Depressing Observations on the Use of Selective Serotonin-Reuptake Inhibitors during Pregnancy
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《新英格兰医药杂志》
Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition that typically occurs in full-term or near-term infants. Before birth, the fetus receives oxygenated blood from the placenta; a high pulmonary arterial pressure results in low blood flow to the lungs and shunting of the oxygenated blood to the systemic circulation through the foramen ovale and the ductus arteriosus. PPHN occurs when pulmonary arterial pressure remains high after birth and poorly oxygenated blood continues to be shunted to the systemic circulation. In one study involving 155 full-term newborns with moderately severe PPHN, 11 died, and nearly half the survivors had serious sequelae including cognitive delay, major neurologic abnormalities, and hearing loss.1
In this issue of the Journal, Chambers et al. report a significant association between the use of selective serotonin-reuptake inhibitors (SSRIs) after the 20th week of pregnancy and PPHN in the offspring.2 This is the latest in a series of troubling reports of possible adverse effects of SSRIs on the fetus. The Food and Drug Administration (FDA) issued a warning in December 2005 stating that the use of paroxetine during the first trimester of pregnancy was associated with an increased risk of birth defects, particularly cardiac defects, as compared with the use of other SSRIs or no use of antidepressants.3 Health Canada4 has warned that the use of SSRIs and other antidepressants may result in a syndrome known as "poor neonatal adaptation,"5,6 which may include feeding problems, respiratory distress, jitteriness, and seizures.
Using a case–control design, Chambers et al. found that the infants of women who took SSRIs during the second half of pregnancy had five to six times the expected risk of the development of PPHN. PPHN is an uncommon condition (estimated incidence, 2 per 1000 live births),7 so even an increase in the risk by a factor of five or six would not result in a large number of cases. Chambers et al. estimate that PPHN occurs in approximately 1 infant of 100 who are exposed to SSRIs. Determining how many infants are exposed is difficult, because data on SSRI use in pregnancy are scarce; neither I nor an FDA panel8 has been able to find published rates in the United States. In a Swedish population,9 0.097 percent of women reported at the first prenatal visit that they were currently using SSRIs; data were not provided for SSRI use later in pregnancy. Using the Swedish exposure rate as a rough estimate of the U.S. rate, one can calculate that approximately 4000 of the 4 million infants born per year would be exposed. If PPHN were to develop in 1 child per 100 exposed, we would expect to see 40 SSRI-related cases per year. This low number might explain why registries and case series of infants exposed to SSRIs in utero have not identified any cases of PPHN. To my knowledge, the only other report of PPHN occurring in neonates exposed to SSRIs prenatally is from a previous cohort study by Chambers et al.10 A recent review of cohort studies6 showed that only 1 of 313 full-term infants exposed to SSRIs in utero had respiratory problems that were severe enough to require intubation; PPHN was not mentioned, although data from the cohort study by Chambers et al. were included.
How far does the current study by Chambers et al. go toward showing that SSRIs cause PPHN? The authors prudently recommend that other studies be conducted to confirm their findings. It is important to note that the association is very unlikely to be due to chance; the authors tested an a priori hypothesis based on their previous work,10 and the current study was well designed and carefully executed. Do the current findings satisfy the standard criteria for determining causality? The authors found the same association in their previous study, which involved a different design,2,10 providing some evidence for the criterion of consistency across studies, but not sufficient evidence for it. The strength of the association found in the current study, an odds ratio of 5 or 6, is reasonably strong evidence, but it is based on a small number of cases. The number in the previous study was even smaller.
Other criteria for assessing causality are the temporal relationship (the exposure must precede the disease), specificity (one exposure should produce only one disease), and biologic plausibility. The first of these criteria is certainly met. The authors do more than just document that the exposure precedes the disease; they show that exposure after 20 weeks of gestation is critical. The specificity criterion is not met, but it is one of the less useful criteria. It is important to note that studies showing "poor neonatal adaptation" after exposure to SSRIs in utero5,6 provide supporting evidence that SSRIs adversely affect the fetus. What about biologic plausibility? The authors suggest that serotonin may increase pulmonary vascular resistance or disrupt normal pulmonary vasodilation after birth by blocking the action of nitric oxide. These hypotheses require more investigation.
Given the concern regarding SSRI use, how should clinicians manage depression in pregnant women? The literature on the management of depression shows a clear consensus for some issues and a lack of clarity for others. Depression is distressingly common: 10 percent or more of pregnant women have clinical depression, according to standard diagnostic criteria.11 In addition, the relapse rate is high when women stop therapy. Moreover, some evidence suggests that the children of women with untreated depression may have adverse effects ranging from low birth weight to developmental delay.12 Thus, although it is preferable to manage depression in pregnant women without the use of antidepressants when possible, often it is not possible. Medications are necessary in many cases.
For pregnant women who require pharmacologic therapy for depression, it is not clear which drug is optimal. Although SSRIs and other, newer antidepressant drugs with greater margins of safety are generally considered the drugs of choice for nonpregnant adults who have moderate-to-severe depression,13 data are lacking on the best way to manage depression in pregnant women. The Pediatrics Subcommittee of the FDA's Anti-Infective Drugs Advisory Committee has noted the urgent need for studies of the "SSRI/SNRI neonatal withdrawal syndrome" to delineate the risks to the fetus more clearly.8 Health Canada has recently warned against SSRI use during pregnancy, but a recommendation regarding alternative therapy was conspicuously absent.4
There is a pressing need for experts to compare SSRIs with other forms of treatment to determine which are the safest, the most effective, and the best tolerated by pregnant women. Meanwhile, clinicians and patients will need to consider the current findings of Chambers et al., along with other available evidence, and decide on an individual basis whether the risks associated with exposure to SSRIs outweigh the benefits of the therapy.
No potential conflict of interest relevant to this article was reported.
Source Information
From the National Institute of Child Health and Human Development, Bethesda, Md.
References
Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002;140:306-310.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-587.
FDA public health advisory: paroxetine. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, December 2005. (Accessed January 5, 2006, at http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm.)
Health Canada advises of potential serious adverse effects of SSRIs and other antidepressants on newborns . Ottawa: Health Canada, August 2004. (Accessed January 24, 2006, at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2004/2004_44_e.html.)
Hines RN, Adams J, Buck GM, et al. NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine. Birth Defects Res B Dev Reprod Toxicol 2004;71:193-280.
Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293:2372-2383.
Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;105:14-20.
Pediatrics Subcommittee of the Anti-Infective Drugs Advisory Committee. Summary minutes of the Pediatrics Subcommittee of the Anti-Infective Drugs Advisory Committee June 9, 2004. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, June 18, 2004. (Accessed January 19, 2006, at http://www.fda.gov/ohrms/dockets/ac/04/minutes/2004-4050M1.pdf.)
Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 2004;158:312-316.
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-1015.
Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 2004;103:698-709.
Field T. Infants of depressed mothers. Infant Behav Dev 1995;18:1-13.
Mann JJ. The medical management of depression. N Engl J Med 2005;353:1819-1834.(James L. Mills, M.D.)
In this issue of the Journal, Chambers et al. report a significant association between the use of selective serotonin-reuptake inhibitors (SSRIs) after the 20th week of pregnancy and PPHN in the offspring.2 This is the latest in a series of troubling reports of possible adverse effects of SSRIs on the fetus. The Food and Drug Administration (FDA) issued a warning in December 2005 stating that the use of paroxetine during the first trimester of pregnancy was associated with an increased risk of birth defects, particularly cardiac defects, as compared with the use of other SSRIs or no use of antidepressants.3 Health Canada4 has warned that the use of SSRIs and other antidepressants may result in a syndrome known as "poor neonatal adaptation,"5,6 which may include feeding problems, respiratory distress, jitteriness, and seizures.
Using a case–control design, Chambers et al. found that the infants of women who took SSRIs during the second half of pregnancy had five to six times the expected risk of the development of PPHN. PPHN is an uncommon condition (estimated incidence, 2 per 1000 live births),7 so even an increase in the risk by a factor of five or six would not result in a large number of cases. Chambers et al. estimate that PPHN occurs in approximately 1 infant of 100 who are exposed to SSRIs. Determining how many infants are exposed is difficult, because data on SSRI use in pregnancy are scarce; neither I nor an FDA panel8 has been able to find published rates in the United States. In a Swedish population,9 0.097 percent of women reported at the first prenatal visit that they were currently using SSRIs; data were not provided for SSRI use later in pregnancy. Using the Swedish exposure rate as a rough estimate of the U.S. rate, one can calculate that approximately 4000 of the 4 million infants born per year would be exposed. If PPHN were to develop in 1 child per 100 exposed, we would expect to see 40 SSRI-related cases per year. This low number might explain why registries and case series of infants exposed to SSRIs in utero have not identified any cases of PPHN. To my knowledge, the only other report of PPHN occurring in neonates exposed to SSRIs prenatally is from a previous cohort study by Chambers et al.10 A recent review of cohort studies6 showed that only 1 of 313 full-term infants exposed to SSRIs in utero had respiratory problems that were severe enough to require intubation; PPHN was not mentioned, although data from the cohort study by Chambers et al. were included.
How far does the current study by Chambers et al. go toward showing that SSRIs cause PPHN? The authors prudently recommend that other studies be conducted to confirm their findings. It is important to note that the association is very unlikely to be due to chance; the authors tested an a priori hypothesis based on their previous work,10 and the current study was well designed and carefully executed. Do the current findings satisfy the standard criteria for determining causality? The authors found the same association in their previous study, which involved a different design,2,10 providing some evidence for the criterion of consistency across studies, but not sufficient evidence for it. The strength of the association found in the current study, an odds ratio of 5 or 6, is reasonably strong evidence, but it is based on a small number of cases. The number in the previous study was even smaller.
Other criteria for assessing causality are the temporal relationship (the exposure must precede the disease), specificity (one exposure should produce only one disease), and biologic plausibility. The first of these criteria is certainly met. The authors do more than just document that the exposure precedes the disease; they show that exposure after 20 weeks of gestation is critical. The specificity criterion is not met, but it is one of the less useful criteria. It is important to note that studies showing "poor neonatal adaptation" after exposure to SSRIs in utero5,6 provide supporting evidence that SSRIs adversely affect the fetus. What about biologic plausibility? The authors suggest that serotonin may increase pulmonary vascular resistance or disrupt normal pulmonary vasodilation after birth by blocking the action of nitric oxide. These hypotheses require more investigation.
Given the concern regarding SSRI use, how should clinicians manage depression in pregnant women? The literature on the management of depression shows a clear consensus for some issues and a lack of clarity for others. Depression is distressingly common: 10 percent or more of pregnant women have clinical depression, according to standard diagnostic criteria.11 In addition, the relapse rate is high when women stop therapy. Moreover, some evidence suggests that the children of women with untreated depression may have adverse effects ranging from low birth weight to developmental delay.12 Thus, although it is preferable to manage depression in pregnant women without the use of antidepressants when possible, often it is not possible. Medications are necessary in many cases.
For pregnant women who require pharmacologic therapy for depression, it is not clear which drug is optimal. Although SSRIs and other, newer antidepressant drugs with greater margins of safety are generally considered the drugs of choice for nonpregnant adults who have moderate-to-severe depression,13 data are lacking on the best way to manage depression in pregnant women. The Pediatrics Subcommittee of the FDA's Anti-Infective Drugs Advisory Committee has noted the urgent need for studies of the "SSRI/SNRI neonatal withdrawal syndrome" to delineate the risks to the fetus more clearly.8 Health Canada has recently warned against SSRI use during pregnancy, but a recommendation regarding alternative therapy was conspicuously absent.4
There is a pressing need for experts to compare SSRIs with other forms of treatment to determine which are the safest, the most effective, and the best tolerated by pregnant women. Meanwhile, clinicians and patients will need to consider the current findings of Chambers et al., along with other available evidence, and decide on an individual basis whether the risks associated with exposure to SSRIs outweigh the benefits of the therapy.
No potential conflict of interest relevant to this article was reported.
Source Information
From the National Institute of Child Health and Human Development, Bethesda, Md.
References
Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002;140:306-310.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-587.
FDA public health advisory: paroxetine. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, December 2005. (Accessed January 5, 2006, at http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm.)
Health Canada advises of potential serious adverse effects of SSRIs and other antidepressants on newborns . Ottawa: Health Canada, August 2004. (Accessed January 24, 2006, at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2004/2004_44_e.html.)
Hines RN, Adams J, Buck GM, et al. NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine. Birth Defects Res B Dev Reprod Toxicol 2004;71:193-280.
Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293:2372-2383.
Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;105:14-20.
Pediatrics Subcommittee of the Anti-Infective Drugs Advisory Committee. Summary minutes of the Pediatrics Subcommittee of the Anti-Infective Drugs Advisory Committee June 9, 2004. Washington, D.C.: Center for Drug Evaluation and Research, Food and Drug Administration, June 18, 2004. (Accessed January 19, 2006, at http://www.fda.gov/ohrms/dockets/ac/04/minutes/2004-4050M1.pdf.)
Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 2004;158:312-316.
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-1015.
Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 2004;103:698-709.
Field T. Infants of depressed mothers. Infant Behav Dev 1995;18:1-13.
Mann JJ. The medical management of depression. N Engl J Med 2005;353:1819-1834.(James L. Mills, M.D.)