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FDA to Revise Risk Categories
The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety of medications across five risk categories—A, B, C, D and X—usually based on available data when a drug is approved. The proposed system will eliminate the letter categories and instead will include sections on pregnancy and lactation, each with information summarizing risks, clinical considerations, and available data.
The implications of the proposed system with respect to psychiatric medications are significant. In previous columns, I have discussed some of the limitations of the category label system for various psychiatric medications. There are examples of medications with a sparse amount of reproductive safety information that does not indicate an adverse effect, which bear a more favorable category label than other medicines for which very extensive reproductive safety are available, but perhaps where animal safety data suggest some cause for concern. There are also examples where evidence of adverse reproductive effects in animals dosed with toxic amounts of a medicine can trump significant amounts of human data supporting reproductive safety.
A dramatic example of the current system's limitations is lithium, a category D drug because of clear evidence of Ebstein's anomaly associated with first-trimester exposure. Yet the absolute risk of the cardiac anomaly is only 0.05% following first-trimester exposure. Considering the high rate of relapse of bipolar disorder associated with stopping lithium before or during pregnancy, this may be a risk many patients are willing to take, in collaboration with their psychiatrists.
The current system also does not distinguish between relative amounts of data, and typically lumps a class of medications into one category, instead of considering the drugs as individual molecules. All the selective serotonin reuptake inhibitors are labeled category C, yet the amount of reproductive safety data available for the individual SSRIs is highly variable. Moreover, information in the letter category system has been limited to reproductive safety during the first trimester and does not address some of the potential risks of exposure during the second and third trimesters, and peripartum period
Part of the problem is that with few exceptions, industry has failed to embrace a global product safety initiative regarding establishing registries for these products in a systematic way shortly after a drug is marketed.
In May, almost a decade after indicating that the pregnancy and lactation labeling system would be changed, the FDA announced the proposed changes, which address these limitations.
The pregnancy section would include a fetal risk summary, which would describe the risks to the fetus associated with exposure to the medicine based on available data; and clinical considerations, which would include information about the effects of the drug if a woman takes it before she knows she is pregnant and the risks of the disease for the mother and baby. A third section would summarize the available human and animal data that provide the basis of the fetal risk summary. The labor and delivery section in the current drug label would be eliminated, with this information included in the pregnancy section. The section on lactation would include the same sections on risk summary, clinical considerations, and data.
The clinical implications of dropping the letter category system are considerable. These categories have frequently been used to switch patients from one medicine to another somewhat arbitrarily. Even well-intentioned doctors have switched a patient to a medicine based on the category label, when there are less available reproductive safety data in humans, but perhaps animal data were of some concern.
Once the new system is in place, this type of arbitrary change in a patient's medication based on the category label will hopefully cease. Moving from a categorical system of classification to a system that is more inclusive of available reproductive safety information should help providers rather than confuse them. Physicians will be provided with more information in a drug's label that actually describes results of studies and will be able to see firsthand the type of information that is available and the quality of data, as well as references to studies. As a result, we will be provided with a more global risk assessment across pregnancy, including the peripartum period and lactation.
Regardless of the system used, the process of making decisions about the use of any medicine, particularly psychotropics, during pregnancy should be made on a case-by-case basis.
The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety of medications across five risk categories—A, B, C, D and X—usually based on available data when a drug is approved. The proposed system will eliminate the letter categories and instead will include sections on pregnancy and lactation, each with information summarizing risks, clinical considerations, and available data.
The implications of the proposed system with respect to psychiatric medications are significant. In previous columns, I have discussed some of the limitations of the category label system for various psychiatric medications. There are examples of medications with a sparse amount of reproductive safety information that does not indicate an adverse effect, which bear a more favorable category label than other medicines for which very extensive reproductive safety are available, but perhaps where animal safety data suggest some cause for concern. There are also examples where evidence of adverse reproductive effects in animals dosed with toxic amounts of a medicine can trump significant amounts of human data supporting reproductive safety.
A dramatic example of the current system's limitations is lithium, a category D drug because of clear evidence of Ebstein's anomaly associated with first-trimester exposure. Yet the absolute risk of the cardiac anomaly is only 0.05% following first-trimester exposure. Considering the high rate of relapse of bipolar disorder associated with stopping lithium before or during pregnancy, this may be a risk many patients are willing to take, in collaboration with their psychiatrists.
The current system also does not distinguish between relative amounts of data, and typically lumps a class of medications into one category, instead of considering the drugs as individual molecules. All the selective serotonin reuptake inhibitors are labeled category C, yet the amount of reproductive safety data available for the individual SSRIs is highly variable. Moreover, information in the letter category system has been limited to reproductive safety during the first trimester and does not address some of the potential risks of exposure during the second and third trimesters, and peripartum period
Part of the problem is that with few exceptions, industry has failed to embrace a global product safety initiative regarding establishing registries for these products in a systematic way shortly after a drug is marketed.
In May, almost a decade after indicating that the pregnancy and lactation labeling system would be changed, the FDA announced the proposed changes, which address these limitations.
The pregnancy section would include a fetal risk summary, which would describe the risks to the fetus associated with exposure to the medicine based on available data; and clinical considerations, which would include information about the effects of the drug if a woman takes it before she knows she is pregnant and the risks of the disease for the mother and baby. A third section would summarize the available human and animal data that provide the basis of the fetal risk summary. The labor and delivery section in the current drug label would be eliminated, with this information included in the pregnancy section. The section on lactation would include the same sections on risk summary, clinical considerations, and data.
The clinical implications of dropping the letter category system are considerable. These categories have frequently been used to switch patients from one medicine to another somewhat arbitrarily. Even well-intentioned doctors have switched a patient to a medicine based on the category label, when there are less available reproductive safety data in humans, but perhaps animal data were of some concern.
Once the new system is in place, this type of arbitrary change in a patient's medication based on the category label will hopefully cease. Moving from a categorical system of classification to a system that is more inclusive of available reproductive safety information should help providers rather than confuse them. Physicians will be provided with more information in a drug's label that actually describes results of studies and will be able to see firsthand the type of information that is available and the quality of data, as well as references to studies. As a result, we will be provided with a more global risk assessment across pregnancy, including the peripartum period and lactation.
Regardless of the system used, the process of making decisions about the use of any medicine, particularly psychotropics, during pregnancy should be made on a case-by-case basis.
The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety of medications across five risk categories—A, B, C, D and X—usually based on available data when a drug is approved. The proposed system will eliminate the letter categories and instead will include sections on pregnancy and lactation, each with information summarizing risks, clinical considerations, and available data.
The implications of the proposed system with respect to psychiatric medications are significant. In previous columns, I have discussed some of the limitations of the category label system for various psychiatric medications. There are examples of medications with a sparse amount of reproductive safety information that does not indicate an adverse effect, which bear a more favorable category label than other medicines for which very extensive reproductive safety are available, but perhaps where animal safety data suggest some cause for concern. There are also examples where evidence of adverse reproductive effects in animals dosed with toxic amounts of a medicine can trump significant amounts of human data supporting reproductive safety.
A dramatic example of the current system's limitations is lithium, a category D drug because of clear evidence of Ebstein's anomaly associated with first-trimester exposure. Yet the absolute risk of the cardiac anomaly is only 0.05% following first-trimester exposure. Considering the high rate of relapse of bipolar disorder associated with stopping lithium before or during pregnancy, this may be a risk many patients are willing to take, in collaboration with their psychiatrists.
The current system also does not distinguish between relative amounts of data, and typically lumps a class of medications into one category, instead of considering the drugs as individual molecules. All the selective serotonin reuptake inhibitors are labeled category C, yet the amount of reproductive safety data available for the individual SSRIs is highly variable. Moreover, information in the letter category system has been limited to reproductive safety during the first trimester and does not address some of the potential risks of exposure during the second and third trimesters, and peripartum period
Part of the problem is that with few exceptions, industry has failed to embrace a global product safety initiative regarding establishing registries for these products in a systematic way shortly after a drug is marketed.
In May, almost a decade after indicating that the pregnancy and lactation labeling system would be changed, the FDA announced the proposed changes, which address these limitations.
The pregnancy section would include a fetal risk summary, which would describe the risks to the fetus associated with exposure to the medicine based on available data; and clinical considerations, which would include information about the effects of the drug if a woman takes it before she knows she is pregnant and the risks of the disease for the mother and baby. A third section would summarize the available human and animal data that provide the basis of the fetal risk summary. The labor and delivery section in the current drug label would be eliminated, with this information included in the pregnancy section. The section on lactation would include the same sections on risk summary, clinical considerations, and data.
The clinical implications of dropping the letter category system are considerable. These categories have frequently been used to switch patients from one medicine to another somewhat arbitrarily. Even well-intentioned doctors have switched a patient to a medicine based on the category label, when there are less available reproductive safety data in humans, but perhaps animal data were of some concern.
Once the new system is in place, this type of arbitrary change in a patient's medication based on the category label will hopefully cease. Moving from a categorical system of classification to a system that is more inclusive of available reproductive safety information should help providers rather than confuse them. Physicians will be provided with more information in a drug's label that actually describes results of studies and will be able to see firsthand the type of information that is available and the quality of data, as well as references to studies. As a result, we will be provided with a more global risk assessment across pregnancy, including the peripartum period and lactation.
Regardless of the system used, the process of making decisions about the use of any medicine, particularly psychotropics, during pregnancy should be made on a case-by-case basis.
Atypical Antipsychotics
Data on the reproductive safety of certain psychotropics, such as selective serotonin reuptake inhibitors and anti-epileptic drugs, have increased in recent years, but information on the attendant risks of fetal exposure to antipsychotics remains sparse.
This is particularly true for the newer atypical antipsychotics, which are increasingly being used in women of reproductive age for a range of psychiatric disorders.
It is therefore critical that providers and women have solid information on which to base decisions about continuing treatment during pregnancy. Data from large studies support the reproductive safety of the typical antipsychotics such as haloperidol or thiothixene, but reproductive safety data for the atypical antipsychotics are sparse.
To date, few prospective studies on atypicals in pregnant women have been published. In a study comparing pregnancy outcomes in 151 subjects exposed to different atypicals—60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine—with nonexposed controls, major malformation rates were not significantly different between the two groups (J. Clin. Psychiatry 2005;66:444–9). However, that sample was relatively small.
Other available safety data on atypical antipsychotics in pregnant women are derived mainly from case reports or small case series, which have not identified an increased risk for major malformations.
Most of the prospectively identified cases of exposure are to olanzapine (133), risperidone (over 500), and quetiapine (42), with very few to aripiprazole and clozapine, and possibly none to ziprasidone. At a meeting in March, some of the first registry data on atypicals were reported from the Australian Pregnancy Registry: There were no major malformations in 38 pregnancies exposed to atypical antipsychotics.
Association of the atypicals with weight gain, diabetes, and hypertension raises another safety issue about their use in pregnancy as weight gain and adiposity in pregnancy have been linked to higher risk of neural-tube defects, independent of folate status (Am. J. Psychiatry 2002;159:136–7).
As is often the case when considering the use of psychotropics during pregnancy, the specific clinical approach depends on when the patient sees the clinician.
For a patient who presents for evaluation before pregnancy on a low dose of an atypical antipsychotic as an adjunct to a mood stabilizer, it may make sense to switch to an antipsychotic for which more reproductive safety data are available. This may not always be feasible because many patients present when they are already pregnant, and if they are well maintained, the provider may be reluctant to make changes.
Because of the absence of indicting data, we tend to maintain patients on atypical antipsychotics if they are already pregnant because of concerns about clinical destabilization. However, we recommend close follow-up for safety issues such as weight gain, diabetes, and hypertension in pregnancy, in collaboration with the obstetrician. In addition, although there are no robust data clearly distinguishing differences in efficacy, some patients seem to derive particular benefit from an atypical antipsychotic.
Based on the limited data available, there does not appear to be a glaring reproductive safety signal for the atypicals. But given the prevalence of use of these medicines in psychiatry, we clearly need more quality data on this drug class, so that that the atypicals can be safely integrated into the treatment algorithms used during pregnancy to treat women across that spectrum of disease states.
We are establishing an atypical antipsychotic pregnancy registry at Massachusetts General Hospital. We hope that data on atypical antipsychotics will be collected in a timely fashion and will make it possible for women and their physicians to make more informed decisions about use of this class of medicines during pregnancy.
Data on the reproductive safety of certain psychotropics, such as selective serotonin reuptake inhibitors and anti-epileptic drugs, have increased in recent years, but information on the attendant risks of fetal exposure to antipsychotics remains sparse.
This is particularly true for the newer atypical antipsychotics, which are increasingly being used in women of reproductive age for a range of psychiatric disorders.
It is therefore critical that providers and women have solid information on which to base decisions about continuing treatment during pregnancy. Data from large studies support the reproductive safety of the typical antipsychotics such as haloperidol or thiothixene, but reproductive safety data for the atypical antipsychotics are sparse.
To date, few prospective studies on atypicals in pregnant women have been published. In a study comparing pregnancy outcomes in 151 subjects exposed to different atypicals—60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine—with nonexposed controls, major malformation rates were not significantly different between the two groups (J. Clin. Psychiatry 2005;66:444–9). However, that sample was relatively small.
Other available safety data on atypical antipsychotics in pregnant women are derived mainly from case reports or small case series, which have not identified an increased risk for major malformations.
Most of the prospectively identified cases of exposure are to olanzapine (133), risperidone (over 500), and quetiapine (42), with very few to aripiprazole and clozapine, and possibly none to ziprasidone. At a meeting in March, some of the first registry data on atypicals were reported from the Australian Pregnancy Registry: There were no major malformations in 38 pregnancies exposed to atypical antipsychotics.
Association of the atypicals with weight gain, diabetes, and hypertension raises another safety issue about their use in pregnancy as weight gain and adiposity in pregnancy have been linked to higher risk of neural-tube defects, independent of folate status (Am. J. Psychiatry 2002;159:136–7).
As is often the case when considering the use of psychotropics during pregnancy, the specific clinical approach depends on when the patient sees the clinician.
For a patient who presents for evaluation before pregnancy on a low dose of an atypical antipsychotic as an adjunct to a mood stabilizer, it may make sense to switch to an antipsychotic for which more reproductive safety data are available. This may not always be feasible because many patients present when they are already pregnant, and if they are well maintained, the provider may be reluctant to make changes.
Because of the absence of indicting data, we tend to maintain patients on atypical antipsychotics if they are already pregnant because of concerns about clinical destabilization. However, we recommend close follow-up for safety issues such as weight gain, diabetes, and hypertension in pregnancy, in collaboration with the obstetrician. In addition, although there are no robust data clearly distinguishing differences in efficacy, some patients seem to derive particular benefit from an atypical antipsychotic.
Based on the limited data available, there does not appear to be a glaring reproductive safety signal for the atypicals. But given the prevalence of use of these medicines in psychiatry, we clearly need more quality data on this drug class, so that that the atypicals can be safely integrated into the treatment algorithms used during pregnancy to treat women across that spectrum of disease states.
We are establishing an atypical antipsychotic pregnancy registry at Massachusetts General Hospital. We hope that data on atypical antipsychotics will be collected in a timely fashion and will make it possible for women and their physicians to make more informed decisions about use of this class of medicines during pregnancy.
Data on the reproductive safety of certain psychotropics, such as selective serotonin reuptake inhibitors and anti-epileptic drugs, have increased in recent years, but information on the attendant risks of fetal exposure to antipsychotics remains sparse.
This is particularly true for the newer atypical antipsychotics, which are increasingly being used in women of reproductive age for a range of psychiatric disorders.
It is therefore critical that providers and women have solid information on which to base decisions about continuing treatment during pregnancy. Data from large studies support the reproductive safety of the typical antipsychotics such as haloperidol or thiothixene, but reproductive safety data for the atypical antipsychotics are sparse.
To date, few prospective studies on atypicals in pregnant women have been published. In a study comparing pregnancy outcomes in 151 subjects exposed to different atypicals—60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine—with nonexposed controls, major malformation rates were not significantly different between the two groups (J. Clin. Psychiatry 2005;66:444–9). However, that sample was relatively small.
Other available safety data on atypical antipsychotics in pregnant women are derived mainly from case reports or small case series, which have not identified an increased risk for major malformations.
Most of the prospectively identified cases of exposure are to olanzapine (133), risperidone (over 500), and quetiapine (42), with very few to aripiprazole and clozapine, and possibly none to ziprasidone. At a meeting in March, some of the first registry data on atypicals were reported from the Australian Pregnancy Registry: There were no major malformations in 38 pregnancies exposed to atypical antipsychotics.
Association of the atypicals with weight gain, diabetes, and hypertension raises another safety issue about their use in pregnancy as weight gain and adiposity in pregnancy have been linked to higher risk of neural-tube defects, independent of folate status (Am. J. Psychiatry 2002;159:136–7).
As is often the case when considering the use of psychotropics during pregnancy, the specific clinical approach depends on when the patient sees the clinician.
For a patient who presents for evaluation before pregnancy on a low dose of an atypical antipsychotic as an adjunct to a mood stabilizer, it may make sense to switch to an antipsychotic for which more reproductive safety data are available. This may not always be feasible because many patients present when they are already pregnant, and if they are well maintained, the provider may be reluctant to make changes.
Because of the absence of indicting data, we tend to maintain patients on atypical antipsychotics if they are already pregnant because of concerns about clinical destabilization. However, we recommend close follow-up for safety issues such as weight gain, diabetes, and hypertension in pregnancy, in collaboration with the obstetrician. In addition, although there are no robust data clearly distinguishing differences in efficacy, some patients seem to derive particular benefit from an atypical antipsychotic.
Based on the limited data available, there does not appear to be a glaring reproductive safety signal for the atypicals. But given the prevalence of use of these medicines in psychiatry, we clearly need more quality data on this drug class, so that that the atypicals can be safely integrated into the treatment algorithms used during pregnancy to treat women across that spectrum of disease states.
We are establishing an atypical antipsychotic pregnancy registry at Massachusetts General Hospital. We hope that data on atypical antipsychotics will be collected in a timely fashion and will make it possible for women and their physicians to make more informed decisions about use of this class of medicines during pregnancy.
Yet More Reproductive Safety Data on SSRIs
Over the last 5 years, several studies analyzing the reproductive safety of the SSRIs, individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have questioned the safety of SSRIs with respect to teratogenic risk. These case-control studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations had divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0).There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Where do these two important studies leave the patient and the clinician? Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–3). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Clinicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case by case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
In addition, clinicians and patients should consider that, while we have not yet absolutely quantified the risk of prenatal exposure of SSRIs (which might not be achievable), a critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse. In fact, perhaps nothing trumps the importance of sustaining maternal emotional well-being during pregnancy, even given the small absolute risks that may be associated with an individual SSRI during pregnancy.
Over the last 5 years, several studies analyzing the reproductive safety of the SSRIs, individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have questioned the safety of SSRIs with respect to teratogenic risk. These case-control studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations had divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0).There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Where do these two important studies leave the patient and the clinician? Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–3). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Clinicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case by case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
In addition, clinicians and patients should consider that, while we have not yet absolutely quantified the risk of prenatal exposure of SSRIs (which might not be achievable), a critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse. In fact, perhaps nothing trumps the importance of sustaining maternal emotional well-being during pregnancy, even given the small absolute risks that may be associated with an individual SSRI during pregnancy.
Over the last 5 years, several studies analyzing the reproductive safety of the SSRIs, individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have questioned the safety of SSRIs with respect to teratogenic risk. These case-control studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations had divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0).There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Where do these two important studies leave the patient and the clinician? Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–3). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Clinicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case by case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
In addition, clinicians and patients should consider that, while we have not yet absolutely quantified the risk of prenatal exposure of SSRIs (which might not be achievable), a critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse. In fact, perhaps nothing trumps the importance of sustaining maternal emotional well-being during pregnancy, even given the small absolute risks that may be associated with an individual SSRI during pregnancy.
More Safety Data on SSRIs
Over the last 5 years, several studies analyzing the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs), individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the available cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study, which prospectively follows both exposed and unexposed people longitudinally, is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have been published that questioned the safety of SSRIs with respect to teratogenic risk. Case-control studies identify cases of an outcome of interest, such as a certain birth defect, and analyze case and control groups of patients to determine if an association exists between various exposures and the outcome. Such studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use large multicenter birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations produced some divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0). There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–33). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Physicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case-by-case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
A critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse.
Over the last 5 years, several studies analyzing the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs), individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the available cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study, which prospectively follows both exposed and unexposed people longitudinally, is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have been published that questioned the safety of SSRIs with respect to teratogenic risk. Case-control studies identify cases of an outcome of interest, such as a certain birth defect, and analyze case and control groups of patients to determine if an association exists between various exposures and the outcome. Such studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use large multicenter birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations produced some divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0). There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–33). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Physicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case-by-case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
A critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse.
Over the last 5 years, several studies analyzing the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs), individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the available cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study, which prospectively follows both exposed and unexposed people longitudinally, is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have been published that questioned the safety of SSRIs with respect to teratogenic risk. Case-control studies identify cases of an outcome of interest, such as a certain birth defect, and analyze case and control groups of patients to determine if an association exists between various exposures and the outcome. Such studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use large multicenter birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations produced some divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684–92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675–83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0). There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732–33). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
Physicians and patients deciding about treatment during pregnancy will need to continue to make decisions on a case-by-case basis, weighing the risks and benefits using the available, incomplete data on the relative risks of exposure to the medicine or to depression, and the patient's wishes.
A critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse.
Assessment of Prenatal SSRI Use
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, while others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, the so-called “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies that date back to the mid-1970s, when similar concerns were raised regarding prenatal exposure to the older tricyclics. About 25% of children born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. The precise underlying mechanism for this finding has never been well understood.
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%–-compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy. The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, the treatment was inadequate. Only 43% of those who were taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, while others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, the so-called “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies that date back to the mid-1970s, when similar concerns were raised regarding prenatal exposure to the older tricyclics. About 25% of children born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. The precise underlying mechanism for this finding has never been well understood.
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%–-compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy. The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, the treatment was inadequate. Only 43% of those who were taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, while others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, the so-called “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies that date back to the mid-1970s, when similar concerns were raised regarding prenatal exposure to the older tricyclics. About 25% of children born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. The precise underlying mechanism for this finding has never been well understood.
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%–-compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy. The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, the treatment was inadequate. Only 43% of those who were taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
Prenatal Use of SSRIs
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, whereas others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, which is known as “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies dating back to the mid-1970s, when similar concerns were raised with prenatal exposure to the older tricyclics. About 25% of children who are born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. (OB. GYN. NEWS, April 15, 2006, p. 12).
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%—compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy.
The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, treatment was inadequate. Only 43% of those taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression that is untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, whereas others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, which is known as “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies dating back to the mid-1970s, when similar concerns were raised with prenatal exposure to the older tricyclics. About 25% of children who are born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. (OB. GYN. NEWS, April 15, 2006, p. 12).
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%—compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy.
The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, treatment was inadequate. Only 43% of those taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression that is untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
Studies released over the last year have raised a spectrum of concerns regarding the use of antidepressants during pregnancy, whereas others have brought into focus the risk for new onset or relapse of depression during pregnancy and the impact of maternal depression during pregnancy on obstetrical outcome and neonatal well-being. These findings received a considerable amount of attention in the literature and in the media.
Among the concerns raised was the extent to which fetal exposure to one selective serotonin reuptake inhibitor (SSRI)—paroxetine—has been associated with an increased risk for cardiovascular malformations. In other studies, SSRI use during pregnancy was associated with compromised neonatal adaptation with symptoms of jitteriness, tachypnea, and tremulousness, which is known as “neonatal abstinence syndrome.”
This finding of transient neonatal jitteriness and tremulousness has been highly consistent across studies dating back to the mid-1970s, when similar concerns were raised with prenatal exposure to the older tricyclics. About 25% of children who are born to mothers treated with SSRIs, particularly late in pregnancy, appear to have these symptoms.
It is noteworthy, however, that the clinical relevance of the syndrome seems small. Even in the most rigorous study to date, which described a subgroup of children exposed in utero to SSRIs, those who had these symptoms required no particular treatment interventions during the acute neonatal period. (OB. GYN. NEWS, April 15, 2006, p. 12).
Also reported last year was our collaborative study with investigators at the University of California, Los Angeles, and Emory University, Atlanta, demonstrating that the rate of depressive relapse associated with antidepressant discontinuation during pregnancy is high—about 70%—compared with 25% among pregnant women who maintained treatment with these medicines across pregnancy.
These new data on teratogenicity, treatment-emergent neonatal syndromes, and relapse risk have provided more well-delineated information on the risks and benefits of antidepressant use during pregnancy.
The information is extremely important in this setting, because antidepressant use during pregnancy in the United States may be as high as 4%–6%, based on estimates by some of our recent work.
A study published last summer by investigators from the University of Michigan, Ann Arbor, illustrates the fact that while depression is relatively common during pregnancy, most women at risk for illness don't receive any treatment, and, when treatment is prescribed, it is often suboptimal.
In the study, 1,837 pregnant women from five hospital-affiliated obstetrics clinics were screened for depression, 276 of whom were identified as being at risk. Only 20% of the at-risk women were receiving some form of antidepressant treatment. Of the group getting treatment, 48% received a combination of medication and counseling with psychotherapy, 21% received antidepressants only, and 31% received psychotherapy only. Still, in many cases, treatment was inadequate. Only 43% of those taking antidepressants for 6–8 weeks were given the recommended daily dose.
Among the women who met the criteria for major depressive disorder, only 33% received any type of treatment; only 11% received what was reported to be adequate antidepressant therapy (Gen. Hosp. Psychiatry 2006;28:289–95). The low rate of treatment of depression during pregnancy may reflect concerns regarding the effects of antidepressants on the fetus. However, even women in the study who received psychotherapy alone did not receive an adequate intensity of treatment.
One has to wonder whether these findings reflect concerns over the past year about fetal exposure to antidepressants. It is notable that, even when a clinical decision is made to use antidepressant therapy, treatment is incomplete.
Incomplete treatment of depression during pregnancy represents a failure in clinical risk-benefit decision, because the woman and child are exposed to both medication and the adverse effects of the disorder. And clinical depression that is untreated during pregnancy is the strongest predictor of postpartum depression—which can have enduring effects for the patient, her newborn, and her family.
The Michigan study underscores the need for effective strategies to detect and treat women at risk for depression during pregnancy. Sustaining euthymia and maintaining emotional well-being during this period should be our major clinical goals.
ACOG's View on SSRIs
The multiple recent reports regarding the reproductive safety of the selective serotonin reuptake inhibitors have raised concerns about a spectrum of potentially adverse outcomes associated with SSRI use during pregnancy. But these reports have produced conflicting results and have been confusing for many patients and clinicians.
To date, no professional medical association has issued formal guidelines regarding treatment with SSRIs during pregnancy. However, in December, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice published an opinion on this topic, which is noteworthy in its clarity and balanced review of the existing data. The opinion artfully underscores the relevant issues for reproductive-age women who suffer from depression and who are being treated with antidepressants (Obstet. Gynecol. 2006;108:1601–3).
The ACOG committee makes clear there is no specific treatment algorithm for this population, recommending that “treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized” and that decisions about treating depression “should incorporate the clinical expertise of the mental health clinician and obstetrician, and the process should actively engage the patient's values and perceptions when framing the discussion of the risks and benefits of treatment.”
The committee points out that many studies have not identified an increased risk for major congenital malformations associated with SSRI use during pregnancy. This is noteworthy, since more is known about the teratogenic risk of SSRIs than about most medications prescribed to pregnant women, including, as examples, various anti-infectives, antiemetics, and medicines used to treat gastroesophageal reflux.
The ACOG opinion does refer to the recent unpublished reports from a Swedish registry and a U.S. claims database associating first-trimester exposure to paroxetine with a greater risk of atrial and ventricular septal defects. (This prompted the Food and Drug Administration to change paroxetine's pregnancy category label from C to D in late 2005.) Interestingly, the committee does not suggest that paroxetine absolutely is contraindicated during pregnancy, but wisely states that paroxetine should be avoided when planning pregnancy and during pregnancy.
Also referenced in the opinion are reports of syndromes of perinatal toxicity or poor neonatal adaptation associated with SSRI exposure in late pregnancy—transient neonatal symptoms that include jitteriness, mild respiratory distress, weak cry, and neonatal ICU admissions—findings that I have addressed in previous columns. With respect to persistent pulmonary hypertension of the newborn (PPHN), the more serious outcome, the opinion summarizes the case control study that found a sixfold greater risk in PPHN associated with SSRI use after 20 weeks' gestation.
The PPHN finding was the topic of another FDA public health advisory in 2006, which, as the ACOG opinion points out, also addressed the risk of depression relapse. That advisory cites our study, which found relapse was fivefold higher among women who stopped antidepressants during pregnancy than it was among those who continued with treatment.
The opinion then states that “the potential risk of SSRI use throughout pregnancy must be considered in the context of the risk of relapse of depression if maintenance treatment is discontinued” and refers to the increased risks of low weight gain and alcohol and substance abuse that are associated with untreated depression.
The ACOG opinion advises that treatment decisions need to be carefully tailored, and “optimally, shared decision making among obstetric and mental health clinicians and women should occur before pregnancy.” But, it concludes, 50% of pregnancies are unplanned; hence, preconception planning will not always be possible “and decisions regarding treatment with SSRIs will undoubtedly occur during gestation.”
In our experience, we see directly what prompts women to make decisions about SSRI use during pregnancy. These decisions are not necessarily driven by severity or duration of illness, or number of past episodes, but more from their perception of risk and the willingness to accept the risk of depression relapse vs. fetal exposure to medication. Every patient applies her own calculus with respect to the amount of risk she and her partner may be willing to accept.
When it comes to prescribing SSRIs, we need to collaborate with patients on a decision in circumstances in which we have imperfect estimates of risk on both sides of the risk-benefit equation. As in any other clinical situation, we tailor treatment based on the clinical scenarios and patients' wishes.
The multiple recent reports regarding the reproductive safety of the selective serotonin reuptake inhibitors have raised concerns about a spectrum of potentially adverse outcomes associated with SSRI use during pregnancy. But these reports have produced conflicting results and have been confusing for many patients and clinicians.
To date, no professional medical association has issued formal guidelines regarding treatment with SSRIs during pregnancy. However, in December, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice published an opinion on this topic, which is noteworthy in its clarity and balanced review of the existing data. The opinion artfully underscores the relevant issues for reproductive-age women who suffer from depression and who are being treated with antidepressants (Obstet. Gynecol. 2006;108:1601–3).
The ACOG committee makes clear there is no specific treatment algorithm for this population, recommending that “treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized” and that decisions about treating depression “should incorporate the clinical expertise of the mental health clinician and obstetrician, and the process should actively engage the patient's values and perceptions when framing the discussion of the risks and benefits of treatment.”
The committee points out that many studies have not identified an increased risk for major congenital malformations associated with SSRI use during pregnancy. This is noteworthy, since more is known about the teratogenic risk of SSRIs than about most medications prescribed to pregnant women, including, as examples, various anti-infectives, antiemetics, and medicines used to treat gastroesophageal reflux.
The ACOG opinion does refer to the recent unpublished reports from a Swedish registry and a U.S. claims database associating first-trimester exposure to paroxetine with a greater risk of atrial and ventricular septal defects. (This prompted the Food and Drug Administration to change paroxetine's pregnancy category label from C to D in late 2005.) Interestingly, the committee does not suggest that paroxetine absolutely is contraindicated during pregnancy, but wisely states that paroxetine should be avoided when planning pregnancy and during pregnancy.
Also referenced in the opinion are reports of syndromes of perinatal toxicity or poor neonatal adaptation associated with SSRI exposure in late pregnancy—transient neonatal symptoms that include jitteriness, mild respiratory distress, weak cry, and neonatal ICU admissions—findings that I have addressed in previous columns. With respect to persistent pulmonary hypertension of the newborn (PPHN), the more serious outcome, the opinion summarizes the case control study that found a sixfold greater risk in PPHN associated with SSRI use after 20 weeks' gestation.
The PPHN finding was the topic of another FDA public health advisory in 2006, which, as the ACOG opinion points out, also addressed the risk of depression relapse. That advisory cites our study, which found relapse was fivefold higher among women who stopped antidepressants during pregnancy than it was among those who continued with treatment.
The opinion then states that “the potential risk of SSRI use throughout pregnancy must be considered in the context of the risk of relapse of depression if maintenance treatment is discontinued” and refers to the increased risks of low weight gain and alcohol and substance abuse that are associated with untreated depression.
The ACOG opinion advises that treatment decisions need to be carefully tailored, and “optimally, shared decision making among obstetric and mental health clinicians and women should occur before pregnancy.” But, it concludes, 50% of pregnancies are unplanned; hence, preconception planning will not always be possible “and decisions regarding treatment with SSRIs will undoubtedly occur during gestation.”
In our experience, we see directly what prompts women to make decisions about SSRI use during pregnancy. These decisions are not necessarily driven by severity or duration of illness, or number of past episodes, but more from their perception of risk and the willingness to accept the risk of depression relapse vs. fetal exposure to medication. Every patient applies her own calculus with respect to the amount of risk she and her partner may be willing to accept.
When it comes to prescribing SSRIs, we need to collaborate with patients on a decision in circumstances in which we have imperfect estimates of risk on both sides of the risk-benefit equation. As in any other clinical situation, we tailor treatment based on the clinical scenarios and patients' wishes.
The multiple recent reports regarding the reproductive safety of the selective serotonin reuptake inhibitors have raised concerns about a spectrum of potentially adverse outcomes associated with SSRI use during pregnancy. But these reports have produced conflicting results and have been confusing for many patients and clinicians.
To date, no professional medical association has issued formal guidelines regarding treatment with SSRIs during pregnancy. However, in December, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice published an opinion on this topic, which is noteworthy in its clarity and balanced review of the existing data. The opinion artfully underscores the relevant issues for reproductive-age women who suffer from depression and who are being treated with antidepressants (Obstet. Gynecol. 2006;108:1601–3).
The ACOG committee makes clear there is no specific treatment algorithm for this population, recommending that “treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized” and that decisions about treating depression “should incorporate the clinical expertise of the mental health clinician and obstetrician, and the process should actively engage the patient's values and perceptions when framing the discussion of the risks and benefits of treatment.”
The committee points out that many studies have not identified an increased risk for major congenital malformations associated with SSRI use during pregnancy. This is noteworthy, since more is known about the teratogenic risk of SSRIs than about most medications prescribed to pregnant women, including, as examples, various anti-infectives, antiemetics, and medicines used to treat gastroesophageal reflux.
The ACOG opinion does refer to the recent unpublished reports from a Swedish registry and a U.S. claims database associating first-trimester exposure to paroxetine with a greater risk of atrial and ventricular septal defects. (This prompted the Food and Drug Administration to change paroxetine's pregnancy category label from C to D in late 2005.) Interestingly, the committee does not suggest that paroxetine absolutely is contraindicated during pregnancy, but wisely states that paroxetine should be avoided when planning pregnancy and during pregnancy.
Also referenced in the opinion are reports of syndromes of perinatal toxicity or poor neonatal adaptation associated with SSRI exposure in late pregnancy—transient neonatal symptoms that include jitteriness, mild respiratory distress, weak cry, and neonatal ICU admissions—findings that I have addressed in previous columns. With respect to persistent pulmonary hypertension of the newborn (PPHN), the more serious outcome, the opinion summarizes the case control study that found a sixfold greater risk in PPHN associated with SSRI use after 20 weeks' gestation.
The PPHN finding was the topic of another FDA public health advisory in 2006, which, as the ACOG opinion points out, also addressed the risk of depression relapse. That advisory cites our study, which found relapse was fivefold higher among women who stopped antidepressants during pregnancy than it was among those who continued with treatment.
The opinion then states that “the potential risk of SSRI use throughout pregnancy must be considered in the context of the risk of relapse of depression if maintenance treatment is discontinued” and refers to the increased risks of low weight gain and alcohol and substance abuse that are associated with untreated depression.
The ACOG opinion advises that treatment decisions need to be carefully tailored, and “optimally, shared decision making among obstetric and mental health clinicians and women should occur before pregnancy.” But, it concludes, 50% of pregnancies are unplanned; hence, preconception planning will not always be possible “and decisions regarding treatment with SSRIs will undoubtedly occur during gestation.”
In our experience, we see directly what prompts women to make decisions about SSRI use during pregnancy. These decisions are not necessarily driven by severity or duration of illness, or number of past episodes, but more from their perception of risk and the willingness to accept the risk of depression relapse vs. fetal exposure to medication. Every patient applies her own calculus with respect to the amount of risk she and her partner may be willing to accept.
When it comes to prescribing SSRIs, we need to collaborate with patients on a decision in circumstances in which we have imperfect estimates of risk on both sides of the risk-benefit equation. As in any other clinical situation, we tailor treatment based on the clinical scenarios and patients' wishes.
Emerging Data on Prenatal Exposure to SSRIs
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies. Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported in recent years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. Physicians need to discuss these relative risks with patients, making the best clinical decision possible based on the individual clinical situation.
Until recently, few studies have tried to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women with depression.
But a study published in August by researchers at the University of British Columbia, Vancouver, using population-based health data and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the researchers sought to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress in infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. The findings suggest that the effect on respiratory distress may be due to SSRI exposure, not maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and these effects may be additive. Confirming this finding may be possible only with a prospective study that more accurately assesses maternal diagnosis and severity over time, and where medication exposure is confirmed prospectively.
In considering the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies. Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported in recent years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. Physicians need to discuss these relative risks with patients, making the best clinical decision possible based on the individual clinical situation.
Until recently, few studies have tried to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women with depression.
But a study published in August by researchers at the University of British Columbia, Vancouver, using population-based health data and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the researchers sought to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress in infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. The findings suggest that the effect on respiratory distress may be due to SSRI exposure, not maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and these effects may be additive. Confirming this finding may be possible only with a prospective study that more accurately assesses maternal diagnosis and severity over time, and where medication exposure is confirmed prospectively.
In considering the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies. Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported in recent years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. Physicians need to discuss these relative risks with patients, making the best clinical decision possible based on the individual clinical situation.
Until recently, few studies have tried to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women with depression.
But a study published in August by researchers at the University of British Columbia, Vancouver, using population-based health data and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the researchers sought to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress in infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. The findings suggest that the effect on respiratory distress may be due to SSRI exposure, not maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and these effects may be additive. Confirming this finding may be possible only with a prospective study that more accurately assesses maternal diagnosis and severity over time, and where medication exposure is confirmed prospectively.
In considering the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.
Lamotrigine and Oral Clefts
Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.
The use of lithium in the first trimester is associated with a 0.05%-0.1% risk for Ebstein's anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%-10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.
As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5–7 years.
And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.
In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral cleft.
The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of about 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.
So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?
Although stopping medication for the first trimester may appear to be an option for patients with bipolar disorder, unfortunately, a significant proportion of bipolar patients who do so will relapse.
Pregnancy does not appear to protect women with bipolar disorder against relapse if the mood stabilizer they are using is discontinued: In both a retrospective and prospective study, approximately 50% of patients relapsed during the first 6 months of pregnancy following discontinuation of mood stabilizer. It is also noteworthy that women with bipolar disorder are already at a fivefold increased risk for postpartum depression, compared with the general population, a risk that increases further if they relapse during pregnancy.
Therefore, many women with bipolar disorder who want to conceive are caught between a rock and a hard place, because many compounds used to treat bipolar disorder are either known teratogens, or are agents for which the available reproductive safety data are extremely sparse, such as the atypical antipsychotics, i.e., olanzapine (Zyprexa), risperidone (Ripserdal), quetiapine (Seroquel), and aripiprazole (Abilify).
Clinicians need to work collaboratively with patients to make treatment decisions, making every effort to minimize risk of relapse and fetal risk, realizing that some patients may have to assume some risk if they are to sustain affective well-being during pregnancy. For women who are on lamotrigine and are planning to conceive, the patients and prescribing clinician should now discuss the increased risk for oral clefts.
Patients who require treatment with a mood stabilizer, particularly those with recurrent disease, may consider a trial of lithium, which, while a teratogen, is associated with an extremely small risk for a cardiovascular malformation.
Certainly, the risk associated with lamotrigine is dramatically more modest than the risk associated with first-trimester exposure to sodium valproate, and many patients may elect to continue lamotrigine.
Although it may seem intuitive to consider one of the atypical antipsychotics as an alternative to lamotrigine or lithium, given their efficacy in bipolar illness, the total absence of systematically derived data regarding the reproductive safety of atypicals makes them a less attractive alternative, and frankly the last resort, as compared with medications with known reproductive safety data.
When drug choice during pregnancy is considered, proceeding with a drug with known small risks as opposed to one with totally unknown risks is advantageous, particularly if the known risk is a modest one, which is the case with lamotrigine and lithium.
Ultimately, the clinician is left having to make decisions on a case-by-case basis, in collaboration with the patient, realizing that no decision is absolutely risk-free. But decisions can be made that minimize morbidity associated with recurrence of bipolar illness, as well as prenatal exposure to any potentially harmful compound.
When presented with the options, women may make very different decisions. Some women in fact may decide to assume a small risk of oral cleft over a 0.05% risk for a heart malformation because they feel that oral clefts can be repaired more easily, while the morbidity and mortality of Ebstein's anomaly is high, even though the risk is exceedingly small. That is why these decisions have to be made individually, because such decisions will be made not based on relative risk or even absolute risk but rather on each patient's perception of risk.
Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.
The use of lithium in the first trimester is associated with a 0.05%-0.1% risk for Ebstein's anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%-10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.
As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5–7 years.
And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.
In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral cleft.
The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of about 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.
So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?
Although stopping medication for the first trimester may appear to be an option for patients with bipolar disorder, unfortunately, a significant proportion of bipolar patients who do so will relapse.
Pregnancy does not appear to protect women with bipolar disorder against relapse if the mood stabilizer they are using is discontinued: In both a retrospective and prospective study, approximately 50% of patients relapsed during the first 6 months of pregnancy following discontinuation of mood stabilizer. It is also noteworthy that women with bipolar disorder are already at a fivefold increased risk for postpartum depression, compared with the general population, a risk that increases further if they relapse during pregnancy.
Therefore, many women with bipolar disorder who want to conceive are caught between a rock and a hard place, because many compounds used to treat bipolar disorder are either known teratogens, or are agents for which the available reproductive safety data are extremely sparse, such as the atypical antipsychotics, i.e., olanzapine (Zyprexa), risperidone (Ripserdal), quetiapine (Seroquel), and aripiprazole (Abilify).
Clinicians need to work collaboratively with patients to make treatment decisions, making every effort to minimize risk of relapse and fetal risk, realizing that some patients may have to assume some risk if they are to sustain affective well-being during pregnancy. For women who are on lamotrigine and are planning to conceive, the patients and prescribing clinician should now discuss the increased risk for oral clefts.
Patients who require treatment with a mood stabilizer, particularly those with recurrent disease, may consider a trial of lithium, which, while a teratogen, is associated with an extremely small risk for a cardiovascular malformation.
Certainly, the risk associated with lamotrigine is dramatically more modest than the risk associated with first-trimester exposure to sodium valproate, and many patients may elect to continue lamotrigine.
Although it may seem intuitive to consider one of the atypical antipsychotics as an alternative to lamotrigine or lithium, given their efficacy in bipolar illness, the total absence of systematically derived data regarding the reproductive safety of atypicals makes them a less attractive alternative, and frankly the last resort, as compared with medications with known reproductive safety data.
When drug choice during pregnancy is considered, proceeding with a drug with known small risks as opposed to one with totally unknown risks is advantageous, particularly if the known risk is a modest one, which is the case with lamotrigine and lithium.
Ultimately, the clinician is left having to make decisions on a case-by-case basis, in collaboration with the patient, realizing that no decision is absolutely risk-free. But decisions can be made that minimize morbidity associated with recurrence of bipolar illness, as well as prenatal exposure to any potentially harmful compound.
When presented with the options, women may make very different decisions. Some women in fact may decide to assume a small risk of oral cleft over a 0.05% risk for a heart malformation because they feel that oral clefts can be repaired more easily, while the morbidity and mortality of Ebstein's anomaly is high, even though the risk is exceedingly small. That is why these decisions have to be made individually, because such decisions will be made not based on relative risk or even absolute risk but rather on each patient's perception of risk.
Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.
The use of lithium in the first trimester is associated with a 0.05%-0.1% risk for Ebstein's anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%-10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.
As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5–7 years.
And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.
In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral cleft.
The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of about 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.
So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?
Although stopping medication for the first trimester may appear to be an option for patients with bipolar disorder, unfortunately, a significant proportion of bipolar patients who do so will relapse.
Pregnancy does not appear to protect women with bipolar disorder against relapse if the mood stabilizer they are using is discontinued: In both a retrospective and prospective study, approximately 50% of patients relapsed during the first 6 months of pregnancy following discontinuation of mood stabilizer. It is also noteworthy that women with bipolar disorder are already at a fivefold increased risk for postpartum depression, compared with the general population, a risk that increases further if they relapse during pregnancy.
Therefore, many women with bipolar disorder who want to conceive are caught between a rock and a hard place, because many compounds used to treat bipolar disorder are either known teratogens, or are agents for which the available reproductive safety data are extremely sparse, such as the atypical antipsychotics, i.e., olanzapine (Zyprexa), risperidone (Ripserdal), quetiapine (Seroquel), and aripiprazole (Abilify).
Clinicians need to work collaboratively with patients to make treatment decisions, making every effort to minimize risk of relapse and fetal risk, realizing that some patients may have to assume some risk if they are to sustain affective well-being during pregnancy. For women who are on lamotrigine and are planning to conceive, the patients and prescribing clinician should now discuss the increased risk for oral clefts.
Patients who require treatment with a mood stabilizer, particularly those with recurrent disease, may consider a trial of lithium, which, while a teratogen, is associated with an extremely small risk for a cardiovascular malformation.
Certainly, the risk associated with lamotrigine is dramatically more modest than the risk associated with first-trimester exposure to sodium valproate, and many patients may elect to continue lamotrigine.
Although it may seem intuitive to consider one of the atypical antipsychotics as an alternative to lamotrigine or lithium, given their efficacy in bipolar illness, the total absence of systematically derived data regarding the reproductive safety of atypicals makes them a less attractive alternative, and frankly the last resort, as compared with medications with known reproductive safety data.
When drug choice during pregnancy is considered, proceeding with a drug with known small risks as opposed to one with totally unknown risks is advantageous, particularly if the known risk is a modest one, which is the case with lamotrigine and lithium.
Ultimately, the clinician is left having to make decisions on a case-by-case basis, in collaboration with the patient, realizing that no decision is absolutely risk-free. But decisions can be made that minimize morbidity associated with recurrence of bipolar illness, as well as prenatal exposure to any potentially harmful compound.
When presented with the options, women may make very different decisions. Some women in fact may decide to assume a small risk of oral cleft over a 0.05% risk for a heart malformation because they feel that oral clefts can be repaired more easily, while the morbidity and mortality of Ebstein's anomaly is high, even though the risk is exceedingly small. That is why these decisions have to be made individually, because such decisions will be made not based on relative risk or even absolute risk but rather on each patient's perception of risk.
Accumulating Data on Prenatal Exposure to SSRIs
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies (FAMILY PRACTICE NEWS, February 1, May 1, 2006). Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported over the last few years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. These are relative risks that physicians need to discuss with patients, making the best clinical decision possible based on the patient's individual clinical situation.
Until recently, few studies have attempted to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women suffering from depression.
However, a study published in August by investigators at the University of British Columbia, Vancouver, using population-based health data in British Columbia and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the investigators attempted to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress among infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. These findings suggest that the effect on respiratory distress may be due to SSRI exposure, rather than maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and that these effects may be additive. Confirming this finding may only be possible with a prospective study that more accurately assesses maternal diagnosis and severity over time and where medication exposure is confirmed prospectively.
During consideration of the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience with this population suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies (FAMILY PRACTICE NEWS, February 1, May 1, 2006). Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported over the last few years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. These are relative risks that physicians need to discuss with patients, making the best clinical decision possible based on the patient's individual clinical situation.
Until recently, few studies have attempted to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women suffering from depression.
However, a study published in August by investigators at the University of British Columbia, Vancouver, using population-based health data in British Columbia and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the investigators attempted to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress among infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. These findings suggest that the effect on respiratory distress may be due to SSRI exposure, rather than maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and that these effects may be additive. Confirming this finding may only be possible with a prospective study that more accurately assesses maternal diagnosis and severity over time and where medication exposure is confirmed prospectively.
During consideration of the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience with this population suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.
Over the last year, several studies on possible neonatal effects of prenatal exposure to SSRIs have been reviewed in this column. These studies have raised concerns about potential risks, including congenital malformations—as may be the case with paroxetine (associated with a putative increased risk for cardiovascular malformations, prompting a change in the pregnancy risk category label from C to D)—and perinatal distress and pulmonary complications, as noted in two recent studies (FAMILY PRACTICE NEWS, February 1, May 1, 2006). Other studies discussed here have highlighted the high risk of depressive relapse associated with discontinuation of antidepressants during pregnancy.
These and further studies reported over the last few years reflect the heightened interest in perinatal psychopharmacology and have provided a more refined scientific focus on the relative risks of prenatal SSRI exposure vs. the potential risks of untreated mood disorder during pregnancy. These are relative risks that physicians need to discuss with patients, making the best clinical decision possible based on the patient's individual clinical situation.
Until recently, few studies have attempted to parse out the neonatal effects of untreated depression and prenatal SSRI exposure. Most of the available data have been in women treated with an SSRI for underlying depression, and have not included a comparison group of unmedicated women suffering from depression.
However, a study published in August by investigators at the University of British Columbia, Vancouver, using population-based health data in British Columbia and linking records of neonatal birth outcomes with hospital records of psychiatric diagnoses at maternal discharge and prenatal SSRI prescriptions, provides an opportunity to tease apart these two potentially important predictors of neonatal outcomes (Arch. Gen. Psychiatry 2006;63:898–906).
The study compared outcomes of babies born to women diagnosed with depression and treated with an SSRI to outcomes of babies born to women diagnosed with depression who were not treated with medication, and to a control group of babies whose mothers were neither depressed nor on antidepressant medication, between 1998 and 2001.
Among babies exposed to SSRIs, birth weights were lower, hospital stays were longer, and gestational ages were shorter, compared with babies in the control group. A similar pattern was seen when the SSRI-exposed babies were compared with those of depressed mothers who were not treated, except for birth weight for gestational age. In addition, significantly more of the infants of medicated women had respiratory distress and jaundice, compared with babies in the other two groups. Feeding problems were significantly more common among SSRI-exposed infants than among infants of unmedicated women with depression. The rate of convulsions was not significantly different between the groups.
Using propensity scores to match severity of depression in untreated and treated women, the investigators attempted to match women by degree of depression in the year before and during pregnancy, essentially controlling for illness severity while looking at neonatal outcomes. When they compared birth outcomes in these two groups, the associations between prenatal SSRI exposure and feeding problems and jaundice were no longer present. What remained significant was a greater rate of respiratory distress among infants of SSRI-treated mothers and the incidence of birth weight below the 10th percentile. These findings suggest that the effect on respiratory distress may be due to SSRI exposure, rather than maternal depression.
The authors appropriately acknowledge the limitations of using claims data and discharge diagnoses as proxies for real diagnostic assessments. They also note that alcohol or illicit drug use, smoking, or socioeconomic conditions beyond income—all of which can affect neonatal well-being—could not be ascertained. Not factored into the study is another critical issue, the risk of postpartum depression, which is strongly associated with depression during pregnancy. In many respects, postpartum depression may have more enduring long-term outcome than other types of fetal exposures. Also unknown is the nature of respiratory distress, and whether it persisted. In one recent study, for example, symptoms of a “neonatal abstinence syndrome” were transient and did not require clinical intervention (Arch. Pediatr. Adolesc. Med. 2006;16:173–6).
The conclusion from the Canadian study, considering its limitations, is that there may be an independent effect of maternal depression on neonatal outcome and an independent effect of medication exposure, and that these effects may be additive. Confirming this finding may only be possible with a prospective study that more accurately assesses maternal diagnosis and severity over time and where medication exposure is confirmed prospectively.
During consideration of the increasing amount of data on both sides of this relative risk equation, it is critical for clinicians to discuss with patients the range of issues, from the potential neonatal effects of these medicines, to the high risk for relapse when antidepressants are discontinued, to the impact of untreated illness on the baby and mother.
Our own research and clinical experience with this population suggest that patients presented with the same information, including women with extremely similar clinical illness histories, will make very different decisions about medication use during pregnancy. So, there is our task: to present this information and to let patients make decisions consistent with their wishes. With the backdrop of continually evolving data, patient decisions will also evolve, decisions not driven by the clinician, but by collaboration between the clinician and patient.