular rate filtration ( GFR ) >50 mL /min;
②No abnormality in urine sediment examination, urine protein <0.5g/24h;
(iii) normal blood pressure; (iv) normal C3 level for more than 6 months.
Question 3: What drugs can be used during pregnancy and lactation in lupus patients?
Most lupus patients need to take hormones and even immunosuppressants for a long time to maintain remission, and the disease is often active during pregnancy, and discontinuation of medication may aggravate the disease activity.
Some drugs have definite teratogenic effects and are contraindicated in pregnancy; some drugs have potential teratogenic effects and must be weighed against the risks and benefits to the mother and fetus; many drugs have no definite teratogenic effects and can be used during pregnancy. Therefore, during pregnancy, lupus patients should use relatively safe drugs to avoid fetal malformations.
Non-steroidal anti-inflammatory drugs
Animal studies have shown that non-steroidal anti-inflammatory drugs can lead to an increased incidence of fetal developmental abnormalities such as diaphragmatic hernia and ventricular septal defect. One clinical study suggested that the use of aspirin and other salicylates in the first trimester may increase the incidence of diaphragmatic hernia, but larger clinical studies have not reached the same conclusion. Several trials conducted in the United States and Europe with a total of 100,000 subjects have shown that aspirin (dose nonspecific) and nonselective cyclooxygenase (COX) inhibitors in the early stages of pregnancy do not increase the incidence of congenital malformations in the fetus. Therefore, the use of non-selective COX inhibitors may be continued in the early and middle stages of pregnancy.
Clinical studies have shown (in more than 10,000 cases) that 60-80 mg/d aspirin in mid- to late pregnancy has no effect on fetal renal function, coagulation, pulmonary arteries, or arterial ducts. The safety of selective COX inhibitors, however, lacks strong data support and should be avoided during pregnancy.
Glucocorticoids
Among the various agents, prednisone, prednisolone or methylprednisolone can be converted to inactive substances in the placenta, with less than 10% of the active drug entering the fetal circulation, which is theoretically insufficient to produce adverse effects; betamethasone and dexamethasone are not readily metabolized by the placenta and may interfere with fetal growth and brain development. Clinical studies have shown an increased incidence of cleft lip in the offspring of those using hydrocortisone or prednisone in early pregnancy (from 0.1% to 0.3% to 0.4%), but the overall incidence is low. Overall, glucocorticoids are not considered to be teratogenic.
When hormone dosage exceeds 10 mg/d of prednisone, it may increase the incidence of preeclampsia, hyperemesis, gestational diabetes, infection and premature rupture of membranes. The effects of hormones on intrauterine development remain controversial, and high doses of hormones may lead to neonatal cataracts and adrenal suppression, so the lowest possible dose should be maintained during pregnancy. Stress doses of hydrocortisone are recommended for delivery in patients on long-term hormone use.
Chloroquine and hydroxychloroquine
Animal studies have shown that high doses (250 to 1500 mg/kg) of chloroquine are toxic to the fetus. Clinical studies (total of several hundred subjects) have shown that treatment with 250 mg chloroquine or 200-400 mg hydroxychloroquine daily in early pregnancy does not increase the incidence of congenital malformations, but higher doses have a teratogenic potential. Some studies have shown that the use of hydroxychloroquine during pregnancy reduces the risk of lupus activity.
Cyclophosphamide
The use of cyclophosphamide at various doses during pregnancy has been shown to be significantly teratogenic (Class III) in humans and various test animals, and therefore the drug is contraindicated during pregnancy. Early gestational dosing causes extensive malformations of the brain, facial structures, limbs, and internal organs, while mid- to late-gestational dosing can cause fetal growth restriction, hematopoietic suppression, and impaired neurological development. The incidence of fetal malformation and miscarriage is not increased by pre-pregnancy dosing, and pregnancy is possible after 3 months of drug withdrawal.
Methotrexate and Leflunomide
Both interfere with folic acid metabolism, affect the central nervous system and bone development, and are contraindicated in pregnancy. Methotrexate can be used for pregnancy after 3 months of discontinuation; the excretion period of leflunomide is up to 2 years due to the presence of enterohepatic circulation and can be shortened to 6 months with cloacalimide.
Azathioprine
Animal studies have shown that 4 to 13 times the therapeutic dose of azathioprine can cause fetal skeletal defects and multiple malformations; however, clinical studies have shown that azathioprine does not cause increased fetal congenital malformations and abnormal immune function in childhood. Studies have shown that the fetus may develop transient asymptomatic chromosomal abnormalities, transient lymphopenia, and severe immune and myelosuppression when azathioprine is administered at doses above 2 mg/(kg・d). Therefore, azathioprine may be used during pregnancy but should not be administered in excess of the above dose (Class II).
Mortylmacrolate
An uncontrolled clinical analysis found a 26.3% miscarriage rate and a 47.6% congenital malformation rate in live-born fetuses in pregnant patients treated with mortification with mortification and is therefore contraindicated in pregnant women (Class III). The drug should be discontinued for at least 6 weeks prior to pregnancy (Class IV).
Cyclosporine
Animal studies have shown that cyclosporine at a dose of 10 mg/(kg・d) has no effect on the fetus, while embryotoxicity may occur at doses of 25-100 mg/(kg・d). In clinical trials, the incidence of congenital malformations, preterm birth and low birth weight in the cyclosporine treated group did not differ from that in the general population; however, precocity and mental retardation were observed in 16% of children 1 to 12 years after birth. Therefore, the lowest effective dose of cyclosporine A (class I) is recommended to be maintained during pregnancy.
Biological agents
Animal studies have not found embryotoxic or teratogenic properties of biological agents, but there is still a lack of data on the safety of biological agents such as anti-tumor necrosis factor antagonists and anti-CD20 antibodies for use during pregnancy, so it is recommended to discontinue such drugs before pregnancy.
Use of drugs during lactation
Hormones are secreted in breast milk in very small amounts, and moderate amounts of hormones are safe for use during lactation (Class II). If the dosage is greater than 40 mg/d, it is recommended to take the drug for 4 hours before breastfeeding. There is a lack of data from studies related to dexamethasone and betamethasone.
Most non-steroidal anti-inflammatory drugs, chloroquine and hydroxychloroquine, are rarely found in breast milk, and no clear adverse effects have been observed with lactation. Cyclophosphamide is secreted in breast milk and has been reported to inhibit hematopoiesis in infants; therefore, its use during lactation is not recommended. There is no consensus on the safety of methotrexate, azathioprine and cyclosporine during lactation. The effects of leflunomide, morte-macrolide, and newer biologics in lactation are unclear.
Question 4: What are the common complications during pregnancy in patients with lupus?
During pregnancy, patients are prone to lupus flares, which are difficult to differentiate from hyperemesis, hemolysis, elevated liver enzymes and thrombocytopenia (HELLP) syndrome and need to be taken seriously by clinicians.
Control of hypertension during pregnancy
Hypertension is prone to occur in the second trimester due to the discontinuation of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists (ARB) in pregnancy and sodium retention in pregnancy. In view of placental blood supply problems, the blood pressure control goal for pregnant patients can be relaxed to less than 140/90 mmHg.
Diuretics can reduce vascular perfusion and affect placental blood supply and should be avoided, but thiazide diuretics can be applied. Considering the safety of pregnancy, non-medical conventional antihypertensive drugs are often chosen as antihypertensive drugs in pregnancy, such as labetalol, hydralazine and methyldopa.
Monitoring Lupus Nephritis in Pregnancy
LN can coexist with pre-eclampsia, and the ultimate management of pre-eclampsia is to terminate the pregnancy, as is the best management of patients with severe LN; delaying surgery may have serious consequences.
LN recurrence in pregnancy may be manifested by active urine sediment (nephrogenic red blood cells and tubular pattern) and positive urine protein, with special attention to urinalysis abnormalities in early and mid-pregnancy, which tend to occur in mid- to late pregnancy in hyperemesis gravidarum. LN recurrence is often associated with decreased complement C3 and C4, but as inflammatory reactants, C3 and C4 are elevated in normal pregnancy and preeclampsia.
Lupus in combination with APS
In pregnancy in patients with lupus with APS, low-dose aspirin should be administered early in pregnancy. Low-molecular-weight heparin (20 to 30 units twice daily) and low-dose aspirin are indicated if the patient has a history of adverse pregnancy, such as miscarriage, preeclampsia, or evidence of inadequate placental blood supply. Low-molecular-weight heparin is converted to regular heparin before delivery, and heparin is discontinued at delivery or 8 hours before cesarean delivery to avoid bleeding. Regular heparin has some anti-inflammatory effect by blocking complement activation.
Intravenous gammaglobulin may be effective and can be repeated, but the interval between applications must be at least 1 month. These patients are in a hypercoagulable state after delivery, so prophylactic heparin therapy is recommended for 6 weeks after delivery.
Many patients with lupus develop or worsen during pregnancy, but there are inconsistent findings as to whether lupus activity is more common during pregnancy. The emerging view is that lupus activity during pregnancy may be associated with discontinuation of all treatments prior to pregnancy.
LN activity is a contraindication to pregnancy
SLE can involve all vital organs throughout the body, most commonly the LN. LN activity has adverse effects on both mother and baby and is a contraindication to pregnancy, so it is usually recommended to start pregnancy after LN has been in remission for more than 6 months to avoid worsening nephritis and the risk of miscarriage or stillbirth. LN should be closely monitored for activity during pregnancy.
Anti-Ro and La antibodies can cause neonatal lupus syndrome
Patients with lupus are often positive for anti-Ro and/or anti-La antibodies, which can be transmitted to the fetus through the placenta after 16 weeks of gestation, and mother-to-child transmission can occur. After birth, the fetus may develop neonatal lupus syndrome, which manifests as a transient lupus-like rash, complete atrioventricular block, hematocrit, and liver function abnormalities. A serious complication is congenital heart block (CHB), which has a mortality rate of up to 20% and requires a permanent pacemaker in most survivors. Complete degradation of maternal-derived autoantibodies within 6 months after birth results in remission of the disease, however, 3rd degree AV block is irreversible.
High incidence of obstetric complications in lupus patients
The incidence of hypertension during pregnancy in lupus patients is as high as 25%, often leading to an increased incidence of obstetric complications such as pre-eclampsia and intrauterine growth retardation (IUGR). Some lupus patients have a combination of antiphospholipid antibody syndrome (APS), which manifests as thrombosis, habitual abortion, intrauterine growth retardation and preterm delivery.
Therefore, lupus patients should consider carefully before planning pregnancy. The best conditions are: no significant organ involvement, stable disease for at least six months, prednisone dosage less than 10 mg/d, discontinuation of all immunosuppressive drugs prohibited during pregnancy for more than six months, normal renal function, negative urine protein (24h urine protein less than 0.5 g), and antiphospholipid antibodies that have been negative for more than three months.
Lupus patients need to fully communicate with rheumatologists before planning pregnancy. Before pregnancy, physical examination, blood pressure measurement, and laboratory tests such as routine blood, liver and kidney function, urinary routine, urine sediment, 24-hour urine protein quantification, complement level, anti-nuclear antibodies [including anti-dsDNA antibodies and anti-extractable nuclear antigen (ENA) antibodies], and antiphospholipid antibodies should be improved.
Question 5: What is the risk of pregnancy loss or preterm delivery in patients with lupus, and are there any special requirements for the mode of delivery and the delivery process?
Increased pregnancy loss due to lupus activity in early pregnancy
Pregnancy loss includes miscarriage, intrauterine fetal death and stillbirth. Overall, miscarriage and stillbirth occur in approximately 20% of lupus pregnancies. Miscarriage is defined as the loss of pregnancy before 28 weeks of gestation, while intrauterine death of the fetus after 28 weeks of gestation is called intrauterine fetal death. Some studies have reported an increased risk of miscarriage after 20 weeks of gestation in patients with lupus. The two most important factors for pregnancy loss are increased lupus activity and APS.
In a Greek study, fetal loss occurred in 6 of 8 (75%) patients with severe lupus activity, compared to 14% in those without lupus activity and only 5% in non-lupus pregnancies. The Johns Hopkins Lupus Research Center reported that increased lupus activity did not affect miscarriage rates, but increased stillbirth rates by a factor of 3. The timing of the onset of lupus activity affects the rate of pregnancy loss, with the greatest risk due to lupus activity in early pregnancy. Early gestational proteinuria, hypoplasticity and hypertension are independent risk factors for pregnancy loss, with a 30-40% pregnancy loss rate in those with any of these risk factors.
Preterm labor is the most common complication of pregnancy in lupus patients
Preterm delivery is defined as delivery before 37 weeks of gestation. The incidence of preterm delivery in patients with lupus pregnancy is about 33%. The causes of preterm labor include preeclampsia, placental hypoplasia and premature rupture of membranes, of which premature rupture of membranes is the main cause of preterm labor in patients with lupus and should be closely monitored. Although most preterm births occur spontaneously, some are medically induced to protect the health of the mother or fetus.
Risk factors for the development of preterm labor include lupus activity before and during pregnancy, use of high doses of prednisone, and hypertension. Higher clinical activity of the disease and higher serologic activity are the two main predictors of preterm delivery. Serologic activity is defined as elevated anti-dsDNA levels and decreased C3 or C4 levels. The Johns Hopkins Lupus Research Center reports that preterm delivery occurs in 66% of those with active lupus during pregnancy compared to 32% of those without lupus activity. 17% of patients with active lupus deliver at 24-28 weeks of gestation compared to 6% of those without lupus activity.
The mode of delivery depends on the disease
After 37 weeks of gestation, if the patient is stable or mildly active and there are no contraindications to vaginal delivery, vaginal delivery is possible.
When lupus activity appears before 37 weeks of gestation, the degree of disease activity and fetal condition should be comprehensively evaluated, and the dosage of glucocorticoids can be increased to control the disease according to the condition, and if the disease can be effectively controlled, the gestational week can be extended as much as possible under close monitoring to increase the possibility of fetal survival and reduce the complications of prematurity; when the disease is still difficult to be controlled by high-dose glucocorticoid therapy or immunosuppressive drugs are needed, consideration can be given to Termination of pregnancy and cesarean section is the preferred delivery method. When lupus is severely active and the gestation period is still early and the fetus has a high chance of survival, treatment of maternal disease should be the main focus (e.g., abandoning the fetus), and induction of vaginal delivery after stabilization of the disease can be considered.