孕期使用苯二氮平類及非苯二氮平類藥物造成子代先天性缺陷及發展性疾病之關聯

Association of Prenatal Use of Benzodiazepines and Z-hypnotics with Congenital Defect and Developmental Disorders in Offspring

林月屏(Yueh-Pin Lin)

指導教授 ： 周明智

中山醫學大學/醫學院/醫學研究所/碩士(2022年)

https://doi.org/10.6834/csmu202200097

摘要

研究目的
隨著孕程進展，孕婦心理身體都面臨巨大的變化，不寧腿症候群、腸胃道不適、呼吸相關疾患及荷爾蒙變化導致無法入睡和睡眠中斷等問題，懷孕期睡眠障礙症會導致宮內胎兒生長遲滯（胎兒在子宮內發育不良）、早產、剖腹產風險更高、分娩時間更長、妊娠糖尿病及妊娠高血壓，懷孕期間造成的急性壓力導致失眠，睡眠認知行為治療的效果有限，藥物介入雖然可緩解睡眠問題，但是不得不擔心藥物對子代產生的副作用，臨床中Benzodiazepines（BZD）和Z-hypnotics是使用率最高的助眠劑，孕期使用助眠劑可能會造成周產期低出生體重、早產、蹣跚嬰兒症候群、APGAR分數較低和新生兒戒斷症候群，然而暴露藥物後對胚胎神經發育的影響目前尚無定論，因此本篇研究針對孕期暴露於BZD及Z-hypnotics的子代進行分析，評估先天性缺陷及發展性疾患的風險。
研究方法
本研究透過婦幼主題式資料連結多項2008-2019年的衛生福利資料檔案，包含出生通報資料（National Birth Reporting Database）、健保資料（National Health Insurance Research Database）及死因登記資料（National Death Index Database）進行回溯性世代研究。本研究評估2009-2016年出生，且母親懷孕時或前1年曾就診睡眠障礙或憂鬱診斷的世代，並依據母親懷孕時是否使用BZDs或 Z-Hypnotics作為藥物暴露，接著以小孩出生開始追蹤小孩日後發生先天性缺陷、過動症或自閉症的風險。
以Cox 比例風險模型分析估計母親懷孕期間暴露BZD或Z-hypnotics其子代出生後發生先天性缺陷、過動症或自閉症的粗風險比（hazard ratio, HR）和95% CI，並以多變項 Cox 比例風險模型分析調整父母親、子代的人口統計數據及共病症來估計母親懷孕期間暴露BZD或Z-hypnotics其子代發生先天性缺陷及發展性疾病調整後的風險比（adjust hazard ratio, aHR）。使用Kaplan-Meier 計算母親懷孕時使用安眠藥 (BZD or Z-hypnotics)其子代自出生後2年內先天性缺陷或10年內過動症和自閉症累計概率， 以log-rank test來檢驗子代發生先天性缺陷、注意力不足/過動症（Attention Deficit Hyperactivity Disorder, ADHD）或自閉類群障礙症（Autism Spectrum Disorder, ASD）是否組別間具有差異。
研究結果
懷孕期間使用BZDs或Z-hypnotics會增加子代先天性缺陷（aHR：1.11，95% CI 1.01 – 1.22），僅暴露 Z-hypnotics（aHR：1.23，95% CI 1.09 – 1.38） 比起僅暴露BZDs （aHR：1.09，95% CI 0.99 – 1.20）在先天性缺陷上更具有相關聯；若母親妊娠期暴露藥物則小孩ADHD（cHR：1.15，95% CI 1.08 – 1.23）及ASD（cHR：1.16，95% CI 1.00 – 1.35）風險增加但經過校正後不具統計意義。Kaplan-Meier生存分析中先天性缺陷觀察24個月，發展性疾病觀察120個月，藥物暴露組的累積先天性缺陷發生率（Log-rank p<0.0001）及累積ADHD發生率（Log-rank p=0.0007）上升。
結論與建議
我們的研究顯示孕期使用BZD 或Z-hypnotics會增加先天性缺陷的風險，尤其在第一孕期統計顯著，和胚胎神經發育時間一致，從累積發生率來看長期會增加神經發展疾病的風險。妊娠前後的睡眠障礙症若決定使用BZD及Z-hypnotics需要十分謹慎的評估，建議低劑量使用減少對子代的影響。

關鍵字

失眠 ； 憂鬱 ； 焦慮 ； 安眠藥 ； 先天性缺陷 ； 注意力不足/過動症 ； 自閉症類群障礙症

並列摘要

Objective
With the progression of pregnancy, pregnant women experience tremendous changes in both physically and psychologically aspect. Restless leg syndrome, gastrointestinal discomfort, respiratory disorders and changes in hormone can be related to sleep disorders such as initial insomnia and sleep interruption. Pregnancy related sleep disorders can lead to intrauterine growth retardation /restriction (IUGR), preterm birth, increasing in risk of caesarean section, increasing of labor period time, gestational diabetes mellitus and gestational hypertension. Sleep cognitive behavioral therapy has limited effect to acute stress related sleep disorders in pregnant women. Though medication could relieve sleep disorders, some concerns about fetal effect emerges. Benzodiazepine (BZD) and Z-hypnotics drugs are two most-using hypnotics. These two drugs using in perinatal period are known to be related to low birth weights, preterm labor, floppy baby syndrome, low Apgar scores at birth and neonatal abstinence syndrome. However, no studies have been conducted to evaluate the effects on neonatal neural development. Therefore, the aim of our study is to analyze the risks between birth defect, developmental disorders and exposure to BZD and Z-hypnotics drugs during pregnancy.

Material and method
This maternal and child health database collected data between 2008 and 2019 in National Birth Reporting Database, National Health Insurance Research Database (NHIRD) and National Death Index Database to conduct retrospective Cohort study. We evaluate children born between 2009 and 2016 with mother diagnosed of sleep disorders or depression during pregnancy or 1 year before pregnancy. Whether BZD or Z-hypnotics drugs use during pregnancy as medication exposure and then follow up the risks of children in birth defect, attention deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).
We measured the crude HR and adjusted HR (aHR), respectively, with a 95% CI for developing birth defect and developmental disorders, using a Cox proportional regression model before and after adjusting for parental and offspring demographic data and medical comorbidities. To estimate the cumulative incidence risk of birth defect and developmental disorders, we conducted a survival analysis using the Kaplan-Meier method, with significance based on the log-rank test.

Results
Compared with the women who were not taking BZD or Z-hypnotics during pregnancy, the risk of birth defect (aHR: 1.11, 95% CI 1.01-1.22) was higher. Exposure to Z-hypnotics has more risk than BZD. Women undergoing BZD or Z-hypnotics treatment in gestation period had mild greater risk of ADHD (cHR: 1.15, 95% CI 1.08-1.23) and ASD (cHR: 1.16, 95% CI 1.00-1.35) but not statistically significant after adjustment. According to the Kaplan-Meier survival analysis, the study cohort had a significantly higher cumulative incidence risk of birth defect(log-rank test, p<0.0001) and ADHD (log-rank test, p=0.0007) as compared with the control cohort

Conclusion
Our study showed BZD and Z-hypnotics drugs using during pregnancy will increase risks of birth defect, especially during first trimester when fetal neural development occurs. Cumulative incidence also showed increasing risk of neurodevelopmental disorder under long term use. If BZD and Z-hypnotics drugs are used to treat sleep disorder during pregnancy, it should be cautious. Low dose use might be considered to eliminate fetal effects.

並列關鍵字

insomnia ； depression ； anxiety ； hypnotics ； benzodiazepines ； Z-hypnotics ； birth defect ； attention deficit/ hyperactivity disorder ； autism spectrum disorder ； ADHD ； ASD

參考文獻

1. National Sleep Foundation. Summary of findings of the 2007 Sleep in America Poll. Available at: http://sleepfoundation.org/media-center/pressrelease/sleep-america-poll-summary-findings

2. Mindell, J. A., Cook, R. A., Nikolovski, J. (2015). Sleep patterns and sleep disturbances across pregnancy. Sleep medicine, 16(4), 483–488.

3. Tomfohr, L. M., Buliga, E., Letourneau, N. L., Campbell, T. S., Giesbrecht, G. F. (2015). Trajectories of Sleep Quality and Associations with Mood during the Perinatal Period. Sleep, 38(8), 1237–1245.

4. Mellor, R., Chua, S. C., Boyce, P. (2014). Antenatal depression: an artefact of sleep disturbance?. Archives of women's mental health, 17(4), 291–302.

5. Skouteris, H., Germano, C., Wertheim, E. H., Paxton, S. J., Milgrom, J. (2008). Sleep quality and depression during pregnancy: a prospective study. Journal of sleep research, 17(2), 217–220.