Weighing New Evidence on SSRI Use

www.womensmentalhealth.org

Until fairly recently, studies and reviews of global teratovigilance data have been relatively reassuring that SSRIs were particularly safe, especially with regard to their teratogenicity. In fact, there are more reproductive safety data available for SSRIs than for many medicines women take during pregnancy. But new reports have raised concerns about the teratogenicity of paroxetine, which we have previously discussed (FAMILY PRACTICE NEWS, Nov. 1, 2005, p. 41), as well as risk for putative neonatal distress syndromes and, most recently, possible increased rates of persistent pulmonary hypertension of the newborn (PPHN) following late-pregnancy exposure to SSRIs.

What do the new reports describe and how do the findings inform clinical care? One study supports previous reports of a “neonatal abstinence syndrome” with characteristic symptoms of jitteriness, sleep disturbance, dysregulation, tachypnea, and myoclonus in infants whose mothers used antidepressants during pregnancy. In this prospective cohort study of 120 infants, examiners used a systematic scale to assess full-term SSRI-exposed newborns with respect to the presence or absence of a wide range of previously reported symptoms.

Of the 60 infants exposed in utero to various SSRIs for a mean of 35.5 weeks, 8 had severe symptoms and 10 had mild symptoms, compared with none of the 60 infants who had not been exposed in utero to these drugs (Arch. Pediatr. Adolesc. Med. 2006;160:173–6). A particularly noteworthy finding is that no infant with symptoms required treatment intervention; symptoms were transient and of little if any clinical significance.

In the second study, investigators using a case-control design described an elevated risk for PPHN, a far more serious syndrome associated with severe respiratory failure, in newborns with in utero exposure to SSRIs late in pregnancy. In this study, which enrolled almost 400 women whose infants had PPHN, matching them to more than 800 control mothers and infants, the use of SSRIs at any point during pregnancy was not associated with PPHN, but there was a significant association between PPHN and in utero exposure to an SSRI after 20 weeks' gestation (N. Engl. J. Med. 2006;354:579–87).

The study describes a very disturbing and striking finding. But an accompanying editorial points out that the number of cases reported is small (N. Engl. J. Med. 2006;354:636–8). And though not mentioned in the editorial, the vulnerability to reporting bias in such a study is great. One wonders whether women without an adverse outcome may be reluctant to disclose use of an antidepressant during pregnancy, compared with those with an adverse outcome as serious as PPHN. Because the conclusions are based on a small number of PPHN cases, a difference of a small number of cases in either direction can strengthen or attenuate a positive finding.

The authors of the second study suggest that the incidence of PPHN associated with SSRI exposure in late pregnancy approaches 1%. However, given the hundreds of women who have used SSRIs during late pregnancy, it is unlikely such a dramatic clinical finding would not have been reported, even anecdotally, before this study—the first of such reports.

These studies, which have had considerable media attention, have alarmed women who are taking antidepressants. In fact, they were published just weeks after we reported the results of a prospective study of 201 women with a history of major depression who were prospectively followed during pregnancy. Women who discontinued their antidepressant medication proximate to conception were at a fivefold greater risk for depressive relapse during pregnancy, compared with those who continued with an antidepressant (JAMA 2006;295:499–507). These data certainly suggest pregnancy is not protective with respect to depression and many women who stop antidepressants will relapse during pregnancy.

Although some women will still stop antidepressant therapy during pregnancy, patients should be informed that depression during pregnancy can increase the risk for other neonatal complications and substantially increase the risk for postpartum depression. Other women will choose to continue antidepressant use during pregnancy, regardless of the findings of these more recent studies, given what for some patients will be viewed as a modest risk for the neonatal outcomes described. Regardless of individual choices, which can vary greatly, it is crucial to present all available information to reproductive-age women on antidepressants who plan to conceive or who are pregnant, so collaborative decisions can be made based on the data and personal wishes. No decision is perfect or risk free. Women provided with the same information may make very different decisions.

www.womensmentalhealth.org

Until fairly recently, studies and reviews of global teratovigilance data have been relatively reassuring that SSRIs were particularly safe, especially with regard to their teratogenicity. In fact, there are more reproductive safety data available for SSRIs than for many medicines women take during pregnancy. But new reports have raised concerns about the teratogenicity of paroxetine, which we have previously discussed (FAMILY PRACTICE NEWS, Nov. 1, 2005, p. 41), as well as risk for putative neonatal distress syndromes and, most recently, possible increased rates of persistent pulmonary hypertension of the newborn (PPHN) following late-pregnancy exposure to SSRIs.

What do the new reports describe and how do the findings inform clinical care? One study supports previous reports of a “neonatal abstinence syndrome” with characteristic symptoms of jitteriness, sleep disturbance, dysregulation, tachypnea, and myoclonus in infants whose mothers used antidepressants during pregnancy. In this prospective cohort study of 120 infants, examiners used a systematic scale to assess full-term SSRI-exposed newborns with respect to the presence or absence of a wide range of previously reported symptoms.

Of the 60 infants exposed in utero to various SSRIs for a mean of 35.5 weeks, 8 had severe symptoms and 10 had mild symptoms, compared with none of the 60 infants who had not been exposed in utero to these drugs (Arch. Pediatr. Adolesc. Med. 2006;160:173–6). A particularly noteworthy finding is that no infant with symptoms required treatment intervention; symptoms were transient and of little if any clinical significance.

In the second study, investigators using a case-control design described an elevated risk for PPHN, a far more serious syndrome associated with severe respiratory failure, in newborns with in utero exposure to SSRIs late in pregnancy. In this study, which enrolled almost 400 women whose infants had PPHN, matching them to more than 800 control mothers and infants, the use of SSRIs at any point during pregnancy was not associated with PPHN, but there was a significant association between PPHN and in utero exposure to an SSRI after 20 weeks' gestation (N. Engl. J. Med. 2006;354:579–87).

The study describes a very disturbing and striking finding. But an accompanying editorial points out that the number of cases reported is small (N. Engl. J. Med. 2006;354:636–8). And though not mentioned in the editorial, the vulnerability to reporting bias in such a study is great. One wonders whether women without an adverse outcome may be reluctant to disclose use of an antidepressant during pregnancy, compared with those with an adverse outcome as serious as PPHN. Because the conclusions are based on a small number of PPHN cases, a difference of a small number of cases in either direction can strengthen or attenuate a positive finding.

The authors of the second study suggest that the incidence of PPHN associated with SSRI exposure in late pregnancy approaches 1%. However, given the hundreds of women who have used SSRIs during late pregnancy, it is unlikely such a dramatic clinical finding would not have been reported, even anecdotally, before this study—the first of such reports.

These studies, which have had considerable media attention, have alarmed women who are taking antidepressants. In fact, they were published just weeks after we reported the results of a prospective study of 201 women with a history of major depression who were prospectively followed during pregnancy. Women who discontinued their antidepressant medication proximate to conception were at a fivefold greater risk for depressive relapse during pregnancy, compared with those who continued with an antidepressant (JAMA 2006;295:499–507). These data certainly suggest pregnancy is not protective with respect to depression and many women who stop antidepressants will relapse during pregnancy.

Although some women will still stop antidepressant therapy during pregnancy, patients should be informed that depression during pregnancy can increase the risk for other neonatal complications and substantially increase the risk for postpartum depression. Other women will choose to continue antidepressant use during pregnancy, regardless of the findings of these more recent studies, given what for some patients will be viewed as a modest risk for the neonatal outcomes described. Regardless of individual choices, which can vary greatly, it is crucial to present all available information to reproductive-age women on antidepressants who plan to conceive or who are pregnant, so collaborative decisions can be made based on the data and personal wishes. No decision is perfect or risk free. Women provided with the same information may make very different decisions.

www.womensmentalhealth.org

Until fairly recently, studies and reviews of global teratovigilance data have been relatively reassuring that SSRIs were particularly safe, especially with regard to their teratogenicity. In fact, there are more reproductive safety data available for SSRIs than for many medicines women take during pregnancy. But new reports have raised concerns about the teratogenicity of paroxetine, which we have previously discussed (FAMILY PRACTICE NEWS, Nov. 1, 2005, p. 41), as well as risk for putative neonatal distress syndromes and, most recently, possible increased rates of persistent pulmonary hypertension of the newborn (PPHN) following late-pregnancy exposure to SSRIs.

What do the new reports describe and how do the findings inform clinical care? One study supports previous reports of a “neonatal abstinence syndrome” with characteristic symptoms of jitteriness, sleep disturbance, dysregulation, tachypnea, and myoclonus in infants whose mothers used antidepressants during pregnancy. In this prospective cohort study of 120 infants, examiners used a systematic scale to assess full-term SSRI-exposed newborns with respect to the presence or absence of a wide range of previously reported symptoms.

Of the 60 infants exposed in utero to various SSRIs for a mean of 35.5 weeks, 8 had severe symptoms and 10 had mild symptoms, compared with none of the 60 infants who had not been exposed in utero to these drugs (Arch. Pediatr. Adolesc. Med. 2006;160:173–6). A particularly noteworthy finding is that no infant with symptoms required treatment intervention; symptoms were transient and of little if any clinical significance.

In the second study, investigators using a case-control design described an elevated risk for PPHN, a far more serious syndrome associated with severe respiratory failure, in newborns with in utero exposure to SSRIs late in pregnancy. In this study, which enrolled almost 400 women whose infants had PPHN, matching them to more than 800 control mothers and infants, the use of SSRIs at any point during pregnancy was not associated with PPHN, but there was a significant association between PPHN and in utero exposure to an SSRI after 20 weeks' gestation (N. Engl. J. Med. 2006;354:579–87).

The study describes a very disturbing and striking finding. But an accompanying editorial points out that the number of cases reported is small (N. Engl. J. Med. 2006;354:636–8). And though not mentioned in the editorial, the vulnerability to reporting bias in such a study is great. One wonders whether women without an adverse outcome may be reluctant to disclose use of an antidepressant during pregnancy, compared with those with an adverse outcome as serious as PPHN. Because the conclusions are based on a small number of PPHN cases, a difference of a small number of cases in either direction can strengthen or attenuate a positive finding.

The authors of the second study suggest that the incidence of PPHN associated with SSRI exposure in late pregnancy approaches 1%. However, given the hundreds of women who have used SSRIs during late pregnancy, it is unlikely such a dramatic clinical finding would not have been reported, even anecdotally, before this study—the first of such reports.

These studies, which have had considerable media attention, have alarmed women who are taking antidepressants. In fact, they were published just weeks after we reported the results of a prospective study of 201 women with a history of major depression who were prospectively followed during pregnancy. Women who discontinued their antidepressant medication proximate to conception were at a fivefold greater risk for depressive relapse during pregnancy, compared with those who continued with an antidepressant (JAMA 2006;295:499–507). These data certainly suggest pregnancy is not protective with respect to depression and many women who stop antidepressants will relapse during pregnancy.

Although some women will still stop antidepressant therapy during pregnancy, patients should be informed that depression during pregnancy can increase the risk for other neonatal complications and substantially increase the risk for postpartum depression. Other women will choose to continue antidepressant use during pregnancy, regardless of the findings of these more recent studies, given what for some patients will be viewed as a modest risk for the neonatal outcomes described. Regardless of individual choices, which can vary greatly, it is crucial to present all available information to reproductive-age women on antidepressants who plan to conceive or who are pregnant, so collaborative decisions can be made based on the data and personal wishes. No decision is perfect or risk free. Women provided with the same information may make very different decisions.