毒理性
哺乳期使用总结：由于帕罗西汀在母乳中的含量较低，婴儿摄入的量很小，大多数测试的婴儿血清中未检测到帕罗西汀。偶尔会出现轻微的副作用，特别是在母亲在怀孕第三期间服用帕罗西汀的婴儿中，但药物在母乳中的贡献尚不清楚。大多数权威评论员认为，在哺乳期间，帕罗西汀是首选的抗抑郁药。在哺乳的婴儿中，偶尔会出现轻微的副作用，如失眠、不安和哭闹增加。
怀孕和产后期间服用SSRI的母亲可能会发现哺乳更加困难，但这可能是她们疾病状态的反映。这些母亲可能需要额外的哺乳支持。与配方奶喂养的婴儿相比，在怀孕第三期间接触SSRI的哺乳婴儿患有不良新生儿适应的风险较低。
对哺乳婴儿的影响：向澳大利亚不良药物反应咨询委员会报告了一个婴儿（年龄和其他细节未报告）可能出现与母乳中帕罗西汀有关的激动和喂养困难。
在一项对照队列研究中，怀孕期间服用帕罗西汀的母亲（诊断未报告）中有36位在第三孕期服用帕罗西汀并哺乳她们的婴儿。其中，8位报告其婴儿出现副作用，包括警觉（6）、便秘（3）、嗜睡（1）和易怒（1）。在第三孕期或哺乳期间未使用帕罗西汀的控制组母亲中，没有报告副作用。药物通过胎盘和母乳获得的相对贡献无法确定。
在一项研究中，将怀孕期间服用SSRI的母亲（主要诊断为抑郁症）的婴儿与未服用SSRI的抑郁母亲婴儿进行了比较，两组在平均12.9个月的随访中，精神和大多数运动发育都正常。其中4位治疗母亲在哺乳期间平均每天服用帕罗西汀28.6毫克，平均7.8个月（程度未说明）。与对照组相比，心理运动发育略有延迟，但无法确定哺乳对异常发育的贡献。
在一项前瞻性队列研究中，评估了27位母亲在哺乳期间（程度未说明）平均每天服用20.7毫克帕罗西汀至少2周的婴儿。两个对照组包括两组未哺乳也未服用SSRI的母亲。27位母亲中有7位在怀孕的某个时期服用了帕罗西汀。3个月时的体重在帕罗西汀组中较低，但多元分析表明，母亲服用帕罗西汀不是决定因素。6个月和12个月的体重与对照组没有差异，其他发育里程碑在正常时间内达到。一名暴露于帕罗西汀的婴儿（年龄未说明）的母亲报告说婴儿易怒。
15位母亲在产后4周内开始每天服用平均20.4毫克的帕罗西汀治疗抑郁症或焦虑症，她们的婴儿在4个月内专一地哺乳，在5月和6月至少哺乳50%。她们的婴儿在6个月时的体重增长符合国家生长标准，母亲报告她们的婴儿没有异常影响。
在一项研究中，6名哺乳期婴儿（程度未说明）年龄在2至33周之间，他们的母亲每天服用10至30毫克的帕罗西汀，在研究期间未发现临床上的不良反应。
一名服用帕罗西汀的母亲所生的婴儿出生时血清帕罗西汀水平约为母亲的三分之一。婴儿是一个遗传性代谢不良者，这显然是高血清水平的原因。尽管婴儿出现了与宫内获得的帕罗西汀有关的症状，但母亲继续每天服用30毫克帕罗西汀并哺乳（程度未说明）。在4个月大时，婴儿体重正常增长，没有神经学副作用的证据。
一名18个月大的婴儿有2周的呕吐史，被发现患有低钾血症、低氯性碱中毒和轻度脱水。婴儿在2和3个月前曾两次因类似情况入院。血清肾素和醛固酮正常。婴儿的母亲大约1年前开始每天服用40毫克帕罗西汀治疗抑郁症并哺乳婴儿（程度未说明）。在母亲的母乳和婴儿的血清中检测到了帕罗西汀，但未量化。停止哺乳后，婴儿在6周后健康成长，代谢状况正常。作者将婴儿的代谢异常归因于帕罗西汀引起的抗利尿激素分泌不当综合征。这种反应可能是由母乳中的帕罗西汀引起的，但缺乏有力证据，其他可能的原因不能排除。
在一项小规模研究中，比较了抑郁母亲在怀孕期间单独或怀孕和哺乳期间服用SSRI的婴儿对疼痛的反应，以及未接触过药物的非抑郁母亲婴儿的对照组。与对照组婴儿相比，在产前单独或通过母乳在产前和产后接触SSRI的婴儿对疼痛的反应减弱。30名婴儿中有19名接触了帕罗西汀。因为没有抑郁、未用药的母亲对照组，不能排除由母亲的抑郁行为引起的效应。作者强调，这些发现并不支持避免在怀孕期间治疗抑郁症或避免在SSRI治疗期间哺乳。
在一项对哺乳期母亲SSRI抗抑郁药副作用的研究中，3名服用帕罗西汀的母亲的婴儿中没有发现需要医疗
◉ Summary of Use during Lactation:Because of the low levels of paroxetine in breastmilk, amounts ingested by the infant are small and paroxetine has not been detected in the serum of most infants tested. Occasional mild side effects have been reported, especially in the infants of mothers who took paroxetine during the third trimester of pregnancy, but the contribution of the drug in breastmilk is not clear. Most authoritative reviewers consider paroxetine one of the preferred antidepressants during breastfeeding. Occasional mild side effects such as insomnia, restlessness and increased crying have been reported in breastfed infants.
Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding, although this might be a reflection of their disease state. These mothers may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.
◉ Effects in Breastfed Infants:Agitation and difficulty feeding in one infant (age and other details not reported) that were possibly related to paroxetine in breastmilk were reported to the Australian Adverse Drug Reaction Advisory Committee.
In a controlled cohort study of mothers who took paroxetine during pregnancy (diagnoses not reported), 36 mothers took paroxetine during the third trimester and breastfed their infants. Of these, 8 reported side effects in their infants including alertness (6), constipation (3), sleepiness (1), and irritability (1). There were no reports of side effects in the control group of mothers who breastfed and did not use paroxetine in the third trimester or during nursing. The relative contribution of transplacental and breastmilk acquisition of the drug could not be determined.
In a study comparing the infants of mothers who took an SSRI during pregnancy for major depression with the infants of depressed mothers who did not take an SSRI, mental development and most motor development was normal at follow-up averaging 12.9 months in both groups. Four of the treated mothers took paroxetine in doses averaging 28.6 mg daily for an average of 7.8 months while breastfeeding (extent not stated) their infants. Psychomotor development was slightly delayed compared to controls, but the contribution of breastfeeding to abnormal development could not be determined.
A prospective cohort study evaluated 27 infants whose mothers took paroxetine (diagnoses not reported) at an average dose of 20.7 mg daily for at least 2 weeks during breastfeeding (extent not stated). Two control groups consisted of two groups of mothers who neither breastfed nor took an SSRI. All but 7 of the 27 mothers took paroxetine during some part of pregnancy. Weight at 3 months was less in the paroxetine group, but multivariate analysis indicated that maternal paroxetine use was not the determining factor. Weights at 6 and 12 months were not different from the control groups and other developmental milestones were reached at the normal times. One of the paroxetine-exposed infants (age not stated) was reported by the mother to be irritable.
Fifteen mothers who took an average paroxetine dosage of 20.4 mg daily for depression or anxiety starting no later than 4 weeks postpartum, breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and mothers reported no abnormal effects in their infants.
In 6 breastfed (extent not stated) infants aged 2 to 33 weeks whose mothers were taking paroxetine 10 to 30 mg daily, no adverse reactions were noted clinically at the time of the study.
An infant born to a mother taking paroxetine had serum paroxetine levels about one-third that of the mother's at birth. The infant was a genetic poor metabolizer which apparently was the cause of the high serum levels. Although the infant had symptoms attributed to paroxetine obtained in utero, the mother continued taking paroxetine 30 mg daily and breastfeeding (extent not stated). At 4 months of age, the infant had gained weight normally and had no evidence of neurological side effects.
An 18-month-old infant with a 2-week history of vomiting was found to have hypokalemia, hypochloremic alkalosis and mild dehydration. The infant had been admitted twice previously 2 and 3 months before with a similar picture. Serum renin and aldosterone were normal. The infant's mother had been taking paroxetine 40 mg daily for about 1 year for depression and breastfeeding the infant (extent not stated). Paroxetine was detected, but not quantified, in the mother's breastmilk and infant's serum. Breastfeeding was discontinued and the infant was thriving 6 weeks later with a normal metabolic profile. The authors attributed the infant's metabolic abnormalities to paroxetine-induced syndrome of inappropriate secretion of antidiuretic hormone. The reaction was possibly caused by paroxetine in breastmilk, but strong evidence was lacking and other possible causes cannot be ruled out.
A small study compared the reaction to pain in infants of depressed mothers who had taken an SSRI during pregnancy alone or during pregnancy and nursing, to a control group of unexposed infants of nondepressed mothers. Infants exposed to an SSRI either prenatally alone or prenatally and postnatally via breastmilk had blunted responses to pain compared to control infants. Nineteen of the 30 infants were exposed to paroxetine. Because there was no control group of depressed, nonmedicated mothers, an effect due to maternal behavior caused by depression could not be ruled out. The authors stressed that these findings did not warrant avoiding drug treatment of depression during pregnancy or avoiding breastfeeding during SSRI treatment.
One study of side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention among 3 infants whose mother was taking paroxetine. No specific information on maternal paroxetine dosage, extent of breastfeeding or infant age was reported.
A nursing mother with bipolar disorder began taking 20 mg of paroxetine at 4 months postpartum and was then started on quetiapine 200 mg twice daily at 6 months postpartum. She breastfed regularly (extent not stated) and no obvious adverse effects were noted in the infant.
Four nursing mothers who were 6.5 to 18.5 weeks postpartum were taking paroxetine in doses of 12.5 to 60 mg daily in addition to quetiapine for major depression postpartum. Their breastfed infants' development were tested at 9 to 18 months of age with the Bayley Scales. Measurements were slightly low on the mental and psychomotor development scale in one infant and on the mental development scale in another; both infants had undetectable (<9.9 mcg/L) serum paroxetine levels. All other infants had scores that were within normal limits. The authors concluded that the low scores of the two infants were probably not caused by the drugs received by the infants in breastmilk.
An uncontrolled online survey compiled data on 930 mothers who nursed their infants while taking an antidepressant. Infant drug discontinuation symptoms (e.g., irritability, low body temperature, uncontrollable crying, eating and sleeping disorders) were reported in about 10% of infants. Mothers who took antidepressants only during breastfeeding were much less likely to notice symptoms of drug discontinuation in their infants than those who took the drug in pregnancy and lactation.
A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Forty-nine of the infants were exposed to paroxetine in utero.
A retrospective study of 42 nursing mothers who had been seen at a psychiatric outpatient facility, followed for at least 8 weeks, and prescribed paroxetine found that adverse effects were reported in 5 (12%) of their infants. One mother was taking 10 mg daily and 4 mothers were taking 20 mg daily. The most commonly reported adverse events in the infants were insomnia and restlessness; constant crying and poor feeding were less commonly reported. All of the adverse effects developed within the first 2 weeks after initiation of maternal treatment and disappeared within the 3 days after drug discontinuation. Adverse effects disappeared in one infant after reducing the maternal dosage from 20 mg daily to 10 mg daily. There was no difference in prevalence of adverse effects between these infants and those in the same study whose mothers were prescribed sertraline.
A mother who was exclusively breastfeeding a 2-month-old infant began taking paroxetine 20 mg daily for depression. After paroxetine was begun, the mother reported severe constipation in the infant, which resolved within 2 days after discontinuing paroxetine with no treatment. No abnormalities were seen on physical examination or laboratory tests. The infant had previously developed agitation and sleeplessness with maternal sertraline use. The infant subsequently tolerated maternal citalopram use.
Five women were treated with paroxetine 7 to 25 mg daily during the third trimester of pregnancy and during breastfeeding. Pediatric evaluations including neurologic assessments and brain ultrasound were conducted during the first 24 hours postpartum. Further follow-up was conducted at 6 or more months of age. Infant clinical status was comparable to unexposed infants from the same pediatric department.
A case series reported 8 women who received paroxetine 20 mg and mirtazapine 15 mg daily for various psychiatric disorders. The women breastfed (extent not stated) their infants who averaged 4.3 weeks of age. Follow-up of the infants after 3 to 6 weeks when mirtazapine was discontinued found one infant who experienced restlessness after 5 days of therapy according to the mother. Discontinuation of mirtazapine had no effect, but the symptoms disappeared when paroxetine was discontinued. No other infants had other adverse effects observed.
◉ Effects on Lactation and Breastmilk:Paroxetine can cause galactorrhea, usually with increased prolactin levels, in nonpregnant, nonnursing patients. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, paroxetine was found to have a 3.1-fold increased risk of causing hyperprolactinemia compared to other drugs. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior in the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.
A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; paroxetine n = 53) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
来源:Drugs and Lactation Database (LactMed)
