56 l JANUARY JOGC JANVIER 2015 DRUGS IN PREGNANCY Key Words: selective serotonin reuptake inhibitor, SSRI, selective norepinephrine reuptake inhibitor, SNRI, depression, risk, pregnancy Competing Interests: None declared J Obstet Gynaecol Can 2015;37(1):56–63 Abstract Studies have consistently reported a decrease in the use of antidepressants during pregnancy compared with the pre-pregnancy period Multiple recent studies have focused on the potential fetal risks of selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), with very little attention paid to maternal risks The maternal risks of these medications are the focus of this review Untreated depression is associated with increased risks of maternal morbidity, both somatic and psychiatric In contrast, use of antidepressants has been associated with increased risks of hypertension, preeclampsia, and bleeding In this review we present the evidence for maternal risks in an attempt to develop a risk-benefit ratio Résumé Les études indiquent uniformément une baisse du recours aux antidépresseurs pendant la grossesse, par comparaison avec la période prégrossesse De multiples études récentes se sont centrées sur les risques fœtaux potentiellement liés aux inhibiteur sélectif du recaptage de la sérotonine (ISRS) et aux inhibiteur sélectif du recaptage de la norépinéphrine (ISRN), tout en ne portant que très peu attention aux risques maternels La présente analyse est axée sur les risques maternels qui sont liés à ces médicaments La dépression ne faisant pas l’objet d’un traitement est associée à des risques accrus de morbidité maternelle, tant somatique que psychiatrique Par contre, l’utilisation d’antidépresseurs a été associée à des risques accrus d’hypertension, de prééclampsie et de saignement Dans le cadre de la présente analyse, nous présentons les données dont nous disposons au sujet des risques maternels afin de tenter d’établir un rapport risques-avantages INTRODUCTION M ajor depressive disorder is the second leading cause of burden of disease in women, 1,2 and up to 20% of women of reproductive age are affected by depression. 3 Depression has a prevalence of 12.8% in the second trimester of pregnancy and 12.0% in the third trimester. 3 Hence, large numbers of women may need antidepressant drugs. 4 Different studies suggest that between 1% and 8% of pregnant women use antidepressants. 5–8 To date, depression remains under-detected and under-treated during pregnancy. 9–12 A major contributor to the degree of under-treatment is concern about potential adverse fetal outcomes as a result of fetal exposure to antidepressants. 7,13 The objective of this review is to present the evidence for maternal risks in an attempt to develop a risk-benefit ratio. SEARCH METHODS We searched Medline and EMBASE for articles published from inception to July 30, 2013, dealing with maternal complications of depression in pregnancy and postpartum. The following search terms were used: “pregnancy,” “depression,” “antidepressants,” “SSRIs,” “SNRIs,” “complications,” “bleeding,” “gestational hypertension,” “hypertension,” “preeclampsia,” “fetus,” and “delivery.” Studies were reviewed and data were extracted according to reported effects or lack of effect on maternal health. FETAL RISKS Numerous studies have suggested that use of antidepressants during pregnancy is associated with poor fetal outcomes, including miscarriage, congenital malformations, stillbirth, preterm birth, low birth weight, adverse short term transient neonatal effects, and persistent The Use of Antidepressants in Pregnancy: Focus on Maternal Risks Yifat Gadot, MD, Gideon Koren, MD The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children, Toronto ON MOTHERISK ROUNDS
The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Nov 30, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
MOTHERISK ROUNDS: The Use of Antidepressants in Pregnancy: Focus on Maternal RisksThe Use of Antidepressants in Pregnancy: Focus on Maternal Risks
56 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY
Competing Interests: None declared .
Abstract
Studies have consistently reported a decrease in the use of antidepressants during pregnancy compared with the pre-pregnancy period . Multiple recent studies have focused on the potential fetal risks of selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), with very little attention paid to maternal risks . The maternal risks of these medications are the focus of this review .
Untreated depression is associated with increased risks of maternal morbidity, both somatic and psychiatric . In contrast, use of antidepressants has been associated with increased risks of hypertension, preeclampsia, and bleeding . In this review we present the evidence for maternal risks in an attempt to develop a risk-benefit ratio .
Résumé
Les études indiquent uniformément une baisse du recours aux antidépresseurs pendant la grossesse, par comparaison avec la période prégrossesse . De multiples études récentes se sont centrées sur les risques fœtaux potentiellement liés aux inhibiteur sélectif du recaptage de la sérotonine (ISRS) et aux inhibiteur sélectif du recaptage de la norépinéphrine (ISRN), tout en ne portant que très peu attention aux risques maternels . La présente analyse est axée sur les risques maternels qui sont liés à ces médicaments .
La dépression ne faisant pas l’objet d’un traitement est associée à des risques accrus de morbidité maternelle, tant somatique que psychiatrique . Par contre, l’utilisation d’antidépresseurs a été associée à des risques accrus d’hypertension, de prééclampsie et de saignement . Dans le cadre de la présente analyse, nous présentons les données dont nous disposons au sujet des risques maternels afin de tenter d’établir un rapport risques-avantages .
INTRODUCTION
Major depressive disorder is the second leading cause of burden of disease in women,1,2 and up to 20% of
women of reproductive age are affected by depression.3 Depression has a prevalence of 12.8% in the second trimester of pregnancy and 12.0% in the third trimester.3
Hence, large numbers of women may need antidepressant drugs.4 Different studies suggest that between 1% and 8% of pregnant women use antidepressants.5–8
To date, depression remains under-detected and under-treated during pregnancy.9–12 A major contributor to the degree of under-treatment is concern about potential adverse fetal outcomes as a result of fetal exposure to antidepressants.7,13
The objective of this review is to present the evidence for maternal risks in an attempt to develop a risk-benefit ratio.
SEARCH METHODS
We searched Medline and EMBASE for articles published from inception to July 30, 2013, dealing with maternal complications of depression in pregnancy and postpartum. The following search terms were used: “pregnancy,” “depression,” “antidepressants,” “SSRIs,” “SNRIs,” “com plica tions,” “bleeding,” “gestational hypertension,” “hypertension,” “preeclampsia,” “fetus,” and “delivery.”
Studies were reviewed and data were extracted according to reported effects or lack of effect on maternal health.
FETAL RISKS
Numerous studies have suggested that use of antidepressants during pregnancy is associated with poor fetal outcomes, including miscarriage, congenital malformations, stillbirth, preterm birth, low birth weight, adverse short term transient neonatal effects, and persistent
The Use of Antidepressants in Pregnancy: Focus on Maternal Risks Yifat Gadot, MD, Gideon Koren, MD The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children, Toronto ON
MOTHERISK ROUNDS
The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
pulmonary hypertension in the newborn.14–38 These studies have been balanced by studies not showing adverse fetal effects.16,39–42 Interestingly, a large recent study documented an increase in the incidence of ventricular septal defect in babies exposed to antidepressants in the first trimester, but also among babies of mothers with untreated depression.43
In contrast, very little attention has been paid to maternal risks associated with depression and SSRIs, and this will be the focus of this review.
PHARMACOLOGY
The SSRIs and SNRIs regulate mood by inhibition of reuptake of serotonin and norepinephrine, respectively, in related brain regions.44 All antidepressants cross the placenta in humans, but this fact should not be misinterpreted as evidence of hazard; most medications cross the placenta, and very few have been shown to cause adverse fetal effects.45 Depression is mostly recurrent, with as much as 90% of affected persons having more than one episode.46 In non- pregnant women with depression, the likelihood of recovery without medication is approximately 20% in the first week but declines as the duration of depression extends, and after six months the likelihood of recovery is less than 1%.47,48
DEMOGRAPHIC CHARACTERISTICS
Pregnant women with depression are more likely to be older, to have pre-existing diabetes (OR 1.32), chronic hypertension (OR 1.34), or asthma,49,50 and, not surprisingly, have an increased risk of requiring hospitalization during pregnancy. Pregnant women with depression have a higher prevalence of use of other psychotropic drugs, with the most common being benzodiazepines (8.9%), opioids (6.0%), benzodiazepine-like hypnotics (4.7%), and antipsychotics (3.0%).49
MATERNAL RISKS OF UNTREATED DEPRESSION
Uncontrolled and untreated depression in pregnancy has been associated with increased risks of miscarriage, low birth weight, and prematurity.50 It has also been linked to gestational hypertension and preeclampsia,51,52 excessive bleeding,38 increased uterine artery resistance,53 and the need for Caesarean section or instrumental vaginal
delivery54; more subjectively, it is associated with painful labour and therefore more need for epidural analgesia.55,56 With regard to the fetus and neonate, untreated depression during pregnancy has been associated with low Apgar scores,57 admission to NICU,54 and fetal death.57,58
In women on antidepressant medication, the effects of withdrawal or discontinuation include affective symptoms, general somatic symptoms, sleep disturbances, and gastrointestinal symptoms, most of which occur within days to weeks of stopping the medication or reducing the dose. Typically, relapse of depression occurs more gradually.59–63 In a study of 36 pregnant women who called the Motherisk Program in Toronto, the only reason women gave for stopping their prescribed medication was fear that the medication would harm their babies.64 All the women experienced abrupt discontinuation syndrome, 11 reported suicidal thoughts, and four required hospitalization. One woman had a therapeutic abortion and one replaced benzodiazepine use with alcohol. After counselling, two- thirds of these women renewed their medication within several days. All babies born to women who re-established medication were healthy and normal.64
In a study using monthly psychiatric assessments throughout pregnancy, 201 pregnant women were enrolled in three American centres.61 All participants had a history of major depression prior to pregnancy, were at less than 16 weeks’ gestation and had been euthymic for at least three months prior to their last menstrual period. Among the 82 women who maintained their medication throughout pregnancy, 21 (26%) had a relapse of depression, compared with 44 of the 65 women who discontinued medication (68%). Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy (hazard ratio 5.0; 95% CI 2.8 to 9.1, P < 0.001).
Postpartum depression is a serious medical emergency that can be often predisposed to untreated depression in late pregnancy.65,66 Suicide is a leading cause of death among young women, predominantly among women with mental illnesses.65,66 Untreated depression may also lead to suboptimal infant care, suboptimal mother–child attachment, lack of care of other children, and an adverse relationship with the partner.48
MONITORING SYMPTOMS OF DEPRESSION IN PREGNANCY
While a psychiatrist should be the lead physician taking care of a depressed pregnant woman, screening pregnant women for depressive symptoms could be done easily by an obstetrician or general practitioner. The five-minute
ABBREVIATIONS SSRI selective serotonin reuptake inhibitor
SNRI selective norepinephrine reuptake inhibitor
TCA tricyclic antidepressant
58 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Edinburgh Scale questionnaire for depressive symptoms enables high predictive values for diagnosis of depressive symptoms.67 The questionnaire was later validated for use during pregnancy.68
We have applied this screening tool in our clinic, and it has assisted us in identifying depressed women who are unaware of their diagnoses. Among 400 women, one in four received a score of ≥ 13 on the Edinburgh Postnatal Depression Scale, which is highly indicative of depressive disease. Some of the women expressed suicidal thoughts, and many were referred to a psychiatrist.39,69
PERCEPTION OF TERATOGENIC RISK
Pregnant women’s perception of the teratogenic risk of using medication is significantly higher than their actual risk.70 Even when the medication they use is not teratogenic, women tend to assume that their child’s risk for malformation is in the range of 25%, which is the level of risk of teratogenesis in women who take thalidomide.70 Hence, it is not surprising that pregnant women would tend to avoid therapy, even for life-threatening medical conditions, and would consider termination of a wanted pregnancy due to fear of teratogenicity.71 These tendencies are the results of misinformation, often provided by medical authorities and the media.70,71 Depressed women are more vulnerable to the hazards of misperception and misinformation,72 and it is therefore important that physicians alleviate fears and empower women to use medications optimally.39,72
MATERNAL RISKS OF DEPRESSION AND SSRIS
The evidence for maternal risks associated with depression and use of SSRIs is summarized in the Table.
Gestational Hypertension and Preeclampsia Gestational hypertension and preeclampsia have been associated with SSRI exposure, especially during late pregnancy.73 Toh et al. reported an incidence of gestational hypertension of 9% among 5532 women not treated with SSRIs during pregnancy and an incidence of 19.1% among 199 women treated with SSRIs.73 Among women who were treated with SSRIs only in the first trimester, there was a 13.1% incidence of gestational hypertension. In contrast, there was a 26.1% incidence of gestational hypertension among women who continued treatment with SSRIs beyond the first trimester. Preeclampsia occurred in 2.4% of women who were not treated with SSRIs, in 3.7% of women treated with SSRIs only in the first trimester, and 15.2% of women who continued treatment beyond the first trimester. Compared to untreated women, the relative
risk of preeclampsia was 1.4 for women who were treated with SSRIs only in the first trimester, and 4.9 for women who continued treatment beyond the first trimester.73
Since their study was observational, the findings of Toh et al. can be attributed either to the treatment with SSRIs itself or to the underlying mood disorder. It has been suggested that the effects of treatment with SSRIs might be mediated through vascular effects and not through placentation, because serotonin has an effect on hemostasis and vascular tone in uterine and placental tissue.74–76 Moreover, SSRIs inhibit synthesis of the vasodilator nitric oxide.77–79 In addition, it has been argued that the SNRIs can affect blood pressure through noradrenergic effects, leading to an increase in diastolic blood pressure.80
The underlying mood disorders might have vascular effects leading to uterine artery resistance and vasoconstriction through discharge of vasoactive hormones and neurotransmitters.58 Depression and anxiety in pregnancy have been associated with a three-fold risk of preeclampsia.52,81 Women treated with SSRIs have more severe depression than women not requiring such treatment, and hence the vascular effects could be due to the severity of the depression rather than the treatment with SSRIs.37 Other confounding factors are pre-pregnancy BMI and socioeconomic and lifestyle determinants.82
In a study of 69 448 pregnancies in women with depression, the use of antidepressants during pregnancy, especially SNRIs and TCAs, was associated with an increased risk of preeclampsia, whereas the risk of preeclampsia in untreated pregnant women with depression (2.4%) was similar to that of pregnant women without depression (2.3%).83 Pregnant women treated with SSRI, SNRI, or TCA monotherapy had relative risks for preeclampsia of 1.22, 1.95, and 3.23, respectively, compared to pregnant women with untreated depression. Furthermore, the relative risk for preeclampsia among women who continued treatment compared with those who discontinued was 1.32 for users of SSRIs, 3.43 for users of SNRIs, and 3.26 for users of TCAs.83
In a study of 100 942 pregnant women with depression, the risk of preeclampsia was 5.4% among women with untreated depression, and was increased among women receiving monotherapy with SNRI during the second trimester and first half of the third trimester (RR 1.52) or TCA during the same time period (RR 1.62), but not with SSRI (RR 1.00).84 It is important to remember that the trials referred to here were not randomized trials, and women assigned to a particular antidepressant may differ from women in the other groups in confounding ways that may explain the differing rates of preeclampsia.
JANUARY JOGC JANVIER 2015 l 59
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Adverse maternal effects associated with SSRIs in pregnancy Study Adverse outcome Finding
Cohen et al . (2006)61 Relapse of depression Continued antidepressants: 26% (n = 21) Discontinued antidepressants: 68% (n = 44) HR 5 .0, 95% CI 2 .8, 9 .1 P < 0 .001
Toh et al . (2009)73 Gestational hypertension Untreated: 9% (of n = 5532) Treated with SSRIs: 19 .1% (of n = 199) . SSRI only in 1st trimester: 13 .1% SSRI beyond 1st trimester: 26 .1%
Toh et al . (2009)73 Preeclampsia Untreated: 2 .4% SSRIs only in 1st trimester-3 .7% (RR 1 .4 compared to untreated) SSRIs beyond 1st trimester-15 .2% (RR 4 .9 compared to untreated)
Palmsten et al . (2012)83 Preeclampsia n = 69 448 Pregnancy without depression 2 .3% Untreated depression 2 .4% Compared to untreated depression: SSRIs RR 1 .22 SNRIs RR 1 .95 TCAs RR 3 .23 Continued use vs . discontinued use: SSRIs RR 1 .32 SNRIs RR 3 .43 TCAs RR 3 .26
Palmsten et al . (2013)84 Preeclampsia n = 100 942 Untreated depression 5 .4% Compared to untreated depression: SSRIs RR 1 .0 SNRIs RR 1 .52 TCAs RR 3 .62 Compared to SSRIs: SNRIs RR 1 .54 TCAs RR 1 .64
Reis and Källén (2010)85 Placenta previa n = 14 821 OR 1 .36
Reis and Källén (2010)85 Placental abruption n = 14 821 OR 1 .29 early antidepressant use OR 1 .05 late use OR 1 .23 early + late use
Reis and Källén (2010)85 Premature rupture of membranes n = 14 821 OR 1 .47 early + late use
Reis and Källén (2010)85 Labour induction OR 1 .29
Reis and Källén (2010)85 Caesarean section OR 1 .38 early antidepressant use OR 1 .35 late use OR 1 .74 early + late use
Reis and Källén (2010)85 Postpartum hemorrhage OR 1 .33 early antidepressant use OR 1 .45 late use OR 1 .58 early + late use
Palmsten et al . (2013)103 Postpartum hemorrhage n = 106 000 Pregnancy without depression 2 .4% Untreated depression 2 .8% Current SSRIs 4% (1 .47-fold increased risk [95% CI 1 .33 to 1 .62]) Current non-SSRIs 3 .8% (1 .39-fold increased risk [95% CI 1 .07 to 1 .81])
Lupattelli et al . (2014)108 Postpartum hemorrhage n = 57 279 Untreated depression: no increased risk Compared to unexposed: SSRIs/SNRIs after vaginal delivery: OR 0 .9 SSRIs/SNRIs after Caesarean section: OR 1 .47
60 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Delivery A Swedish study of 14 821 pregnant women exposed to antidepressant medication (SSRI, SNRI, and TCA) showed an increased risk of placenta previa (OR 1.36 when antidepressants were taken early in pregnancy), placental abruption (OR 1.29 for early use, OR 1.05 for late use, and 1.23 for both early and late use), premature rupture of membranes (OR 1.47 for both early and late use), the need for induction of labour (OR 1.29), and Caesarean section (OR 1.38 for early use, OR 1.35 for late use, and 1.74 for both early and late use).85
Postpartum Hemorrhage Postpartum hemorrhage is a primary cause of maternal mortality throughout the world,86–88 and is associated with severe maternal morbidity, blood transfusion, and admission to intensive care.83,89 The incidence of postpartum hemorrhage has increased in the United States since the 1990s.90–93 and has also increased in Canada.94 Several studies have emphasized an increased risk of bleeding events such as perioperative bleeding when using antidepressants, because they inhibit serotonin reuptake,95–100 possibly thereby depleting platelet serotonin.101
Salkeld et al. detected a borderline 1.3-fold increased risk of postpartum hemorrhage when SSRIs were taken in the 90 days before delivery,102 and Reis and Källén reported an increased risk of bleeding during the postpartum period among 14 821 women taking SSRIs, SNRIs, and TCAs (OR 1.33 for early use, OR 1.45 for late use, and 1.58 for both early and late use).85
Palmsten et al. studied the risk of postpartum hemorrhage among 106 000 pregnant women with mood/anxiety disorders, 15.1% of whom had been using antidepressants at the time of delivery.103 After adjustment for confounders, they concluded that women with past exposure to SSRI monotherapy did not have an increased risk of postpartum hemorrhage, whereas in those with past exposure to SNRI monotherapy the risk was slightly increased (but not statistically significant).103
As noted above, the association between SSRI use and bleeding may be partially related to the inhibition of serotonin reuptake in platelets.104 Typically, pronounced uterine bleeding from the placental implantation site is prevented by uterine myometrial contractions105 in response to serotonin.106 It is possible that SSRIs increase the risk of postpartum hemorrhage through different pathways. A potential weakness of the 2013 study by Palmsten et al.84 was that the women were of low income, younger, and more likely to be Black.84,107
In contrast to the above, Lupattelli et al. recently reported that pregnant women’s exposure to SSRIs/SNRIs or TCAs/other antidepressants in the first trimester (OR for SSRIs/SNRIs 0.91 and OR for TCAs/other antidepressants 0.83), second trimester (OR for SSRIs/SNRIs 0.81 and OR for TCAs/ other antidepressants 0.96) or postpartum (OR for SSRIs/ SNRIs after vaginal delivery 0.90, OR after Caesarean section 1.47) did not show any elevated risk for vaginal bleeding compared to unexposed subjects.108 Untreated pregnant women with depression had a mildly elevated (but statistically significant) risk of vaginal bleeding in the first trimester (OR 1.22) and second trimester (OR 1.28) but not postpartum. The conflicting results and the borderline statistical significance of the positive studies suggest that even if use of antidepressants causes intrapartum and/or postpartum bleeding, the absolute risk is modest.
BENEFITS AND RISKS
Untreated depression during pregnancy or postpartum is associated with increased maternal and neonatal morbidity and mortality.9–11 Depression during pregnancy affects numerous aspects of maternal health, from difficulty in conducting everyday life to an elevated risk of suicide or self-harm (Table).10
Fears of teratogenicity often prompt pregnant women to abruptly discontinue highly needed antidepressant treatment, leading to withdrawal symptoms or a relapse of the primary psychiatric illness.109 These women manifest higher rates of morbidity and hospitalization, including suicide attempts and impaired adherence to the steps required to maintain a healthy pregnancy.110,111 Postpartum depression can cause severe morbidity in both mother and child, and it is strongly predisposed to untreated depression in late pregnancy. Suicide is a leading cause of death among young women with mental illnesses.59,60
The main reason for pregnant women with depression to consider avoiding treatment is the perception that use of SSRIs or SNRIs confers significant teratogenic effects. However, no clear teratogenic pattern has emerged in the many studies addressing this question. Moreover, there are many more trials with negative findings than positive ones. Recent evidence has shown that the proportion of fetal cardiac malformations is equally high in the offspring of women with treated and untreated depression, probably due to ascertainment bias.43 Clinicians who provide care for pregnant women with depression have to weigh the rare adverse maternal and fetal effects of antidepressant medications against the effects of not treating women who need these medications for a potentially life-threatening condition.
JANUARY JOGC JANVIER 2015 l 61
DRUGS IN PREGNANCY…
56 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY
Competing Interests: None declared .
Abstract
Studies have consistently reported a decrease in the use of antidepressants during pregnancy compared with the pre-pregnancy period . Multiple recent studies have focused on the potential fetal risks of selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), with very little attention paid to maternal risks . The maternal risks of these medications are the focus of this review .
Untreated depression is associated with increased risks of maternal morbidity, both somatic and psychiatric . In contrast, use of antidepressants has been associated with increased risks of hypertension, preeclampsia, and bleeding . In this review we present the evidence for maternal risks in an attempt to develop a risk-benefit ratio .
Résumé
Les études indiquent uniformément une baisse du recours aux antidépresseurs pendant la grossesse, par comparaison avec la période prégrossesse . De multiples études récentes se sont centrées sur les risques fœtaux potentiellement liés aux inhibiteur sélectif du recaptage de la sérotonine (ISRS) et aux inhibiteur sélectif du recaptage de la norépinéphrine (ISRN), tout en ne portant que très peu attention aux risques maternels . La présente analyse est axée sur les risques maternels qui sont liés à ces médicaments .
La dépression ne faisant pas l’objet d’un traitement est associée à des risques accrus de morbidité maternelle, tant somatique que psychiatrique . Par contre, l’utilisation d’antidépresseurs a été associée à des risques accrus d’hypertension, de prééclampsie et de saignement . Dans le cadre de la présente analyse, nous présentons les données dont nous disposons au sujet des risques maternels afin de tenter d’établir un rapport risques-avantages .
INTRODUCTION
Major depressive disorder is the second leading cause of burden of disease in women,1,2 and up to 20% of
women of reproductive age are affected by depression.3 Depression has a prevalence of 12.8% in the second trimester of pregnancy and 12.0% in the third trimester.3
Hence, large numbers of women may need antidepressant drugs.4 Different studies suggest that between 1% and 8% of pregnant women use antidepressants.5–8
To date, depression remains under-detected and under-treated during pregnancy.9–12 A major contributor to the degree of under-treatment is concern about potential adverse fetal outcomes as a result of fetal exposure to antidepressants.7,13
The objective of this review is to present the evidence for maternal risks in an attempt to develop a risk-benefit ratio.
SEARCH METHODS
We searched Medline and EMBASE for articles published from inception to July 30, 2013, dealing with maternal complications of depression in pregnancy and postpartum. The following search terms were used: “pregnancy,” “depression,” “antidepressants,” “SSRIs,” “SNRIs,” “com plica tions,” “bleeding,” “gestational hypertension,” “hypertension,” “preeclampsia,” “fetus,” and “delivery.”
Studies were reviewed and data were extracted according to reported effects or lack of effect on maternal health.
FETAL RISKS
Numerous studies have suggested that use of antidepressants during pregnancy is associated with poor fetal outcomes, including miscarriage, congenital malformations, stillbirth, preterm birth, low birth weight, adverse short term transient neonatal effects, and persistent
The Use of Antidepressants in Pregnancy: Focus on Maternal Risks Yifat Gadot, MD, Gideon Koren, MD The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children, Toronto ON
MOTHERISK ROUNDS
The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
pulmonary hypertension in the newborn.14–38 These studies have been balanced by studies not showing adverse fetal effects.16,39–42 Interestingly, a large recent study documented an increase in the incidence of ventricular septal defect in babies exposed to antidepressants in the first trimester, but also among babies of mothers with untreated depression.43
In contrast, very little attention has been paid to maternal risks associated with depression and SSRIs, and this will be the focus of this review.
PHARMACOLOGY
The SSRIs and SNRIs regulate mood by inhibition of reuptake of serotonin and norepinephrine, respectively, in related brain regions.44 All antidepressants cross the placenta in humans, but this fact should not be misinterpreted as evidence of hazard; most medications cross the placenta, and very few have been shown to cause adverse fetal effects.45 Depression is mostly recurrent, with as much as 90% of affected persons having more than one episode.46 In non- pregnant women with depression, the likelihood of recovery without medication is approximately 20% in the first week but declines as the duration of depression extends, and after six months the likelihood of recovery is less than 1%.47,48
DEMOGRAPHIC CHARACTERISTICS
Pregnant women with depression are more likely to be older, to have pre-existing diabetes (OR 1.32), chronic hypertension (OR 1.34), or asthma,49,50 and, not surprisingly, have an increased risk of requiring hospitalization during pregnancy. Pregnant women with depression have a higher prevalence of use of other psychotropic drugs, with the most common being benzodiazepines (8.9%), opioids (6.0%), benzodiazepine-like hypnotics (4.7%), and antipsychotics (3.0%).49
MATERNAL RISKS OF UNTREATED DEPRESSION
Uncontrolled and untreated depression in pregnancy has been associated with increased risks of miscarriage, low birth weight, and prematurity.50 It has also been linked to gestational hypertension and preeclampsia,51,52 excessive bleeding,38 increased uterine artery resistance,53 and the need for Caesarean section or instrumental vaginal
delivery54; more subjectively, it is associated with painful labour and therefore more need for epidural analgesia.55,56 With regard to the fetus and neonate, untreated depression during pregnancy has been associated with low Apgar scores,57 admission to NICU,54 and fetal death.57,58
In women on antidepressant medication, the effects of withdrawal or discontinuation include affective symptoms, general somatic symptoms, sleep disturbances, and gastrointestinal symptoms, most of which occur within days to weeks of stopping the medication or reducing the dose. Typically, relapse of depression occurs more gradually.59–63 In a study of 36 pregnant women who called the Motherisk Program in Toronto, the only reason women gave for stopping their prescribed medication was fear that the medication would harm their babies.64 All the women experienced abrupt discontinuation syndrome, 11 reported suicidal thoughts, and four required hospitalization. One woman had a therapeutic abortion and one replaced benzodiazepine use with alcohol. After counselling, two- thirds of these women renewed their medication within several days. All babies born to women who re-established medication were healthy and normal.64
In a study using monthly psychiatric assessments throughout pregnancy, 201 pregnant women were enrolled in three American centres.61 All participants had a history of major depression prior to pregnancy, were at less than 16 weeks’ gestation and had been euthymic for at least three months prior to their last menstrual period. Among the 82 women who maintained their medication throughout pregnancy, 21 (26%) had a relapse of depression, compared with 44 of the 65 women who discontinued medication (68%). Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy (hazard ratio 5.0; 95% CI 2.8 to 9.1, P < 0.001).
Postpartum depression is a serious medical emergency that can be often predisposed to untreated depression in late pregnancy.65,66 Suicide is a leading cause of death among young women, predominantly among women with mental illnesses.65,66 Untreated depression may also lead to suboptimal infant care, suboptimal mother–child attachment, lack of care of other children, and an adverse relationship with the partner.48
MONITORING SYMPTOMS OF DEPRESSION IN PREGNANCY
While a psychiatrist should be the lead physician taking care of a depressed pregnant woman, screening pregnant women for depressive symptoms could be done easily by an obstetrician or general practitioner. The five-minute
ABBREVIATIONS SSRI selective serotonin reuptake inhibitor
SNRI selective norepinephrine reuptake inhibitor
TCA tricyclic antidepressant
58 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Edinburgh Scale questionnaire for depressive symptoms enables high predictive values for diagnosis of depressive symptoms.67 The questionnaire was later validated for use during pregnancy.68
We have applied this screening tool in our clinic, and it has assisted us in identifying depressed women who are unaware of their diagnoses. Among 400 women, one in four received a score of ≥ 13 on the Edinburgh Postnatal Depression Scale, which is highly indicative of depressive disease. Some of the women expressed suicidal thoughts, and many were referred to a psychiatrist.39,69
PERCEPTION OF TERATOGENIC RISK
Pregnant women’s perception of the teratogenic risk of using medication is significantly higher than their actual risk.70 Even when the medication they use is not teratogenic, women tend to assume that their child’s risk for malformation is in the range of 25%, which is the level of risk of teratogenesis in women who take thalidomide.70 Hence, it is not surprising that pregnant women would tend to avoid therapy, even for life-threatening medical conditions, and would consider termination of a wanted pregnancy due to fear of teratogenicity.71 These tendencies are the results of misinformation, often provided by medical authorities and the media.70,71 Depressed women are more vulnerable to the hazards of misperception and misinformation,72 and it is therefore important that physicians alleviate fears and empower women to use medications optimally.39,72
MATERNAL RISKS OF DEPRESSION AND SSRIS
The evidence for maternal risks associated with depression and use of SSRIs is summarized in the Table.
Gestational Hypertension and Preeclampsia Gestational hypertension and preeclampsia have been associated with SSRI exposure, especially during late pregnancy.73 Toh et al. reported an incidence of gestational hypertension of 9% among 5532 women not treated with SSRIs during pregnancy and an incidence of 19.1% among 199 women treated with SSRIs.73 Among women who were treated with SSRIs only in the first trimester, there was a 13.1% incidence of gestational hypertension. In contrast, there was a 26.1% incidence of gestational hypertension among women who continued treatment with SSRIs beyond the first trimester. Preeclampsia occurred in 2.4% of women who were not treated with SSRIs, in 3.7% of women treated with SSRIs only in the first trimester, and 15.2% of women who continued treatment beyond the first trimester. Compared to untreated women, the relative
risk of preeclampsia was 1.4 for women who were treated with SSRIs only in the first trimester, and 4.9 for women who continued treatment beyond the first trimester.73
Since their study was observational, the findings of Toh et al. can be attributed either to the treatment with SSRIs itself or to the underlying mood disorder. It has been suggested that the effects of treatment with SSRIs might be mediated through vascular effects and not through placentation, because serotonin has an effect on hemostasis and vascular tone in uterine and placental tissue.74–76 Moreover, SSRIs inhibit synthesis of the vasodilator nitric oxide.77–79 In addition, it has been argued that the SNRIs can affect blood pressure through noradrenergic effects, leading to an increase in diastolic blood pressure.80
The underlying mood disorders might have vascular effects leading to uterine artery resistance and vasoconstriction through discharge of vasoactive hormones and neurotransmitters.58 Depression and anxiety in pregnancy have been associated with a three-fold risk of preeclampsia.52,81 Women treated with SSRIs have more severe depression than women not requiring such treatment, and hence the vascular effects could be due to the severity of the depression rather than the treatment with SSRIs.37 Other confounding factors are pre-pregnancy BMI and socioeconomic and lifestyle determinants.82
In a study of 69 448 pregnancies in women with depression, the use of antidepressants during pregnancy, especially SNRIs and TCAs, was associated with an increased risk of preeclampsia, whereas the risk of preeclampsia in untreated pregnant women with depression (2.4%) was similar to that of pregnant women without depression (2.3%).83 Pregnant women treated with SSRI, SNRI, or TCA monotherapy had relative risks for preeclampsia of 1.22, 1.95, and 3.23, respectively, compared to pregnant women with untreated depression. Furthermore, the relative risk for preeclampsia among women who continued treatment compared with those who discontinued was 1.32 for users of SSRIs, 3.43 for users of SNRIs, and 3.26 for users of TCAs.83
In a study of 100 942 pregnant women with depression, the risk of preeclampsia was 5.4% among women with untreated depression, and was increased among women receiving monotherapy with SNRI during the second trimester and first half of the third trimester (RR 1.52) or TCA during the same time period (RR 1.62), but not with SSRI (RR 1.00).84 It is important to remember that the trials referred to here were not randomized trials, and women assigned to a particular antidepressant may differ from women in the other groups in confounding ways that may explain the differing rates of preeclampsia.
JANUARY JOGC JANVIER 2015 l 59
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Adverse maternal effects associated with SSRIs in pregnancy Study Adverse outcome Finding
Cohen et al . (2006)61 Relapse of depression Continued antidepressants: 26% (n = 21) Discontinued antidepressants: 68% (n = 44) HR 5 .0, 95% CI 2 .8, 9 .1 P < 0 .001
Toh et al . (2009)73 Gestational hypertension Untreated: 9% (of n = 5532) Treated with SSRIs: 19 .1% (of n = 199) . SSRI only in 1st trimester: 13 .1% SSRI beyond 1st trimester: 26 .1%
Toh et al . (2009)73 Preeclampsia Untreated: 2 .4% SSRIs only in 1st trimester-3 .7% (RR 1 .4 compared to untreated) SSRIs beyond 1st trimester-15 .2% (RR 4 .9 compared to untreated)
Palmsten et al . (2012)83 Preeclampsia n = 69 448 Pregnancy without depression 2 .3% Untreated depression 2 .4% Compared to untreated depression: SSRIs RR 1 .22 SNRIs RR 1 .95 TCAs RR 3 .23 Continued use vs . discontinued use: SSRIs RR 1 .32 SNRIs RR 3 .43 TCAs RR 3 .26
Palmsten et al . (2013)84 Preeclampsia n = 100 942 Untreated depression 5 .4% Compared to untreated depression: SSRIs RR 1 .0 SNRIs RR 1 .52 TCAs RR 3 .62 Compared to SSRIs: SNRIs RR 1 .54 TCAs RR 1 .64
Reis and Källén (2010)85 Placenta previa n = 14 821 OR 1 .36
Reis and Källén (2010)85 Placental abruption n = 14 821 OR 1 .29 early antidepressant use OR 1 .05 late use OR 1 .23 early + late use
Reis and Källén (2010)85 Premature rupture of membranes n = 14 821 OR 1 .47 early + late use
Reis and Källén (2010)85 Labour induction OR 1 .29
Reis and Källén (2010)85 Caesarean section OR 1 .38 early antidepressant use OR 1 .35 late use OR 1 .74 early + late use
Reis and Källén (2010)85 Postpartum hemorrhage OR 1 .33 early antidepressant use OR 1 .45 late use OR 1 .58 early + late use
Palmsten et al . (2013)103 Postpartum hemorrhage n = 106 000 Pregnancy without depression 2 .4% Untreated depression 2 .8% Current SSRIs 4% (1 .47-fold increased risk [95% CI 1 .33 to 1 .62]) Current non-SSRIs 3 .8% (1 .39-fold increased risk [95% CI 1 .07 to 1 .81])
Lupattelli et al . (2014)108 Postpartum hemorrhage n = 57 279 Untreated depression: no increased risk Compared to unexposed: SSRIs/SNRIs after vaginal delivery: OR 0 .9 SSRIs/SNRIs after Caesarean section: OR 1 .47
60 l JANUARY JOGC JANVIER 2015
DRUGS IN PREGNANCY The Use of Antidepressants in Pregnancy: Focus on Maternal Risks
Delivery A Swedish study of 14 821 pregnant women exposed to antidepressant medication (SSRI, SNRI, and TCA) showed an increased risk of placenta previa (OR 1.36 when antidepressants were taken early in pregnancy), placental abruption (OR 1.29 for early use, OR 1.05 for late use, and 1.23 for both early and late use), premature rupture of membranes (OR 1.47 for both early and late use), the need for induction of labour (OR 1.29), and Caesarean section (OR 1.38 for early use, OR 1.35 for late use, and 1.74 for both early and late use).85
Postpartum Hemorrhage Postpartum hemorrhage is a primary cause of maternal mortality throughout the world,86–88 and is associated with severe maternal morbidity, blood transfusion, and admission to intensive care.83,89 The incidence of postpartum hemorrhage has increased in the United States since the 1990s.90–93 and has also increased in Canada.94 Several studies have emphasized an increased risk of bleeding events such as perioperative bleeding when using antidepressants, because they inhibit serotonin reuptake,95–100 possibly thereby depleting platelet serotonin.101
Salkeld et al. detected a borderline 1.3-fold increased risk of postpartum hemorrhage when SSRIs were taken in the 90 days before delivery,102 and Reis and Källén reported an increased risk of bleeding during the postpartum period among 14 821 women taking SSRIs, SNRIs, and TCAs (OR 1.33 for early use, OR 1.45 for late use, and 1.58 for both early and late use).85
Palmsten et al. studied the risk of postpartum hemorrhage among 106 000 pregnant women with mood/anxiety disorders, 15.1% of whom had been using antidepressants at the time of delivery.103 After adjustment for confounders, they concluded that women with past exposure to SSRI monotherapy did not have an increased risk of postpartum hemorrhage, whereas in those with past exposure to SNRI monotherapy the risk was slightly increased (but not statistically significant).103
As noted above, the association between SSRI use and bleeding may be partially related to the inhibition of serotonin reuptake in platelets.104 Typically, pronounced uterine bleeding from the placental implantation site is prevented by uterine myometrial contractions105 in response to serotonin.106 It is possible that SSRIs increase the risk of postpartum hemorrhage through different pathways. A potential weakness of the 2013 study by Palmsten et al.84 was that the women were of low income, younger, and more likely to be Black.84,107
In contrast to the above, Lupattelli et al. recently reported that pregnant women’s exposure to SSRIs/SNRIs or TCAs/other antidepressants in the first trimester (OR for SSRIs/SNRIs 0.91 and OR for TCAs/other antidepressants 0.83), second trimester (OR for SSRIs/SNRIs 0.81 and OR for TCAs/ other antidepressants 0.96) or postpartum (OR for SSRIs/ SNRIs after vaginal delivery 0.90, OR after Caesarean section 1.47) did not show any elevated risk for vaginal bleeding compared to unexposed subjects.108 Untreated pregnant women with depression had a mildly elevated (but statistically significant) risk of vaginal bleeding in the first trimester (OR 1.22) and second trimester (OR 1.28) but not postpartum. The conflicting results and the borderline statistical significance of the positive studies suggest that even if use of antidepressants causes intrapartum and/or postpartum bleeding, the absolute risk is modest.
BENEFITS AND RISKS
Untreated depression during pregnancy or postpartum is associated with increased maternal and neonatal morbidity and mortality.9–11 Depression during pregnancy affects numerous aspects of maternal health, from difficulty in conducting everyday life to an elevated risk of suicide or self-harm (Table).10
Fears of teratogenicity often prompt pregnant women to abruptly discontinue highly needed antidepressant treatment, leading to withdrawal symptoms or a relapse of the primary psychiatric illness.109 These women manifest higher rates of morbidity and hospitalization, including suicide attempts and impaired adherence to the steps required to maintain a healthy pregnancy.110,111 Postpartum depression can cause severe morbidity in both mother and child, and it is strongly predisposed to untreated depression in late pregnancy. Suicide is a leading cause of death among young women with mental illnesses.59,60
The main reason for pregnant women with depression to consider avoiding treatment is the perception that use of SSRIs or SNRIs confers significant teratogenic effects. However, no clear teratogenic pattern has emerged in the many studies addressing this question. Moreover, there are many more trials with negative findings than positive ones. Recent evidence has shown that the proportion of fetal cardiac malformations is equally high in the offspring of women with treated and untreated depression, probably due to ascertainment bias.43 Clinicians who provide care for pregnant women with depression have to weigh the rare adverse maternal and fetal effects of antidepressant medications against the effects of not treating women who need these medications for a potentially life-threatening condition.
JANUARY JOGC JANVIER 2015 l 61
DRUGS IN PREGNANCY…
Related Documents
