专家视点——红斑狼疮患者妊娠的特殊挑战

芝加哥——在美国风湿病学会主办的一场研讨会上，杜克大学的Megan Clowse博士指出，妊娠期活动性系统性红斑狼疮(SLE)的风险远高于大部分药物的风险：妊娠期活动性SLE可使妊娠丢失的风险增加1倍，妊娠前3个月的活动性SLE可使妊娠丢失的风险增加3倍，还目前还没有一种药物可导致妊娠丢失率达到40%。因此，患有活动性SLE的妊娠女性应持续用药。

Megan Clowse博士

预防SLE急性加重的最佳药物是羟氯喹(Plaquenil)。由于在使用大剂量氯喹(Aralen)的儿童中观察到听力异常，因此羟氯喹被归为妊娠C类药，但羟氯喹本身对胎儿并无明显风险，特别是在按照风湿病治疗剂量应用时。一些报告显示，妊娠期间停用羟氯喹可能会促进SLE急性加重，进而导致妊娠预后恶化。如果患者已停用羟氯喹多年，并且在妊娠期间无SLE症状，则无需使用羟氯喹。

对于SLE活动程度强的女性，可考虑使用硫唑嘌呤(Azasan，Imuran)。由于在分娩时观察到胎儿免疫抑制风险，因此该药被归为妊娠D类药。与SLE患者相比，肾移植患者的早产发生率更高，来自肾移植患者的广泛数据支持硫唑嘌呤用于妊娠期SLE。硫唑嘌呤是预防妊娠期SLE急性加重的最有效药物，但其治疗妊娠期SLE急性加重的疗效则不那么显著。Clowse博士在其最新研究中发现，在SLE活动性高的女性中，硫唑嘌呤不能预防妊娠丢失，而且反而与妊娠丢失率增加相关。

当发生SLE急性加重时，应及时治疗。泼尼松可能是最有效的治疗药物，但静脉输注免疫球蛋白可能也是合理选择。泼尼松通过胎盘代谢，仅有10%的母体剂量到达胎儿。相比之下，氟化皮质类固醇倍他米松(Betnesol注射液)不通过胎盘代谢，并可到达胎儿，因此不应在妊娠期间使用。泼尼松可能会导致出生体重降低，并可导致唇裂和腭裂发生的风险增加2倍，但这种风险主要影响妊娠早期。

妊娠期间应避免使用的药物包括环磷酰胺(Cytoxan)、霉酚酸酯(CellCept)和贝利木单抗(Benlysta)。对接受霉酚酸酯治疗的18例肾移植患者的26次妊娠进行分析后发现，11次妊娠以自然流产告终，10次为早产，4例为先天性异常(Transplantation 2006;82:1698-702)。出生缺陷发生率为26%，高于在一般人群中观察到的3%，并且有3例婴儿出现小耳畸形，这不单是耳廓发育不全，而是耳朵位于头部的错误位置，导致婴儿耳聋。

尽管尚未在动物中观察到贝利木单抗有致畸性，但葛兰素史克公司近期开展了一项全球贝利木单抗妊娠注册研究，以前瞻性收集妊娠前4个月或妊娠期间使用贝利木单抗的女性的出生缺陷和其他妊娠预后数据(电话：1-877-681-6296)。

Clowse博士表示其最近使用阿司匹林81 mg/d来预防妊娠期SLE患者发生先兆子痫。来自高危的非狼疮患者的数据表明，阿司匹林可降低早产、子痫前期、孕产妇高血压和低出生体重发生的风险，并且不会增加先天异常或动脉导管闭锁的风险。

风湿科医生和产科医生应密切监测患有SLE的妊娠女性。重要的监测项目包括：(1)高血压：特别在妊娠早期，因为高血压可导致妊娠丢失、早产和子痫前期发生的风险增加40%；(2)蛋白尿：由于肾功能增强，蛋白尿可能会在妊娠期间出现轻微增加，尿液蛋白量增加1倍以上或1 g均应引起重视。

为获得最佳的妊娠预后，建议女性患者在SLE活动期间避免妊娠。对于SLE患者，单纯孕酮避孕可能是最安全的避孕方法，甲羟孕酮注射液(Depo-Provera)的耐受性通常较好，3年依托孕烯埋植剂(Implanon)的耐受性优于左炔诺孕酮埋植剂(Norplant)。

Clowse博士是UCB公司的顾问，并从关节炎基金会获得资金支持。

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By: PATRICE WENDLING, Ob.Gyn. News Digital Network

CHICAGO – The risk of active disease in pregnant women with systemic lupus erythematosus far outweighs the risks of most medications.

Indeed, the risk of pregnancy loss doubles if lupus is active during pregnancy and jumps fourfold if the autoimmune disease is active in the 3 months before conception.

"My general rule is that the inflammation of active lupus is more dangerous to a pregnancy than medications," said Dr. Megan Clowse, director of the Duke University Autoimmunity in Pregnancy Registry in Durham, N.C. "We don’t have a medication that will cause a 40% pregnancy loss. So I think it’s important to continue medications within this population, although some drugs are certainly better than others."

She advocates the use of hydroxychloroquine (Plaquenil) as the best way to prevent a systemic lupus erythematosus (SLE) flare. It’s a pregnancy category C drug because of reports of hearing abnormalities in children exposed to high doses of chloroquine (Aralen), but there are no clear fetal risks with hydroxychloroquine itself, particularly at the doses used by rheumatologists, she said. Moreover, several reports have suggested that hydroxychloroquine discontinuation during pregnancy may precipitate SLE flares, thereby worsening pregnancy prognosis.

The one exception to hydroxychloroquine use in SLE is the patient who’s been off the drug for years and is no longer symptomatic but becomes pregnant. "I don’t force those women back on their hydroxychloroquine, but basically everybody else should be on it," Dr. Clowse said at a symposium sponsored by the American College of Rheumatology.

For women with more active SLE, consider the use of azathioprine (Azasan, Imuran). It is a pregnancy category D drug due to the risk for fetal immunosuppression at delivery, but its use in SLE pregnancy is supported by extensive data among renal transplant patients, who have a higher rate of prematurity than SLE patients.

Azathioprine is most effective in preventing SLE flare in pregnancy, but Dr. Clowse said she has not been as impressed with its ability to treat flares during pregnancy. In her own recent study, azathioprine did not prevent pregnancy loss, and was actually associated with higher rates of loss among women with high-activity SLE.

When SLE flares occur, they need to be treated promptly, she stressed. Prednisone is probably the most effective treatment, although intravenous immunoglobulin may be a reasonable option. Prednisone is metabolized by the placenta, allowing only 10% of the maternal dose to reach the fetus. In contrast, the fluorinated corticosteroid betamethasone (Betnesol injection) is not metabolized and is transferred to the fetus, so it should not be used during pregnancy. Prednisone may decrease birth weight and is associated with a modest, threefold increased risk for cleft lip and palate, but this is really a first-trimester risk, she noted.

Drugs to avoid in pregnancy include cyclophosphamide (Cytoxan), mycophenolate mofetil (CellCept), and belimumab (Benlysta). A review of 26 pregnancies in 18 renal transplant patients receiving mycophenolate reported that 11 ended in spontaneous abortions and 10 in preterm births, and there were 4 cases of congenital anomalies (Transplantation 2006;82:1698-702). Not only was the 26% birth defect rate staggering compared with the 3% seen in the general population, but three of the infants had microtia. This was not simply underdeveloped pinnae, but the ears were located in the wrong place on the head, resulting in the babies being deaf, Dr. Clowse warned.

Although teratogenicity has not been observed in animals on belimumab, GlaxoSmithKline recently launched a global Benlysta Pregnancy Registry to prospectively collect data on birth defects and other pregnancy outcomes from women receiving belimumab within the 4 months prior to and/or during pregnancy (telephone: 1-877-681-6296).

Dr. Clowse said she recently began putting most of her pregnant SLE patients on aspirin 81 mg/day to prevent preeclampsia. Data from high-risk, nonlupus patients suggest aspirin may decrease the risk of preterm birth, preeclampsia, maternal hypertension, and low-birth weight without increasing the risk of congenital anomalies or ductus arteriosus closure observed with regular aspirin.

"It also, to be honest, takes away that whole discussion of low anticardiolipin antibodies and what do you do," she added.

Pregnant women with SLE should be closely monitored by a rheumatologist and an obstetrician skilled in high-risk pregnancies. Key parameters to monitor are hypertension, particularly in the first trimester, as this can increase the risk of pregnancy loss, preterm birth, and preeclampsia by up to 40%; and proteinuria, which may rise modestly during pregnancy due to increased renal function. More than a doubling or a 1-g increase of proteinuria, however, should raise the alarm, Dr. Clowse said.

To achieve the best possible pregnancy outcome, women with SLE should be advised to avoid pregnancy when SLE is active. Dr. Clowse said it’s recently come to her attention that in North Carolina and other parts of the United States where abstinence-only education has been the law of the land for the past dozen years, this may mean having that first conversation about contraception with a patient already in her 20s.