Since rheumatologic diseases mainly affect women of childbearing age, pregnancy is an unavoidable problem in the management of rheumatologic diseases. In addition to inflammatory arthritis, most patients with active rheumatologic diseases, pregnancy can cause worsening of the disease and increase the incidence of serious obstetric complications such as preeclampsia and adverse fetal outcomes. Therefore, it is crucial to ensure that the rheumatologic disease is well controlled before pregnancy. In addition, the many anti-inflammatory drugs and immunosuppressive agents necessary for the treatment of rheumatic immune diseases may lead to infertility and adverse fetal outcomes. This article reviews pregnancy-related comorbidities in rheumatologic diseases and the safe use of medications during pregnancy and lactation.
Effects of Pregnancy on Rheumatic Immune Diseases
Systemic lupus erythematosus
Although controversial, it is generally accepted that approximately 50% of patients with systemic lupus erythematosus (SLE) will have a relapse or exacerbation of the disease during pregnancy, and this can occur at all stages of pregnancy and during the postpartum period of 3 months. the risk of SEL relapse during pregnancy is significantly increased in patients with recurrent SLE, renal involvement, and active SLE within 6 months prior to conception. In addition, many patients have relapses during pregnancy associated with discontinuation of therapeutic drugs. Most relapses are mild, with skin manifestations and arthritis being the most common, and can be controlled with low-dose hormones and weaker immunosuppressants such as hydroxychloroquine and azathioprine. 10% to 40% of patients have thrombocytopenia in combination. Severe active SLE accounts for 15%-30% of patients, mainly showing renal and central nervous system involvement. Combined hypertension is an important cause of increased incidence of adverse obstetric outcomes in pregnancy in patients with SLE. In combination with pulmonary hypertension, the mortality rate during pregnancy is up to 50% and should be taken seriously.
Antiphospholipid syndrome
Pregnancy itself and antiphospholipid antibodies increase the risk of various arterial and venous thrombosis, and patients with antiphospholipid syndrome (APS) require oral low-dose aspirin or even anticoagulation with heparin.
Patients with APS are particularly prone to pre-eclampsia and often have severe manifestations. For example, seizures may occur in the first 20 weeks of pregnancy or recurrent pre-eclampsia. The causes may be related to multiple placental thrombosis, placental infarction, and uteroplacental insufficiency. Some mild cases of pre-eclampsia may resolve with bed rest and antihypertensive therapy, but in persistent cases and those with eclampsia, pregnancy should be terminated promptly. patients with APS also have a higher than normal rate of hemolysis, elevated liver enzymes, and thrombocytopenia syndrome, which is more severe and usually requires hormonal therapy or even termination of pregnancy, and plasma exchange may provide relief.
Systemic vasculitis
Similar to SLE, maternal and infant mortality in pregnancy is increased when the disease is active, so it is important to distinguish between pre-eclampsia and renal vasculitis activity. Pregnancy may also increase the risk of thrombosis in patients with leukoaraiosis.
Systemic sclerosis
Patients with systemic sclerosis (SSc) who are stable at the time of conception usually do not deteriorate during pregnancy, but
the disease may progress in the postpartum period. The clinical manifestations of SSc during pregnancy may resemble normal pregnancy reactions, such as gastroesophageal reflux and exertional dyspnea. Vomiting during pregnancy in those with esophageal involvement may result in tearing of the culpable mucosa, causing life-threatening hemorrhage. The most serious complications of SSc are renal crisis and secondary hypertension, and
SSc is not easily distinguished from pre-eclampsia and HELLP syndrome and is difficult to control. Nifedipine is usually used to control blood pressure, and angiotensin-converting enzyme inhibitors (ACEI) may be used in emergency situations to save lives, although they may cause congenital malformations and renal insufficiency in the fetus. In contrast to pre-eclampsia, delivery does not improve hypertension and renal crisis. Patients who have had renal crisis during a previous pregnancy should avoid another pregnancy until the condition has stabilized, usually at an interval of 3-5 years.
Rheumatoid arthritis and spondyloarthropathy
In contrast to SLE, 75% to 95% of patients with rheumatoid arthritis (AR) have significant remission during pregnancy and may have a relapse or new onset after delivery. This may be due to the fact that SEL is dominated by a humoral immune response (Th2 type), whereas AR is more often induced by a cellular response (Thl type). During pregnancy, the Th2-type response increases due to endogenous estrogen, leading to overexpression of IL-4 and IL-10, which increases the autoantibody response in SLE; whereas Th2 has an immunosuppressive effect on AR. At the same time, the function of multinucleated leukocytes in synovial fluid is inhibited by a-mono-fetoprotein during pregnancy, which reduces synovial inflammation. The recurrence of AR in the postpartum period may be due to a decrease in pregnancy-associated immunomodulatory hormones and may also be related to the proinflammatory effects of elevated lactogen levels. 25% of patients with severe spondyloarthropathies worsen during pregnancy, but it is difficult to distinguish whether mechanical changes in spinal activity or inflammatory activity during pregnancy are responsible.
Impact of rheumatoid diseases on reproductive function
Although patients with SLE have reproductive function, studies have shown a significantly lower pregnancy rate in patients with SEL before and after disease diagnosis compared to the normal population (2.11%:3.4%). Menstrual cycle disorders and anovulatory cycles may occur in SEL patients with active disease and high-dose hormone therapy; end-stage renal failure secondary to lupus nephritis may cause amenorrhea, which may be due to an autoimmune response or premature ovarian failure caused by cyclophosphamide; and conception may be compromised by concomitant ovarian venous thrombosis in those with combined APS.
RA, ankylosing spondylitis, vasculitis and SSc have no direct effect on reproductive function. There is a correlation between dry syndrome (SS) and endometriosis, which may lead to infertility in severe cases, but primary SSc tends to develop after childbearing age.
Impact of rheumatic immune diseases on pregnancy outcome
Compared to the normal population, pregnancies in patients with SLE have higher rates of stillbirth, miscarriage, and preterm delivery; increased rates of preeclampsia and cesarean delivery; and an increased risk of intrauterine growth retardation. A previous history of miscarriage or stillbirth, conception with active nephritis, hypertension, and antiphospholipid antibodies are associated with an increased risk of habitual early miscarriage, failed placental implantation, intrauterine growth retardation, and preterm delivery, which may be related to the action of antiphospholipid antibodies on anionic phospholipids and glycoproteins on the trophoblast. In addition, the formation of thrombus secondary to APS can involve the placenta, causing placental ischemic infarction and placental insufficiency, which also contributes to the development of intrauterine growth retardation. Preterm delivery is also common in pregnancies in patients with vasculitis and systemic sclerosis.
Effects of rheumatic immune diseases on the newborn
SLE and SS are the rheumatic diseases most likely to be transmitted from mother to fetus. These fetuses can be born with neonatal lupus syndrome, which presents with a transient lupus-like rash, complete atrioventricular block, hematocrit and liver function abnormalities. The rash is the most common, typically presenting as an annular or elliptical desquamative erythema similar to that of adult subacute cutaneous lupus. Congenital heart block (CHB) is the most severe manifestation, with a mortality rate of up to 20%; 67% of surviving newborns will also require permanent pacemaker implants. After 6 months of life, the maternal autoantibodies are completely degraded and the disease resolves, but atrioventricular block is irreversible. Similar mother-to-child transmission has been reported in vasculitis and APS.
Effect of anti-rheumatic drugs on pregnancy
Discontinuation of therapeutic drugs during pregnancy is an important cause of relapse of rheumatic immune diseases such as lupus, but many drugs have significant teratogenic and gonadal suppressive effects, and selection of the correct drug class and appropriate dose are important measures to maintain therapy and prevent disease activity during pregnancy. Current data on drug safety are mainly from in vitro and animal studies, and clinical data are mostly from studies of non-rheumatic immune diseases, or case reports with very low levels of evidence.
Glucocorticoids
When prednisone, prednisolone and methylprednisolone are converted to inactive substances in the placenta, less than 10% of the active drug enters the fetal circulatory system and does not increase the incidence of congenital malformations in the fetus, and an increase in the birth rate of low birth weight infants has been reported. Doses of prednisone ≥10 mg/d may increase the incidence of preeclampsia, gestational hypertensive syndrome, gestational diabetes, infection, and premature rupture of membranes. High doses of hormones may also cause neonatal cataracts and adrenal suppression, so maintaining the lowest possible dose of hormones is key to treatment. Betamethasone and dexamethasone are not readily metabolized by the placenta and may interfere with fetal growth and brain development, making them unsuitable for routine use in pregnancy, but they are potentially beneficial in promoting lung maturation in preterm infants or treating fetal myocarditis.
Non-steroidal anti-inflammatory drugs
Non-selective and selective epoxygenase (COX) inhibitors can affect ovulation, embryo implantation and placental circulation, thus causing infertility and miscarriage. The longer the duration of drug use and the closer to conception, the greater the risk of miscarriage. Large clinical studies have not found an increased incidence of congenital malformations in the fetus with aspirin and non-selective COX inhibitors, and they can be used safely in early pregnancy. However, in mid- and late pregnancy, NSAIDs can cause pulmonary hypertension, premature ductus arteriosus, and decreased renal perfusion in the newborn, and can cause prolongation of maternal pregnancy and labor because of their ability to block the synthesis of prostacyclin and inhibit its vasodilatory and smooth muscle contraction effects. The use of selective COX inhibitors in early pregnancy lacks strong data support, and the adverse effects in mid to late pregnancy are mild compared to non-selective inhibitors. Small doses of aspirin (<325 mg/d) are safe to use throughout pregnancy and are particularly
The mechanism may be to reduce the incidence of miscarriage through antithrombotic, anticomplementary, and pathological apoptosis inhibition.
Immunosuppressants
The risk of premature ovarian failure in patients with severe lupus nephritis treated with cyclophosphamide has been reported to be 11-59%, depending on the age at initiation of therapy, the cumulative dose of the drug, and the route of administration. In women treated with cyclophosphamide, the best way to prevent amenorrhea and infertility is to use a synthetic gonadotropin-releasing hormone agonist (GnRH-a), which reduces the incidence of premature ovarian failure from 30% to 5%. Methotrexate, leflunomide, azathioprine, and sulfadiazine do not affect the reproductive function of women,
However, sulfadiazine can reduce sperm and cause male infertility, and folic acid supplementation is not effective, but it can be restored after 2 months of discontinuation.
Various doses of cyclophosphamide have significant teratogenic effects. The use of cyclophosphamide in early pregnancy can lead to extensive malformations of the fetal brain, face, limbs and internal organs, while the use in the middle and late stages can cause fetal growth restriction, hematopoietic suppression and impaired neurological development. Pre-pregnancy use does not increase the incidence of fetal malformations and miscarriage, and conception can be considered 3 months after stopping the drug. Methotrexate and leflunomide interfere with folic acid metabolism and affect the central nervous system and bone development and are contraindicated during pregnancy. Methotrexate may significantly increase the rate of miscarriage and fetal developmental abnormalities and is contraindicated during pregnancy,
Because of its long half-life and hepatic-intestinal circulation, it should be discontinued at least before pregnancy.
Conventional doses of azathioprine (2 mg/kg/day), salazosulfadiazine (2 g/d), chloroquine (250 mg/d), and hydroxychloroquine (200-400) mg/d) are safe in pregnancy, but fetal developmental abnormalities have been reported in cases above _these doses. No teratogenic effects have been found in clinical studies with cyclophilin A, but animal studies suggest possible embryotoxicity at doses of 25-100 mg/kg/day, with a few reports of impaired lymphocyte maturation in infancy and delayed mental development in childhood in follow-up studies. It is recommended that the lowest effective dose be maintained during pregnancy and that blood pressure and renal function be monitored at all times.
Biologics
Of the newer biologics, only etanercept and infliximab have been reported in a small number of applications during pregnancy and no significant fetal toxicity has been found, but data are scarce and not yet sufficient to affirm their safety.
Effects of drug administration during lactation
Even in patients taking 80m/d prednisone, the concentration of the drug in breast milk is only 5%-25% of the blood concentration, which is much lower than the secretion of endogenous cortisol, but a prednisone dosage of more than 40mg/d is recommended before breastfeeding. Dexamethasone and betamethasone lack study data. Most NSAIDs and chloroquine/Qianglaquine have low levels in breast milk and no clear adverse effects have been observed with lactation. Human immunoglobulin is permitted for use during lactation. Diarrhea and rash have been reported with lactational use of salazosulfadiazine, which should be avoided during lactation in premature and affected infants with hyperbilirubinemia and glucose mono-6 phosphate dehydrogenase deficiency, but has no effect on healthy full-term neonates. Cyclophosphatidylamine is secreted in breast milk and has been reported to inhibit hematopoietic function in infants; it is not recommended for use during lactation. There is no consensus on the safety of methotrexate, azathioprine, and cyclophilin A during lactation. The effects of leflunomide, morte-macrolide, and newer biologics on lactation are unknown.
Summary
Pregnancy has different effects on different rheumatic immune diseases. Patients with SEL, APS, systemic vasculitis, pSS, and SSc have increased pregnancy-related complications and maternal and infant mortality compared to the normal population, so pregnancy should be avoided during active disease. A variety of anti-rheumatic immune disease drugs such as cyclophthalamide may cause infertility or fetal malformations in patients, but there are data supporting the safety of small doses of aspirin, hormones and cyclophilin A as well as conventional doses of azathioprine, salazosulfadiazine and chloroquine and hydroxychloroquine in pregnancy. Although the combination of rheumatologic diseases with pregnancy greatly increases the complexity of the condition and the difficulty of treatment, causing many patients to forego the opportunity to have children. However, detailed evaluation before pregnancy, regular treatment, ensuring conception when the disease is stable, and close monitoring and proper medication use during pregnancy, perinatal period and postpartum lactation will hopefully make a successful pregnancy and delivery of healthy offspring a reality for patients with rheumatic immune diseases.