Mental Health

Drug Treatment for Mood Disorders in Pregnancy

Drug Treatment for Mood Disorders in Pregnancy

Introduction

Almost all psychiatric disorders at onset or worsening during pregnancy require pharmacological treatment to obtain a prompt remission of maternal mental impairment and, thus, to prevent further complications to the mother–infant pair.

In fact, the detrimental impact of untreated prenatal depressive episodes on delivery outcomes, infant neuropsychological development, and social behavior during adolescence is well recognized.[1•,2•] Moreover, antenatal monopolar depression is also known as a strong predictor of postpartum depression.[3] As regards bipolar disorder, discontinuing mood-stabilizing drugs during pregnancy carries a high risk for new morbidity, especially for early depressive and dysphoric states.[4] Poor pregnancy outcomes (including preterm births, low birth weight, and babies small for gestational age) have also been associated with maternal bipolar disorder.[5•]

Drug Treatment for Mood Disorders in Pregnancy

Posted: 01/23/2011

Salvatore Gentile

Abstract

Purpose of review During the last few years, several researches, often showing contradictory findings, have investigated the safety of psychotropic medications used for treating mood disorders in pregnancy. Hence, the necessity exists to update this information constantly in order to ensure the safest option for the mother–infant pair.
Recent findings The risk of fetal anomalies associated with early in-utero exposure to antidepressants seems to be increased after paroxetine and clorimipramine exposure, whereas prenatal exposure to nearly all antidepressants is linked to the potential onset of the Prenatal Antidepressant Exposure Syndrome. As regards classic mood stabilizers, the teratogenic risk historically reported with lithium should probably be softened, whereas valproate is the medication which shows the strongest association with fetal anomalies. An increased risk of autism-spectrum disorders and infant neurodevelopmental delay is also associated with valproate exposure through the placenta. No significant reproductive safety data are available on atypical antipsychotics, although such medications may indirectly increase the rate of fetal malformation by inducing gestational diabetes.
Summary Avoiding the use of clorimipramine, paroxetine, valproate, and atypical antipsychotics during pregnancy is advisable. However, when starting or continuing pharmacological treatment during pregnancy, clinicians should consider not only the intrinsic iatrogenic risk of birth defects or perinatal complications, but also the general safety profile for the expectant mother. Indeed, specific adverse reactions (such as nausea, vomiting, constipation, and excessive weight gain) may aggravate the classic clinical findings of pregnancy, thus indirectly facilitating the occurrence of pregnancy complications and fetal and neonatal problems.

Introduction

Almost all psychiatric disorders at onset or worsening during pregnancy require pharmacological treatment to obtain a prompt remission of maternal mental impairment and, thus, to prevent further complications to the mother–infant pair.

In fact, the detrimental impact of untreated prenatal depressive episodes on delivery outcomes, infant neuropsychological development, and social behavior during adolescence is well recognized.[1•,2•] Moreover, antenatal monopolar depression is also known as a strong predictor of postpartum depression.[3] As regards bipolar disorder, discontinuing mood-stabilizing drugs during pregnancy carries a high risk for new morbidity, especially for early depressive and dysphoric states.[4] Poor pregnancy outcomes (including preterm births, low birth weight, and babies small for gestational age) have also been associated with maternal bipolar disorder.[5•]

Notwithstanding these effects, up to 70% of patients with mood symptoms during pregnancy withdraw psychotropic medications and refuse psychiatric counseling. Notably, care does not resume during the postpartum period.[6,7] Without doubt, fear of harmful fetal events plays a decisive role in posing mental barriers to pharmacological treatment for prenatal mood disorders.

Hence, the necessity exists to assess the reproductive safety profile of psychotropic agents commonly used in psychiatric practice for treating mood disorders (such as antidepressants, mood stabilizers, and atypical antipsychotics), in order to establish whether or not the well established benefits of drug treatment for mothers outweigh the potential risk for the fetus and newborn. In particular, this review analyses the structural teratogenicity (the risk of fetal major malformations associated with drug exposure during the first trimester of pregnancy) and the perinatal teratogenicity (the risk of poor obstetrical outcomes and neonatal complications associated with drug exposure in late pregnancy) for such classes of psychotropics.

Antidepressants

Among psychotropics, antidepressant agents are the medications most frequently used during pregnancy.

Selective Serotonin Reuptake Inhibitors and Serotonin/Norepinephrine Reuptake Inhibitors

Serotoninergic antidepressants represent the class of antidepressants which show the highest number of studies on their reproductive safety.

Structural Teratogenicity Until 2005, selective serotonin reuptake inhibitors (SSRIs) had been deemed relatively safe for pregnant women because, at that time, no changes in the prevalence of congenital anomalies were observed in infants exposed prenatally to these antidepressants compared with those nonexposed.[8]

In recent years, however, several concerns have been raised about the teratogenic safety of SSRIs. In particular, as regards the risk of congenital birth defects, on the basis of data still unpublished at the time, in 2005 the US Food and Drug Administration (FDA) requested the manufacturer to change the pregnancy category of one of the most frequently used SSRIs, paroxetine, from C to D, as the drug was suspected of increasing the risk of fetal structural malformations and, particularly, of cardiac anomalies.[9] These results, based on a retrospective analysis of a large US database, were published only 2 years later.[10] The most recent retrospective analysis of information included in the Swedish Health Register[11] also suggests a statistically significant relationship between prenatal exposure to paroxetine and an increase in the specific risk of hypospadias. Nevertheless, studies that exclude any teratogenic liability of paroxetine are also available.[12]

Other SSRIs, such as fluoxetine, sertraline and citalopram, however, have been implicated in increasing the risk of fetal cardiac defects,[13–15] whereas preliminary data on escitalopram are, for the moment at least, quite reassuring.[16]

Nonetheless, given the inconsistency of the findings and limitations of the methodology of the published studies, the detrimental impact on the developing fetus suggested for most of the SSRIs remains, if existing, substantially uncertain.[17••]

As regards serotonin/norepinephrine reuptake inhibitors (SNRIs), the largest prospective, controlled studies[18] specifically focused on investigating the risk of fetal malformations following early pregnancy exposure to venlafaxine found no increase in the teratogenic risk. However, contradictory results emerged when venlafaxine was investigated jointly with other serotoninergic antidepressants.[19] Until now, no significant studies are available on the use of duloxetine during early pregnancy.

Perinatal Teratogenicity Measurable concentrations of antidepressant agents in amniotic fluid have been demonstrated,[20] thus suggesting that maternally administered antidepressants may be accessible to the fetus in an adjunctive manner. Indeed, circulars sent out in 2004 by the FDA, Health Canada, and pharmaceutical sectors highlighted concerns on the use of SSRIs and SNRIs during late pregnancy.[21–24] Moreover, the FDA issued a second advisory on 19 July 2006, based on evidence showing their use may be linked to persistent pulmonary hypertension of the newborn (PPHN), a potentially life-threatening condition.[25] Despite this last association still remaining controversial,[26–28] a wide spectrum of neonatal complications (including cardiac, respiratory, neurological, gastrointestinal, and metabolic problems – due to either toxic or withdrawal phenomena –[29] recently labeled Prenatal Antidepressant Exposure Syndrome[30••]) have been reported after exposure to SSRIs (and other classes of antidepressants) during the last stages of pregnancy. Hence, the finding that newborns exposed to SSRI/SNRI in utero may have twice the risk of being referred to neonatal intensive care units is not surprising.[31]

Tricyclic Antidepressants

No recent studies are available on the reproductive safety of tricyclic antidepressants (TCAs).

Structural Teratogenicity A review in progress assessing published information on the use of TCAs during early pregnancy (S. Gentile, A. Wieck, unpublished observation) seems to indicate a relationship between clorimipramine exposure and fetal cardiac defects, whereas no definitive conclusions can be drawn on other TCA agents.

Perinatal Teratogenicity An increased risk of developing the Prenatal Antidepressant Exposure Syndrome has also been reported in neonates exposed to TCAs during the last stage of their intrauterine life.[27]

Other Antidepressants

In this subsection, the little available information on antidepressant medications belonging to classes other than SSRIs, SNRIs, or TCAs is summarized.

Structural Teratogenicity Probably due to a less frequent use in psychiatric practice than that of serotoninergic antidepressants, teratogenic studies on other antidepressants (bupropion, mirtazapine, nefazodone, reboxetine, and trazodone) are scarce. However, until now there are no signals that such medications may increase the rate of birth defects.

Perinatal Teratogenicity At least for mirtazapine and reboxetine, the risk of perinatal complications seems to be confirmed.[32]

Classic Mood Stabilizers

The reproductive safety of classic mood stabilizers has been investigated in several studies.

Lithium

Lithium was the first drug with proven mood-stabilizing properties.

Structural Teratogenicity A relatively recent update of published information regarding the risk of fetal structural malformations associated with placental exposure to lithium suggests that this medication is not a significant human teratogen.[33] Hence, the ‘historical’ concern of an increased risk of Ebstein’s Anomaly in ‘lithium babies’ should be softened, on the basis of the following results:

  1. Case reports, overall including 24 babies, described just one case of Ebstein’s Anomaly.
  2. Retrospective and prospective studies, overall involving more than 500 pregnant women, identified eight cases of this cardiac malformation.
  3. In case–control studies, just one of the 266 malformed babies had been prenatally exposed to lithium.

In the light of such findings, the main clinical concern regarding the use of lithium during early pregnancy remains the need to frequently monitor maternal serum drug levels and, eventually, to adjust daily dose when symptoms due to hyperemesis gravidarum, such as vomiting, may lead to dehydration and, thus, to a rapid increase in lithium levels.[34]

Perinatal Teratogenicity An interesting study by Newport et al. [35] demonstrated that, if lithium is used during late pregnancy, the risk for neonatal complications, such as lower Apgar scores, longer hospital stays, and central nervous system and neuromuscular adverse reactions, cannot be ruled out. Moreover, this risk directly relates to the level of the drug in infant serum. Other lithium-induced perinatal complications include preterm birth and macrosomia.[36] Moreover, thyroid toxicity (congenital goiter), nephrogenic diabetes insipidus, cardiovascular and renal dysfunctions, and PPHN all have been anecdotally reported in babies exposed to lithium through placenta.[36]

Of note, serum lithium levels should be frequently monitored even during late pregnancy (when changes in glomerular filtration rate can alter lithium clearance and increased frequency of urination may reduce serum lithium concentrations[37]).

Antiepileptic Drugs

With the exception of lamotrigine, these medications show the worst reproductive safety profile.

Structural Teratogenicity A growing body of evidence has demonstrated definitively the teratogenic liability of valproate. The rate of fetal major malformations associated with valproate exposure through placenta has consistently been found to be two to three times higher compared with that of carbamazepine or lamotrigine. Indeed, a recent, controlled study has estimated at 11.3% the prevalence of birth defects in newborns of epileptic women treated with valproate monotherapy.[38•] The risk of valproate-induced fetal malformations seems to be dose-dependent, because this rate may further increase two-fold for maternal daily doses higher than 800–1000 mg.[39] The overall spectrum of valproate-induced fetal malformations has been included under the definition of ‘fetal valproate syndrome’ (see Table 1). The risk of valproate-induced birth defects may rise still more when the drug is used in combined therapies (the most dangerous association being suspected is valproate plus lamotrigine). However, this finding remains controversial, because recent analysis of data recorded in the Australian Register of Antiepileptic Drugs in Pregnancy[40] found that, for pregnancies exposed to valproate, the relative risk of fetal malformation was lower in polytherapy (7.26%) than in monotherapy (17.9%); the difference did not depend on valproate dosage. Logistic regression also suggested that co-administration of lamotrigine may have reduced the malformation risk from valproate.

Table 1. The fetal valproate syndrome

Epicanthic foldsInfraorbital groove
Medial eyebrows deficiencyFlat nasal bridge
Long thin upper lipShort nose with anteverted nares
Thick lower lipSmall, downturned mouth
Cardiac malformationsSpina bifida
Hypospadias

On the contrary, although for many years carbamazepine has been deemed as highly teratogenic (see Table 2), recent research[41] has shown that the overall prevalence of malformations associated with this medication seems to be similar to that of lamotrigine (conversely, so far deemed as relatively safe for pregnant women, apart from its own suspected liability to increase the risk of nonsyndromic cleft lip and/or palate[42,43]). In any case, therapeutic monitoring of both drugs is advisable during pregnancy. Recent findings have actually confirmed that the elimination of lamotrigine and the active metabolite of carbamazepine is enhanced during pregnancy.[44]

Table 2. The fetal carbamazepine syndrome

Epicanthic foldsShort nose with hypoplastic nares, long philtrum
Orofacial cleftUpward slanting palpebral fissures
Cardiac malformationsSpina bifida

Perinatal Teratogenicity Adverse pregnancy and birth outcomes (including prematurity, low birth weight, low Apgar scores, and head circumference less than 2.5 percentile) are more frequent in women treated with antiepileptic drugs.[45••]

Atypical Antipsychotics

Atypical antipsychotics are increasingly used as treatment of bipolar disorder.

Structural Teratogenicity

Recent research on the risk of congenital malformations in infants exposed to such medications through the placenta is sparse. Reis and Källén[46] found a slight, nonspecific risk of congenital defects in infants whose mothers had been treated with different antipsychotics, either typical or atypical, whereas data collected both prospectively and retrospectively suggested that atypical antipsychotics were not associated with an increased risk for major malformations.[47] Risperidone is the only atypical antipsychotic which shows a specific, relatively large study investigating its teratogenic potential. This study analyzed data on more than 700 pregnancies retrospectively or prospectively identified through the Benefit Risk Management Worldwide Safety Database, a register established by the Benefit Risk Management, a division of Johnson & Johnson Pharmaceutical Research & Development, LLC.[48] The drug was not associated with an increase in the risk of fetal malformation.

Perinatal Teratogenicity

To quantify placental permeability to antipsychotic medications and to document obstetrical outcomes for women taking these agents proximate to delivery, Newport and colleagues[49] conducted a prospective, observational study on a small number of women treated with atypical antipsychotics during pregnancy. Maternal and umbilical cord plasma samples collected at delivery were analyzed for medication concentrations. Placental passage, defined as the ratio of umbilical cord to maternal plasma concentrations, was highest for olanzapine, followed by risperidone and quetiapine. Obstetrical outcomes (ascertained through maternal reports and reviews of obstetrical records) showed tendencies toward higher rates of neonatal intensive care unit admission (30.8%) among neonates exposed to olanzapine. Recently, it has been reported that pregnancy exposure to olanzapine might be associated with higher birthweight compared with exposure to other psychotropic medications.[50] However, the risk of having babies small for gestational age and with low birth weight among mothers with schizophrenia seems to be unaffected by antipsychotic exposure during pregnancy.[51]

Conclusion

Given these results, it is clear that no psychotropic medications are fully devoid of risks if used during pregnancy. On the other hand, it is irresponsible to leave severely mentally ill women untreated, even if pregnant or lactating. Hence, clinicians should abandon any attempt to individuate the safest option and should rechannel their attention toward individuating the least worrying option.

Most of the classes of psychotropics or single psychotropic agents, however, have shown no specific advantages in their reproductive safety. For this reason, when pharmacological treatment is deemed indispensable for treating mood disorders at onset during pregnancy, clinicians should consider not only the risk of birth defects or perinatal complications, but also the general safety profile for the expectant mother. Indeed, specific iatrogenic adverse reactions (such as nausea, vomiting, constipation, and excessive weight gain) related to psychotropic treatment may further aggravate the classic clinical findings for pregnancy, thus indirectly facilitating the occurrence of both pregnancy complications and fetal and neonatal risks. Both prematurity and low birth weight have been reported in mothers who had suffered from intractable vomiting during pregnancy.[52] Vomiting in pregnancy may also lead to increased rates of maternal complications, such as gallbladder and liver dysfunction, renal failure, and retinal hemorrhage. For some women, this symptom, especially when due to hyperemesis gravidarum, may continue during postpartum and may be complicated by the onset of food aversions, muscle pain, nausea, and post-traumatic stress disorder-related features.[52] Excessive weight gain in pregnancy is associated with an increased risk of cardiac and pulmonary diseases, gestational hypertension and diabetes, thromboembolisms, obstructive sleep apnea, breast cancer, and fetal congenital abnormalities.[53,54] Sometimes, constipation can also lead to maternal problems, including hemorrhoids, rectal prolapse, fecal impaction, and pelvic floor damage.[55,56] Consequently, psychotropic drugs more likely to induce these untoward events should be avoided. In the light of these results, the following specific considerations can be drawn.

Antidepressants

All but a few agents have been involved in at least one study suggesting structural teratogenesis. Therefore, it is difficult to identify the less dangerous drug.

Starting Antidepressant Treatment during Pregnancy Despite this premise, a conservative approach should exclude the use of paroxetine and clorimipramine, because both show a relatively high number of worrying results. Nonetheless, both older and newer antidepressants have been associated with the occurrence of Prenatal Antidepressant Exposure Syndrome. Recent research suggests that the risk of such a complication may be related to the length of antidepressant exposure during pregnancy rather than the timing (early versus late pregnancy) of exposure.[57] It has been also reported that this risk cannot be reduced by suspending medication during the third trimester.[58••] Thus, ensuring that delivery happens in hospitals equipped with neonatal intensive care units is a mandatory precaution in all women taking antidepressants during pregnancy.

As regards the general safety profile, among SSRIs fluvoxamine is generally associated with the highest incidence of nausea and vomiting,[59] whereas citalopram, together with paroxetine, is the SSRI more likely to induce weight gain.[60] However, mirtazapine is significantly more likely than SSRIs to cause bodyweight changes. On the other hand, SNRIs are associated with a relatively high frequency of constipation compared with other classes of modern antidepressants.[61]

Thus, among SSRIs, fluoxetine, sertraline, and escitalopram should be considered first-line agents during pregnancy, while bupropion should be taken into consideration when clinicians deem the use of serotoninergic antidepressants to be contraindicated. In fact, bupropion shows a general safety profile (dry mouth, insomnia, and hyperhidrosis[62]) unlikely to interfere with the problems characterizing the physiological course of pregnancy. Moreover, results from recent research suggesting that in-utero exposure to bupropion may increase the risk of developing attention-deficit/hyperactivity disorder[63] should be interpreted with great caution, due to the methodological limitations of this study.

Managing Pharmacological Treatment in Women who Become Pregnant while Taking Antidepressant Medications Apart from paroxetine and clorimipramine (which show the highest number of signals[64] suggesting structural teratogenesis) and fluvoxamine (which shows insufficient teratogenic data), differences in risk between the other antidepressant drugs are not particularly evident. Hence, most of these mothers may take advantage of continuing the previous effective pharmacological regimen rather than experiencing a pharmacological shift (which may expose the fetus to two different medications and, contemporarily, the mother to psychiatric relapse due to a poor response to the new antidepressant).

Classic Mood Stabilizers

Classic mood stabilizers and, especially, some antiepileptic drugs are associated with several and serious reproductive safety concerns.

Starting Mood-stabilizing Treatment during Pregnancy When choosing a classic mood stabilizer, given the undetermined teratogenic risk and the limited indications of carbamazepine (in some countries merely approved as an antimanic agent) and the alarms related to valproate use in pregnancy (recently also associated with severe cognitive dysfunctions and increased risk of autism-spectrum disorders),[65••,66] we strongly discourage the use of both compounds during pregnancy. In contrast, the efficacy/reproductive safety profile of lamotrigine and lithium seems to suggest the use of the former in pregnant women diagnosed with bipolar II disorder. Despite the general safety profile being favorable to lamotrigine (lithium is indeed associated with weight gain), lithium should still be preferred in those women with bipolar I disorder. However, ensuring that delivery happens in hospitals equipped with neonatal intensive care units is mandatory in all pregnant women taking lithium.

Managing Pharmacological Treatment in Women who Become Pregnant while Taking Mood-stabilizing Medications It is frequent that pregnant women, especially those diagnosed with severe psychiatric disorder, become aware of their condition when it is too late to take advantage of pharmacological shift or withdrawal. Hence, when conception happens during valproate or carbamazepine treatment, these mothers should be informed about the reproductive risks associated with both medications. In this way, these mothers would be able to make a conscious decision on whether or not to continue the pregnancy.

Atypical Antipsychotics

In general, data on the use of atypical antipsychotics in pregnancy are limited.

Starting Antipsychotic Treatment during Pregnancy The only atypical antipsychotics that show a relatively high number of reports regarding their use in pregnancy are olanzapine, quetiapine, and risperidone.[67••] Unfortunately, all these medications are likely to induce weight gain, increased appetite, and even gestational diabetes.[68,69] For these reasons, such atypical antipsychotics should be avoided during the gestational period. Aripiprazole and ziprasidone should also be avoided because of the lack of reproductive safety data. Therefore, when antipsychotic treatment is indispensable during pregnancy (for example, in the case of delusional depression or severe manic phases), typical agents, specifically chlorpromazine, should be preferred, because this drug evidences less worrying teratogenic data.[65••] Unfortunately, however, the use of both typical and atypical antipsychotics during late pregnancy seems to be inevitably associated with an increased risk of perinatal complications (including extrapyramidal signs, which may persist up to 1 year of age, respiratory distress, seizures, and transient neurodevelopmental delay).[65••] Thus, ensuring that delivery happens in hospitals equipped with neonatal intensive care units is also strongly advisable for those women needing antipsychotic treatment during late pregnancy.

Managing Pharmacological Treatment in Women who Become Pregnant while Taking Antipsychotic Medications Because several atypical agents are associated with either indirect teratogenesis (increased risk of birth defects associated with gestational metabolic complications) or insufficient teratogenic data, shifting mothers who become pregnant during atypical antipsychotic treatment to typical agents seems to be advisable.

Curr Opin Psychiatry. 2011;24(1):34-40. © 2011 Lippincott Williams & Wilkins

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    Papers of particular interest, published within the annual period of review, have been highlighted as:
    • of special interest
    •• of outstanding interest
    Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 82).

Curr Opin Psychiatry. 2011;24(1):34-40. © 2011 Lippincott Williams & Wilkins

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