Currently, no drug approved by the U.S. Food and Drug Administration is available for treating morning sickness. Bendectin, the combination of the antihistamine doxylamine with pyridoxine (vitamin B6) – used in the United States and Canada in the 1960s and 1970s for treating nausea and vomiting of pregnancy – was pulled from the market because of litigious claims. But this combination has been shown to be safe in large studies conducted since that time, and has been approved and available continuously as Diclectin in Canada.
Doxylamine is an older antihistamine and has central nervous system effects, including sedation, and Diclectin is not yet approved in the United States. Therefore, there is room for alternatives for treating nausea and vomiting in pregnancy (NVP). Currently, trials are being conducted in the United States in a process aimed at reintroducing the combination of doxylamine and pyridoxine to the U.S. market, in view of its impressive safety record.
Metoclopramide, a prokinetic drug used for more than 40 years to treat nausea and vomiting due to various causes, is one alternative to the doxylamine-pyridoxine combination. Because metoclopramide acts mostly through the gut, not the CNS, it has a physiologic advantage in terms of potential side effects and is the drug of choice for NVP in some countries, but not in North America, where it is usually used only for severe cases. It can be associated with extrapyramidal symptoms, which tend to be self-limited and have rarely been reported in the context of morning sickness.
To date, the safety data on the use of metoclopramide during pregnancy have been limited, based on studies involving about 800 pregnancies in the literature. But a large, retrospective cohort study published in June, conducted by investigators at Ben-Gurion University of the Negev, Beer-Sheva, Israel, in collaboration with the Motherisk program in Toronto, provided reassuring data regarding its safety during the first trimester of pregnancy.
The study linked medication database records for females aged 15-49 years who were members of a health maintenance organization in Southern Israel, with databases containing maternal and infant records for the medical center that serves the area. Of the 81,703 infants born to these women between Jan. 1, 1998, and March 31, 2007, a remarkable 3,458 (4.2%) had been exposed to metoclopramide during the first trimester.
This number exceeded what we expected and created a rare opportunity to analyze the reproductive safety of this drug in a large study with good quality data and the ability to adjust for confounding factors, including parity, maternal age, and smoking status. The mean number of daily doses was about seven, and the mean age of the women was almost 28 years.
When compared with the infants of the 78,245 women in the health maintenance organization who had not taken metoclopramide during the first trimester, there was no increased risk of major or minor congenital malformations, low birth weight, preterm delivery, or perinatal death among the infants whose mothers had taken metoclopramide during the first trimester, after adjustment for confounding factors (N. Engl. J. Med. 2009;360:2528-35). The results did not change when pregnancy terminations were included.
Metoclopramide is another option for treating nausea and vomiting, the most common condition in pregnancy, which often receives inadequate attention from clinicians, despite studies showing NVP causes significant social and psychological morbidity. Clinicians who may be hesitant to prescribe an antiemetic for patients who are suffering from NVP should be able to prescribe with confidence a treatment for which more data are now available to support its safety.
An important consideration when treating women who have NVP is the impact that heartburn and reflux can have on the severity of these symptoms. Quite a few women who call the dedicated NVP line at Motherisk (800-436-8477) reported also having acid reflux symptoms, along with nausea and vomiting, which led to a study that demonstrated for the first time that heartburn and acid reflux can exacerbate the severity of nausea and vomiting.
The prospective study, published in the Canadian Journal of Gastroenterology in April, compared 194 women with NVP and heartburn, reflux, or both, with 188 women with NVP without heartburn or reflux. We found that the women with heartburn and reflux had significantly higher scores on scales that measured the degree of emesis and nausea, and significantly lower well-being scores, which our analysis determined was related to heartburn and reflux, not to preexisting GI conditions or symptoms, hyperemesis gravidarum in previous pregnancies, or other confounding factors (Can. J. Gastroenterol. 2009;23:270-2).
In another study that is in press, we also found that treating women who have reflux and heartburn associated with NVP with an H2 receptor blocker or a proton pump inhibitor decreased nausea and vomiting dramatically, without the need for increasing the dose of the antiemetic. The results of this study support managing acid reflux in women with these symptoms to help control nausea and vomiting – a strategy that has not received much consideration previously. Recent meta-analyses by Motherisk have shown that both H2 blockers and proton pump inhibitors are safe during pregnancy, further supporting the management of reflux.
Dr. Koren is a professor of pediatrics, pharmacy, pharmacology, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership in Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. He has received consulting and lecture fees, as well as grant support, from Duchesnay Inc., manufacturer of Diclectin.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
目前，尚无任何药品获美国食品药品管理局(FDA)批准用于治疗早孕反应。上世纪六七十年代，一种含抗组胺剂多西拉敏(doxylamine)和维生素B6(pyridoxine)的药物Bendectin被美国和加拿大用于治疗孕妇的恶心呕吐反应，后因遭遇诉讼索赔而撤出市场。但此后一些大规模试验已经证实了该复方的安全性，并在加拿大以Diclectin为名获批继续使用。
多西拉敏是过去使用的一种抗组胺剂，它对中枢神经系统会产生包括镇静在内的影响，且Diclectin尚未在美国获得批准。因此，早孕反应(NVP)的替代疗法仍留有空间。鉴于多西拉敏和维生素B6复方具有良好的安全性，目前美国正在进行相关试验，旨在重新将该制剂推向美国市场。
胃复安是治疗恶心呕吐的胃动力药物，由于种种原因已使用超过40年，是多西拉敏和维生素B6复方的一种替代用药。胃复安主要通过消化道而非中枢神经系统起作用，故在潜在副作用上具有生理性优势，是北美地区以外的许多国家治疗早孕反应的备选药物，但通常只用于严重的早孕反应。胃复安可与锥体外系症状相关，常呈自限性，在早孕反应的治疗中少有报告。
迄今为止，文献报道约800例孕期使用胃复安的孕妇，但安全性数据仍然有限。以色列比尔谢巴市内盖夫本古里安大学的研究人员与多伦多Motherisk计划合作，在6月发表了一项大型回顾性队列研究，提供了在妊娠头3个月使用胃复安的安全性数据。
研究将以色列南部参加商业医疗保健机构、年龄在15~49岁的女性用药数据库记录与该地区医疗中心的孕产妇和婴儿记录数据库联系起来。在1998年1月1日到2007年3月31日出生的81,703个婴儿中，3,458个(占4.2%)婴儿在妊娠头3个月有胃复安暴露史。
这一数据超出了我们的预期，创造了一个难得的机会，使我们能在一项大型研究中使用高质量数据分析该药物对生产的安全性，并能将各种混杂因素包括活产胎次、产妇年龄、吸烟状况考虑在内。这批产妇平均每天吸烟7支，平均生产年龄大约28岁。
该机构中妊娠头3个月未使用胃复安的78,245名妇女，其婴儿发生主要或次要先天性畸形、低出生体重、早产或围产期死亡的风险没有增加(N. Engl. J. Med. 2009;360:2528-35) 。直到妊娠结束，上述结果并无改变。
尽管研究显示早孕反应可引起严重的社会心理疾病，胃复安是妊娠最常见的恶心和呕吐的候选药物，然而临床医生往往对此重视不够。医生可能对给遭受早孕反应之苦的孕妇开具止吐药而心存疑虑，现有支持胃复安安全性的数据则给他们增加了信心。
治疗早孕反应妇女要考虑的一个重要因素是胃灼热和反流可影响恶心呕吐严重程度。不少妇女拨打Motherisk计划NVP专线(800-436-8477)报告称有恶心、呕吐和反酸症状，这推动了一项研究，首次证明胃灼热和反流可能加剧恶心和呕吐症状的严重程度。
该前瞻性研究发表在《加拿大胃肠病学杂志》(Canadian Journal of Gastroenterology)4月刊上，对194例有胃灼热或反流症状或两者兼有的NVP妇女和188例无胃灼热或反流症状NVP妇女做了对比研究。研究发现，有胃灼热和反流症状的妇女在反映呕吐和恶心程度的量表上评分较高，而健康评分显著下降，该分析与胃灼热和反流相关，而与已有的胃肠道环境或症状、怀孕初期的妊娠剧吐或其他混杂因素无关(Can. J. Gastroenterol. 2009;23:270-2)。
在付印的另一文章同样发现，采用H2受体阻滞剂或质子泵抑制剂治疗早孕反应相关的胃灼热和反流可显著减少恶心和呕吐，而不需要增加止吐药剂量。上述研究结果支持处理早孕反应妇女的胃酸倒流以控制恶心呕吐，这一策略在以前并未受到很大关注。最近Motherisk的荟萃分析表明，在怀孕期间使用H2受体阻滞剂和质子泵抑制剂是同样安全的，这进一步支持了控制胃酸反流的策略。
Koren博士是多伦多大学儿科学、药学、药理学、内科学和医学遗传学教授，领导多伦多“儿童医院怀孕和哺乳期药物治疗领先研究”计划，同时也是多伦多Motherisk计划的负责人。Koren博士接受过Diclectin生产厂商Duchesnay公司的咨询费、演讲酬金以及基金资助。
爱思唯尔 版权所有
