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作者：Caroline Cassels  
出處：WebMD醫學新聞

　　September 25, 2009 — 新研究顯示，懷孕初期服用選擇性血清素再吸收抑制劑(SSRIs)的婦女，其所生的小孩，隔膜心臟缺損的風險略為顯著增加。
　　
　　9月25日的線上BMJ期刊中，丹麥Aarhus大學研究者進行的一個大型、族群基礎世代研究結果顯示，懷孕期間使用一種SSRI，小孩的隔膜心臟畸形發生機會增加1.99倍(95%信心區間[CI]為1.13 – 3.53)。
　　
　　不過，各種SSRIs對於隔膜心臟缺損的風險不同。
　　
　　【各種SSRIs對於隔膜心臟缺損的風險勝算比】 SSRI
勝算比
95% CI

Sertraline
3.25
1.21 – 8.75

Citalopram
2.52
1.04 – 6.10

Fluoxetine
1.34
0.33 – 5.41


　　此外，懷孕期間處方過一種以上的SSRI的婦女所生的小孩，隔膜心臟缺損的風險增加四倍，基於此一發現，研究者認為，同時使用不同的SSRIs或者在懷孕初期改變所用的SSRI，會產生問題。
　　
　　研究者解釋，這些數據的意義是，心臟缺損的絕對差異低。研究者報告指出，舉例來說，在未曝露於此情況的小孩中，隔膜心臟缺損的盛行率約為0.5%(2315/493,113)，母親處方有任何一種SSRI的小孩為0.9% (12/1370)，母親處方一種以上SSRI的小孩為2.1% (4/193)。
　　
　　【懷孕期間使用SSRI的情形普遍且增加中】
　　根據文獻，多達20%的孕婦有憂鬱症，懷孕期間使用SSRIs的情形普遍且增加中。不過，特定SSRIs的致畸胎作用未被確認。
　　
　　最近的研究指出，與懷孕期間使用SSRI有關的生育缺損發生率增加，最常見的是心臟缺損。此一風險導致美國食品藥物管理局在2005年提出懷孕期間使用paroxetine的相關警告。
　　
　　為了研究懷孕第一期服用SSRIs與嚴重畸形之間的關聯，研究者使用丹麥四個全國登記資料庫中、496,881名在1996至2203年出生之單胞胎孩童的資料。
　　
　　此外，研究者分析了調劑處方、生產、母親和新生兒之醫院診斷等資料。曝露於一種SSRI的定義是在妊娠開始前28天到之後112天內使用者。該研究的主要結果測量方式，是根據歐洲先天異常監督機構的嚴重畸形分類。
　　
　　研究者發現，相較於未曝露組小孩中，曝露組小孩嚴重畸形或非心臟畸形的發生率沒有顯著增加。
　　
　　不過，使用sertraline和citalopram婦女的小孩，其隔膜心臟缺損發生率增加，但是使用fluoxetine者的小孩則沒有。此外，曝露期間調劑處方超過一種SSRI的母親所生的小孩，隔膜心臟缺損風險顯著增加。
　　
　　作者們寫道，我們的結果認為，SSRI對於心臟缺損有某種影響，現有的研究結果並不確定，這可能是因為劑量或研究族群的差異所致。如果確定此關聯是因果關係，代表曝露組小孩的先天心臟缺損風險有限增加。需要更大型樣本的後續研究，以便有更足夠的研究強度來探討與更嚴重畸形之間的可能關聯。
　　
　　【衡量利益與風險】
　　加州大學聖地牙哥分校小兒科副教授Christina Chambers博士在編輯評論中寫道，本研究顯示的小風險，必須和減量治療或不治療的風險加以衡量。
　　
　　Chambers博士指出，如果嚴重先天畸形風險的確增加，本研究和其他研究認為，個別孕婦的絕對風險很低。再者，此類藥物中常用的每種藥品，都至少有一篇研究顯出關聯，所以難以結論說哪一種SSRI比較安全。
　　
　　同時，Chambers博士建議，婦女及其醫師看看美國婦產科學院以及美國小兒科協會最近發表的指引，以幫助決定治療決策。
　　
　　這些建議指出，考慮懷孕或者已經懷孕的重度憂鬱異常婦女，可以開始或繼續使用她們的藥物。對於傾向避免使用或停用藥物的婦女，心理治療可能是個有效的選項。不過，Chambers博士指出，心理治療的效果通常因個別病患的精神病史而異。
　　
　　Chambers博士指出，需要更多更大型的研究，之後才能提出有關懷孕期間使用SSRI的明確結論。
　　
　　她寫道，雖然有關SSRIs與懷孕結果的研究結果很多，對於臨床實務並無法提出明確解答。醫師和病患需權衡使用SSRIs的相關風險以及減量治療或不治療的風險。
　　
　　BMJ. 線上發表於2009年9月25日。


Small but Significant Risk for Heart Defects Linked to SSRI Use During Pregnancy
By Caroline Cassels
Medscape Medical News
September 25, 2009 — Children born to women taking selective serotonin reuptake inhibitors (SSRIs) in early pregnancy have a small but significant increased risk for septal heart defects, new research shows.
A large, population-based cohort study conducted by researchers at Aarhus University in Denmark and published online September 25 in BMJ shows overall monotherapy with an SSRI during pregnancy was associated with an odds ratio of 1.99 (95% confidence interval [CI], 1.13 – 3.53) for septal heart malformations in children.
However, for individual SSRIs the risk for septal heart defects varied.
Odds Ratios for Septal Heart Defects for Individual SSRIs
SSRI  Odds Ratio  95% CI  
Sertraline 3.25 1.21 – 8.75
Citalopram 2.52 1.04 – 6.10
Fluoxetine 1.34 0.33 – 5.41
In addition, children of women who were prescribed more than 1 type of SSRI during pregnancy had a 4-fold increased risk for septal heart defects — a finding that suggests that simultaneous use of different SSRIs or a change in type of SSRI during early pregnancy may be problematic.
Putting these figures into context, the authors note that the absolute differences in heart defects were low. For example, the prevalence of septal heart defects was 0.5% (2315/493,113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than 1 type of SSRI, the investigators report.
SSRI Use in Pregnancy Common, Increasing
According to the article, depression affects up to 20% of pregnant women, and use of SSRIs during pregnancy is common and increasing. However, the teratogenic effects of specific SSRIs are unconfirmed.
Recent studies have indicated an increased prevalence of various birth defects associated with SSRI use in pregnancy — most consistently, heart defects. This suspected risk led to the 2005 warning by the US Food and Drug Administration related to the use of paroxetine during pregnancy.
To investigate the association between SSRIs taken in the first trimester of pregnancy and major malformations, the researchers used data from 4 Danish nationwide registries in 496,881 singleton children born between 1996 and 2003.
In addition, the investigators analyzed data on filled prescriptions, delivery, and hospitals diagnosis on mothers and newborns. Exposure to an SSRI was defined as 28 days before to 112 days after the beginning of gestation.
The study's main outcome measure was major malformations categorized according to the European Surveillance of Congenital Anomalies.
The investigators found there was no significant increased prevalence of major malformations or noncardiac malformations among exposed children vs nonexposed children.
However, there was an increased prevalence of septal heart defects for children of women who used sertraline and citalopram, but not fluoxetine. In addition, children whose mothers had filled prescriptions for more than 1 type of SSRI in the exposure window had a significantly increased risk for septal heart defects.
"Our results suggest a class effect of the SSRI on heart defects, and the equivocal results from existing studies could represent differences in doses or study population. The associations, if causal, represent limited risk of an exposed child having congenital heart defects. Future studies need much larger sample sizes, preferably with sufficient power to further investigate potential associations with more severe malformations," the authors write.
Weighing Risks and Benefits
In an accompanying editorial, Christina Chambers, PhD, associate professor of pediatrics, University of California–San Diego, writes that the small risk for harm shown in this study must be weighed against the risk of suboptimal or no treatment.
Dr. Chambers notes that "if an increased risk for major congenital malformations does exist, this study and others suggest that the absolute risk for the individual pregnant women is very low. Furthermore, each of the more commonly used drugs in this class has been implicated in at least 1 study so it is difficult to conclude that 1 SSRI is 'safer' than another."
In the meantime, Dr. Chambers recommends that women and their physicians look to the recently published guidelines from the American College of Obstetrics and Gynecology and the American Psychiatric Association to help guide their treatment decisions.
These recommendations state that women with major depressive disorder who are contemplating pregnancy or who are currently pregnant can start or continue taking their medications. For women who prefer to avoid or discontinue drugs, psychotherapy can also be an effective treatment option. However, Dr. Chambers notes that its efficacy is often determined by an individual's psychiatric history.
Dr. Chambers added that more research, with larger numbers of participants, is needed before any definitive conclusions can be drawn about SSRI use during pregnancy.
"Although research about SSRIs and pregnancy outcomes is plentiful, it does not necessarily provide definitive answers for clinical practice. Clinicians and patients need to balance the small risks associated with SSRIs against those associated with undertreatment or no treatment," she writes.
BMJ. Published online September 25, 2009.