| Abstract|| |
Aims: Untreated perinatal depression and anxiety disorders are known to have significant negative impact on both maternal and fetal health. Dilemmas still remain regarding the use and safety of psychotropics in pregnant and lactating women suffering from perinatal depression and anxiety disorders. The aim of the current paper was to review the existing evidence base on the exposure and consequences of antidepressants, anxiolytics, and hypnotics in women during pregnancy and lactation and to make recommendations for clinical decision making in management of these cases.
Materials and Methods: We undertook a bibliographic search of Medline/PubMed (1972 through 2014), Science Direct (1972 through 2014), Archives of Indian Journal of Psychiatry databases was done. References of retrieved articles, reference books, and dedicated websites were also checked.
Results and Conclusions: The existing evidence base is extensive in studying multiple outcomes of the antidepressant or anxiolytic exposure in neonates, and some of the findings appear conflicting. Selective serotonin reuptake inhibitors are the most researched antidepressants in pregnancy and lactation. The available literature is criticized mostly on the lack of rigorous well designed controlled studies as well as lacunae in the methodologies, interpretation of statistical information, knowledge transfer, and translation of information. Research in this area in the Indian context is strikingly scarce. Appropriate risk-benefit analysis of untreated mental illness versus medication exposure, tailor-made to each patient's past response and preference within in the context of the available evidence should guide clinical decision making.
Keywords: Antidepressants, anxiolytics, birth outcomes, lactation, pregnancy, psychotropic
|How to cite this article:|
Ram D, Gandotra S. Antidepressants, anxiolytics, and hypnotics in pregnancy and lactation. Indian J Psychiatry 2015;57, Suppl S2:354-71
| Introduction|| |
Drug management of pregnant and breastfeeding women afflicted with comorbid psychiatric disorders offers a potential challenge for management. Perinatal psychiatry is emerging as an important consultation subspecialty considering a growing number of pregnancies in women with more severe and chronic mental disorders and up to one-third of women being exposed to psychotropics during pregnancy. 
A risk-benefit assessment in terms of risks of untreated psychiatric symptoms against those due to adverse effects of psychotropic medications to the fetus and mother must be considered.  This risk may present as spontaneous abortion or premature labor, toxicity or withdrawal symptoms to the fetus, morphological teratogenicity, and risk of breastfeeding while on psychotropic. Psychiatric illness impairs the level of functioning and ability for the woman who is pregnant to care for herself and fetus. It may lead to malnutrition, refusal or inability to participate in prenatal care, premature delivery, intended harm to the fetus or neonate through suicide or neonaticide, precipitous delivery or high-risk delivery. ,,,,,
The purpose of this paper was to present a complete review of the literature and guide clinical decision making for the use of antidepressants, anxiolytics, and hypnotics during the pregnant state and postpartum during lactation. A bibliographic search of Medline/PubMed (1975 through 2014), Science Direct (1975 through 2014), Archives of Indian Journal of Psychiatry databases was done. References of retrieved articles, reference books, and dedicated websites were also checked. The paper will present the usage of these psychotropics in two sections, one devoted to the state of pregnancy, and the other to the postpartum state, primarily lactation.
| Section 1|| |
Issues related to psychotropic drug use in pregnancy
Pharmacokinetic changes in pregnancy
Adverse drug events are often linked to the pharmacokinetic variations in maternal, placental, or fetal variables.  Physiological changes in maternal absorption include slower gastric emptying, increased mucus production, decreased acid secretion. There is increased intravascular and extravascular volume of distribution, decreased plasma binding concentration, and albumin binding capacity. Microsomal liver enzymes get induced by circulating steroids, and there is biliary stasis. Glomerular filtration rate and renal blood flow are increased. Finally, nonionized, lipid-soluble, low molecular weight drugs have a better transplacental absorption. Vulnerability factors for the fetus include small total plasma volume, decreased albumin with increased levels of free drugs, decreased hepatic enzyme formation, decreased GFR, and immature blood-brain barrier. 
The change in psychotropic dose can be complex depending on the trimester(s) of exposure. For example, to maintain serum levels within the therapeutic range, particularly in the third trimester, the dose of tricyclic antidepressant (TCA) must be increased 1.6 times the mean dose required when the patients are not pregnant.  In addition, some drugs tend to concentrate in the fetus, and their effects may be prolonged even after delivery.  It is advisable to monitor the effectiveness of treatment throughout pregnancy to achieve the lowest effective dose of any agent, and further, to discontinue psychoactive drug(s) by tapering the dose, especially for antianxiety drugs, 2 weeks before the estimated delivery date to minimize neonatal effects. However, in patients with the severe disease, it may precipitate discontinuation syndromes or recurrence of signs and symptoms. Consultation liaison with other physicians (e.g., psychiatrist, pediatrician, or obstetrician), is always advisable. 
Why are we so less informed about psychotropic drug usage in pregnancy?
Case reports or retrospective cohort epidemiologic studies happen to be the primary source for risk estimation of psychotropic drug exposure during pregnancy. The bottlenecks in such evidence base include possible reporting bias and the many confounding variables, such as lack of accounting for nutritional and health status; maternal age; use of alcohol, tobacco, or illicit drugs; environmental toxins; history of miscarriages and stillbirths; genetic history; use of multiple drugs including nonprescription drugs; gestational age at time of drug exposure; compliance; total dose; and the effects of the psychiatric illness or other illnesses present.
Prospective, randomized, and well-controlled investigational studies  on the risks of exposure to psychoactive drugs during pregnancy are neither feasible nor ethical. Doses used in prehuman animal trials do not reliably predict the human response. 
Overestimation of the fetal risk to a specific drug or a combination of medications is possible. Case reports do not establish causation.
It is necessary to distinguish between the natural prevalence rate and the rate at which the defect occurs in a population and the additional risk potentially attributable to a drug. Studies of large populations are required, yet usually unattainable, to determine the relative risk from specific potential teratogens.
Assessing neurobehavioral effects from in utero exposure to centrally acting drugs, especially beyond the immediate neonatal period should consider the dose, offspring's age and gender, and behavior test system. 
In view of such events  as the thalidomide crisis in the 1960's and the teratogenic effects of diethylstilbestrol in 1979, US Food and Drug Administration (FDA) developed strict guidelines regarding drug labeling,  use of medications in pregnancy with safety parameters before it was marketed [Table 1]. Some recommend that FDA ratings be replaced by narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of teratogenic risk.
In the backdrop of these limitations, we proceed to share the available data in usage of some specific categories of psychotropic agents.
Antidepressant medications in pregnancy
Antidepressant exposure during pregnancy may manifest in terms of one of the four outcomes: 
Pregnancy loss due to miscarriage
Psychotropic drug exposure during pregnancy might lead to miscarriage or abortions.
Risk of teratogenesis
Of the major birth defects studied in association with antidepressant use, omphalocele occurs in 1 per 5386 births, gastroschisis occurs in 1 per 2229, anencephaly 1 in every 4859, and craniosynostosis in 4-10 per 10,000 births in the general population.  A teratogen is defined as an agent that interferes with the process of organogenesis and produces some type of organ malformation or dysfunction.  Exposure to a toxic agent before 2 weeks of gestation is not associated with congenital malformations.  For each organ or organ system, there exists a critical period during which development takes place and may be susceptible to the effects of a teratogen. 
Refers to a spectrum of physical and behavioral symptoms observed in the acute neonatal period that are attributed to drug exposure at or near the time of delivery.
Long-term neurobehavioral sequelae
Manifest as insults that occur after neural tube closure produce changes in behavior and function, as opposed to gross structural abnormalities. Behavioral teratogenesis refers to the potential of a psychotropic drug administered prenatally to cause long-term neurobehavioral sequelae. 
During gestation, the degree of fetal antidepressant exposure is largely dictated by the placental passage of the medication. Although formal data are limited, it is assumed that all antidepressants cross the placenta.  Transfer across the placenta has been grouped into three categories: (1) Type I, complete transfer. These medications rapidly equilibrate in concentration between the maternal and fetal compartments; (2) Type II, excessive transfer. The umbilical cord concentrations are greater than maternal serum concentrations; (3) Type III, incomplete transfer. The umbilical cord concentration is less than maternal serum concentration. 
Preliminary data in terms of case reports , exist that medication levels decrease as the pregnancy progresses. Other case reports ,,,,, focusing on the disparity between the placental passage of TCA and selective serotonin reuptake inhibitor (SSRI) based on in vivo case series and ex vivo perfusion data yield controversial results. Whether or not such exposure accounts for purported withdrawal symptoms in the neonate is unclear.
Lately research evidence is being generated to ascertain the link between SSRI pharmacogenetics and specific fetal/neonatal outcomes.  The scientific inquiry is toward individual gene sequencing may provide more knowledge for safe maternal pharmacotherapies on an individualized basis and therefore contributing to better stratify the risk for the possible adverse neonatal outcome.
The available data do not seem to have addressed the issue of miscarriage due to the prenatal exposure to TCAs. In general, most case reports  do not support an increased risk of miscarriage following antidepressant use, but these assess SSRI risk than that of TCA.
Three prospective and more than 10 retrospective studies ,,, have examined the risk of organ dysgenesis in over 400 cases of first-trimester exposure to TCAs. Pooled data from these studies defy the findings of early case reports suggesting a possible association between first-trimester exposure to TCAs and limb malformation. Among the TCAs, desipramine and nortriptyline are preferred because they are less anticholinergic and the least likely to exacerbate orthostatic hypotension that occurs during pregnancy. 
A TCA withdrawal syndrome with characteristic symptoms of jitteriness, irritability, and less commonly, the seizure has been observed. ,,,, Withdrawal seizures have been reported only with clomipramine. ,,,, These symptoms have been given the rubric of postneonatal adaptation syndrome (PNAS). More recent reports have indicated that of all the infants exposed to TCAs in utero, 20-50% develop PNAS, ,, In addition, transient neonatal toxicity attributed to the anticholinergic effect of TCAs, including symptoms of functional bowel obstruction and urinary retention, have also been reported. ,,
Animal studies , demonstrate changes in behavior and neurotransmitter function after prenatal exposure to various psychotropic agents. The findings are difficult to extrapolate to humans. The data regarding neurobehavioral abnormalities following fluoxetine or TCAs exposure during pregnancy are limited but reassuring. In a landmark study, Nulman et al.  followed a cohort of children up to preschool age who had been exposed to either TCAs (n = 80) or fluoxetine (n = 55) during pregnancy (most commonly during the first trimester) and compared these subjects to a cohort of nonexposed controls (n = 84). No significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and nonexposed children were observed. A more recent report  from the same group followed a cohort of children exposed to fluoxetine (n = 40) or TCAs (n = 47) for the entire duration of the pregnancy and yielded similar results. Simon et al.  conducted a long-term case-control study that followed prenatal and developmental outcomes of 209 infants exposed to TCA during in utero and found results comparable to normal controls and even better than for SSRI exposed group in some aspects. However, these data are preliminary and further investigation into the long-term neurobehavioral effects of prenatal exposure to antidepressants, as well as other psychotropic medications, is warranted.
Selective serotonin reuptake inhibitor
The evidence regarding the safety of SSRIs in pregnancy has shown a change in the findings in the literature reported before and after 2005.  Majority of the studies done before 2005 ,,, report no significant association of poor fetal or pregnancy outcomes with SSRIs especially fluoxetine use, however, the literature reported after 2005 ,,, have unearthed some such associations. However, several reports , describe small increases in rates of spontaneous abortion among women treated during the first trimester of pregnancy with SSRIs or dual action agents (selective norepinephrine reuptake inhibitors [SNRIs]). This shift in literature has been attributed to limitations in statistical inference in rates of miscarriage between exposed and nonexposed women, insufficient statistical power, confounding by the depression itself that may contribute to increasing risk of spontaneous abortion, reporting bias of miscarriage when some subjects might have opted for termination of pregnancy. ,
Data reported earlier ,, have evaluated rates of congenital malformation in approximately 1100 fluoxetine-exposed infants and did not suggest an increased risk of congenital malformations with in utero exposure to SSRIs. Chambers et al.  noted an increase in risk for multiple minor malformations in fluoxetine-exposed infants. This study had several methodological limitations as, unexplained significant difference in terms of important variables, such as age, presence of psychiatric illness, and exposure to other medications between the fluoxetine-exposed women and control groups, nonblinded raters were used, and selection bias. , The post marketing surveillance registry data , from the manufacturer of fluoxetine and two other retrospective studies support these findings. These data collected from over 2500 cases indicate no increase in the risk of major congenital malformation in fluoxetine-exposed infants. A meta-analyses  combining studies with exposures to TCAs and SSRIs did not demonstrate an increase in the risk of congenital malformation. One prospective study  of 531 infants with first-trimester exposure to SSRIs (mostly citalopram, n = 375) did not demonstrate an increased risk of organ malformation. In a retrospective study  of 63 infants with first-trimester exposure to paroxetine, no increase in teratogenic risk was observed. In a prospective, controlled cohort study, Kulin et al.  reported on outcomes in neonates exposed in utero to fluvoxamine (n = 26), paroxetine (n = 97), and sertraline (n = 147). Pregnancy outcomes did not differ between the exposed and nonexposed groups in terms of risk for congenital malformation. Birth weights and gestational age were similar in both groups. Though this information on these SSRIs is reassuring, one of the major limitations of this study is that the analysis grouped the three antidepressants together versus analyzing each antidepressant separately for teratogenic risk.
More recent data reports findings which are inconsistent and make it difficult to implicate individual SSRIs associated with risk of congenital malformations. Two studies Alwan et al.  and Louik et al.  have linked the use of SSRI drugs to rare malformations, but both studies have limitations of recall bias and a high rate of nonresponders.
Some studies such as by Wogelius et al.  identified malformations from discharge diagnoses in women with and without intrauterine SSRI exposure. Limitations in this study included surveillance bias and overestimation of risks due to the identification of less serious malformations.
Isolated reports have found malformation risks with some specific SSRI exposure in utero. These include hypertrophic stenosis,  congenital heart defects, and other major abnormalities ,,, with fluoxetine, omphalocele, ,,, and cardiac septal defects ,, with sertraline, and omphalocele ,,, congenital heart defects, ,, and neural tube defects  with citalopram. Other studies however, have not suggested an association between fluoxetine, ,,,,,,,,,, sertraline, ,,,,,,, or citalopram ,,,, and major congenital abnormalities. While the data are very limited, escitalopram has not been associated with risk of major malformation. ,,,
Paroxetine has emerged as one of the most notorious SSRIs in terms of reported risks of malformation and recommendations in pregnancy. Strings of evidence have accumulated in this respect with a small study performed by GlaxoSmithKline in 2005  which suggested an increase in cardiac malformations in infants exposed to paroxetine in utero compared with controls. Thereafter, multiple studies ,,,,,,, although not all , have found an association between prenatal paroxetine exposure and an increased risk of congenital malformations (atrial and ventricular septal defects), yet the causality and magnitude of that risk are unclear. A recent meta-analysis found that paroxetine was associated with a 1.7-fold risk increase of cardiac malformation.  This finding was criticized due to the limitations in the methodology of the published studies.  Another meta-analysis that examined 37 studies from January of 1992 to September 2008, linking an increased risk of major congenital malformations with paroxetine exposure concluded that first trimester paroxetine exposure is associated with an increased prevalence of combined cardiac defects (prevalence odds ratio (POR) =1.46%; 95% confidence interval [CI]: 1.17-1.82) and aggregated defects (POR = 1.24; 95% CI: 1.08-1.43). ,
To overcome the limitation of the inadequate power of individual studies, evidence from meta-analysis might be more reliable. Five meta-analyses have investigated the risk for major malformations in association with antidepressant use during pregnancy. Four of these studies found no statistically significant increased risk of major malformations in the first trimester of pregnancy. ,,, The fifth meta-analysis found an increased risk of cardiac malformations in infants exposed to paroxetine in the first-trimester. 
Case reports ,,, and prospective studies , have described perinatal complications in fluoxetine exposed infants, including poor neonatal adaptation, respiratory distress, feeding problems, and jitteriness. Several other studies ,,, have not observed perinatal distress in infants exposed to fluoxetine. Limitations of these reports are that the effects of an antenatal mood disorder on the neonatal outcome are not taken into account given the absence of measurement of maternal mood across pregnancy. Case reports ,,,,, of neonatal withdrawal in neonates exposed to paroxetine have been published. In a prospectively ascertained sample  of 55 neonates exposed to paroxetine proximate to delivery (dose range 10-60 mg, median 20 mg), 22% (n = 12) had complications necessitating intensive treatment. The most common symptoms included respiratory distress (n = 9), hypoglycemia (n = 2), and jaundice (n = 1), all of which resolved over 1-2 weeks without specific intervention. Other prospective studies ,,, have similar findings. While the available evidence is conflicting, the overall data suggest that PNAS can occur in neonates exposed to SSRIs and SNRIs, yet have most often been reported after exposure to paroxetine, fluoxetine, and venlafaxine.  Furthermore, it is crucial to investigate other factors that modulate vulnerability to neonatal toxicity (e.g., prematurity and low birth weight). 
Another major association of in utero SSRI exposure is the risk of persistent pulmonary hypertension of the newborn (PPHN). Various prospective and case-control studies ,,,,, have implicated an association with multiple SSRIs with the risk of development of PPHN. These include fluoxetine, paroxetine, TCAs, monoamine oxidase inhibitors (MAOI) and SNRIs. In 2006, based on data reported at that time, the FDA published a Public Health Advisory regarding an increased risk of PPHN associated with the use of SSRIs after the 20 th week of pregnancy. This was repealed in December 2011 when the FDA released a Drug Safety Communication  which stated that there is insufficient evidence that antidepressant exposure during pregnancy causes PPHN. This is a result of the current evidence base which has reported either a small association between PPHN and maternal antidepressant use during pregnancy or no association. 
One study  evaluated the long-term sequelae of exposure to fluoxetine during pregnancy and found no effect on cognition, language development, or the treatment of preschool and early-school children. Another small study  followed up 31 infants exposed in utero to different SSRIs up to 6-40 months found lower scores in Bayley psychomotor development index. A more recent study  aiming to explore whether infants' language development is altered by prenatal exposure to SRIs and whether such effects differ from exposure to maternal mood disturbances were studied at 36 week gestation (while still in utero) on a consonant and vowel discrimination task and at 6 and 10 months of age on a nonnative speech and visual language discrimination task. Whereas the control infants (non-SRI-treated mothers with little or no depression) responded as expected (success at 6 months and failure at 10 months) the SRI-exposed infants (mothers depressed and treated with SSRI) failed to discriminate the language differences at both age and the depressed-only infants (Mothers depressed but non SSRI treated) succeeded at 10 months instead of 6 months. Fetuses at 36-week gestation in the control condition performed as expected, with a response on vowel but not consonant discrimination, whereas the SRI-exposed fetuses showed accelerated perceptual development by discriminating both vowels and consonants. The authors concluded that prenatal depressed maternal mood and SRI exposure were found to shift developmental milestones bi-directionally on infant speech perception tasks.
More recent studies  are linking in utero exposure to SSRI and MAOI to an increased risk of autism spectrum disorders, particularly without intellectual disability. These data come from a Swedish Stockholm county population-based nested case-control study  with 4429 cases of autism spectrum disorder (1828 with and 2601 without intellectual disability) and 43,277 age and sex matched controls in the full sample (1679 cases of autism spectrum disorder and 16,845 controls with data on maternal anti-depressant use nested within a cohort (n = 589,114) of young people aged 0-17 years. Similar results are obtained in a recent rodent study. 
Monoamine oxidase inhibitors
A study  on 21 prenatal exposures to monoamine oxidase inhibitors (MAOIs) found a relative risk of 3.4 for congenital malformations. In contrast, a case report  of phenelzine use throughout pregnancy described a healthy outcome for the patient and her infant. In some of more recent studies, , MAOI have been studied in conjunction with other SSRIs and SNRIs. One such retrospective case-control study  did not report adverse fetal outcomes with MAOI use. However, in another population-based prospective cohort study, MAOI along with other SSRIs have been found to be associated with increased risk of PPHN for early exposure in pregnancy (relative risks [RR] =2.30), for later exposure (RR = 2.56) and for both early and later exposure (RR = 3.44) Nevertheless, MAOIs are best avoided in pregnant women because of the risk of hypertensive crisis.
Some efforts were made in 2006  to review this issue. The data is presented below.
Only two studies have evaluated the use of venlafaxine in pregnancy. In one study,  venlafaxine was used in 150 women, and incidence of major malformations was similar to the expected rate of 1-3%. In the second study,  10 subjects who received venlafaxine during pregnancy gave birth to healthy babies. A large prospective cohort study  that included venlafaxine and other non-SSRI antidepressants found that the prevalence of cardiac malformations was well below the prevalence rate at 0.6% in the antidepressants as a group. Data obtained from the Swedish Medical Birth Registry  also do not suggest an increased risk of congenital malformations after exposure to SNRI/NRIs. The limitations in terms of small sample confounded interpretations.
A small case series  (n = 7) of mirtazapine use in pregnancy found no perinatal complications or congenital malformations in the infants. In another prospective comparative study,  aiming to explore the teratogenic potential of mirtazapine found that it was not associated with a risk for major malformations.
Nefazodone, trazodone, and vilazodone
Einarson et al.  evaluated the effect of prenatal exposure to nefazodone and trazodone, and found no significant difference in the number of major congenital malformation. No data on vilazodone could be found. 
In a study,  136 women exposed to bupropion during the first trimester of pregnancy were taken and there were 105 live births with no major malformations, however, this study was plagued with a small sample size. Recent data have been surfacing for bupropion safety. The Bupropion pregnancy register final report  by GlaxoSmithKilne reported 3.6% and 1.3% of infants exposed to bupropion were reported to have congenital abnormalities and congenital heart defects, respectively, from 1997 to 2008. A retrospective case-control study  that examined the risk of bupropion exposure 1-month prior to conception until 3 months after conception found that exposed infants were more likely to have left outflow tract heart defects, but not other defects (odds ratio [OR] =2.6; 95% CI: 1.2-5.7). Another case-control study  did not find an increased risk of congenital malformations when they compared first-trimester bupropion exposure to first-trimester exposure to other antidepressants; and to bupropion exposure outside the first trimester. A recent review  points out that even with the possible increased of congenital heart defects the absolute risk of a congenital heart defect remains low at 2.1/1000 births in exposed infants when compared to the estimated prevalence of 0.82/1000 births in the general population. 
Guidelines to clinical decision making for antidepressant use in pregnancy
General principles in reducing the risk of an adverse outcome in pregnancy exposed to any psychotropic would include adequate planning for pregnancy. One should consider the pregnancy as "high-risk pregnancy," consider informed consent, use the lowest effective dose for the shortest period of time necessary, while focusing on psychotropic medications, clinicians should not ignore other risk factors for poor perinatal outcome, such as obesity, smoking, and the use of alcohol or other substances of abuse and healthy behavior, including adherence to a prenatal vitamin regimen and to a schedule of prenatal care visits and maintenance of a healthy diet must be supported. 
Management of depression during pregnancy depends on the severity of the disorder. Mild depressive symptoms during pregnancy may improve with nonpharmacological treatments (interpersonal therapy). Pharmacological intervention is warranted in pregnant women with severe depression, including diminished oral intake, incapacitating vegetative symptoms, suicidality, and presence of psychotic symptoms.  Poor response to psychotherapy and patients who cannot devote time to psychotherapy sessions due to overwhelming demands of work, child-care, single parenthood, and financial strain also form candidates for pharmacotherapy. 
For women who are stable and from the past history appear to remain well for at least several months without taking the medications discontinuation of an antidepressant prior to conception might be thought of. Another reasonable approach is to continue antidepressants until conception is confirmed as by that time developing embryo will receive minimal medication exposure since the uteroplacental circulation does not form until 10-12 days postconception. 
For new-onset depression in pregnancy, an SSRI is generally accepted as the first line due to the fact that they are well-characterized and even though risks are reported the volume of data is reassuring, and further absolute risks interpreted are minimal.  However, if a patient has had a positive response to any specific agent from any class of antidepressants that agent should be strongly considered.  Women may be more likely to have a response to serotonergic agents, such as the SSRIs and venlafaxine, than to nonserotonergic TCAs. Slow increases in the dose are helpful in managing side effects. Dosages of certain drugs (i.e. TCAs, lithium) may need to be increased in the third trimester.
If possible, the MAOIs should be avoided for reasons cited in the text. Data are too limited to provide a recommendation for some newer antidepressants, but literature is emerging for caution especially for paroxetine and bupropion use.
Short-term discontinuation of an antidepressant may produce withdrawal symptoms  is associated with a 75% risk of relapse during pregnancy. , Therapy should be tailor made to the patient taking into account the number and severity of previous episodes and the time to relapse after previous attempts at medication discontinuation. For women with histories of rapid and severe relapses after medication discontinuation, antidepressants need to be maintained throughout the pregnancy. Overall, in order to provide optimal clinical care to women and their developing child, it is imperative to consider risks of treatment in the context of illness severity, consequences of no treatment, under-treatment, and individual treatment preferences. 
Anxiolytics and hypnotics in pregnancy
The literature on the pharmacological treatment of anxiety disorders occurring in pregnancy is very limited; what is available focuses on treatments of panic disorder and obsessive-compulsive disorder (OCD). Pharmacological agents such as SSRI (fluoxetine), TCA (imipramine), and MAOI (phenelzine) and benzodiazepine agonists (alprazolam, lorazepam, clonazepam, and diazepam) are the mainstay in the management of panic disorders, whereas primary anti-obsessional agents include clomipramine, fluoxetine, fluvoxamine, and sertraline. 
The effects due to the use of primary antidepressants as anxiolytics have already been covered in the section on antidepressant use during pregnancy. Since larger doses of TCAs are generally required in the management of OCD, the likelihood of withdrawal syndrome is increased. A withdrawal syndrome has been reported with clomipramine. ,, A growing controversy is the possibility of perinatal syndromes related to SSRI use during the third trimester of pregnancy. In Summer 2004, the FDA opted to instruct the makers of the SSRI and SNRI antidepressants to place warnings on the package inserts describing the possible occurrence of neurobehavioral symptoms in neonates exposed to these medications late in the third trimester and through labor and delivery. The subcommittee  also recommended changes to the dosage and administration section of the drug label advising physicians to consider taper and discontinuation of these agents prior to labor and delivery. Recent studies , have challenged this notion pointing that there is no evidence suggesting this approach reduces the incidence of PNAS or improves infant outcomes. It also carries the risk of precipitating relapse or postpartum depression and anxiety, particularly in high-risk individuals.
Benzodiazepine agonists in pregnancy
All major classes of benzodiazepine compounds diffuse readily across the placenta to the fetus. 
The major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. A benzodiazepine-induced "floppy infant syndrome" characterized by muscular hypotonia, low Apgar scores, hypothermia, impaired response to cold, and neurologic depression can occur at the time of delivery in benzodiazepine-dependent neonates, even with the lower doses used to treat anxiety disorders. Withdrawal signs include hypertonia, hyper-reflexia, restlessness, irritability, seizures, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, chewing movements, and abdominal distention. These signs can appear shortly after delivery to 3 weeks after birth and last up to several months depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. 
The data regarding the teratogenic potential of benzodiazepines when pooled suggests adequate reproductive safety. 
Animal studies ,,, have suggested its occurrence with some of the benzodiazepines. In humans, the findings were mixed, no motor or cognitive deficits were observed in children at 8 months of age, and no effects on IQ were observed at 4 years of age.  Conversely, delayed motor development and mental retardation were reported in 7 of 8 children with in utero exposure to various benzodiazepines. 
Salient issues relevant to individual agents are as follows
Diazepam has a long-acting metabolite, dimethyldiazepam, whose mean elimination half-life is 73 (30-100) hours in adults. The evidence that diazepam causes congenital malformations, especially cleft lip/palate is controversial,  however, association with floppy infant syndrome and PNAS has been reported. ,
Clonazepam has the longest mean elimination half-life of 23 (18-50) hours in adults. A limited surveillance study  revealed three major birth defects (0.8 expected) in 19 pregnant women exposed to clonazepam. Other effects attributed to this molecule include congenital heart disease, ventral septal defect, hip dislocation, uteropelvic junction obstruction, bilateral inguinal hernia, undescended testicle, paralytic ileus of the small bowel, cyanosis, lethargy, hypotonia, and apnea.  But in most cases, clonazepam was used along with other antiepileptics like phenytoin and barbiturates. In a large study  of 10,698 infants with congenital anomalies, maternal use of clonazepam during pregnancy was not significantly represented. Targeted sonography for anomaly screening is recommended at 18-20 weeks of gestation. 
Exposure to lorazepam has been linked to anal atresia and neonatal withdrawal symptoms, such as low Apgar scores, depressed respiration, hypothermia, poor suckling, and jaundice. The neonatal withdrawal symptoms can be severe because of shorter half-life. Hence, whenever possible lorazepam should be avoided during pregnancy. 
Use of alprazolam in pregnancy does not increase the risk of major malformations. It has been linked with malformations like cleft lip, inguinal hernia, hypospadias, cryptorchidism, tracheoesophageal fistula, patent ductus arteriosus, microcephaly, strabismus, congenital hip dislocation, fused lacrimal duct, Down's syndrome, cat's eye with Pierre Robin syndrome, pyloric stenosis, umbilical hernia, ankle inversion, lipomeningocele, neonatal withdrawal syndrome. Whenever possible, its use should be avoided in the first trimester. 
Guidelines for clinical decision making in the use of anxiolytics and hypnotics during pregnancy
Exposure to any type of benzodiazepine during the first 3 months of pregnancy should be avoided. However, its use during pregnancy is not absolutely contraindicated. For many anxiety disorders, nonpharmacological treatment are the first line, however, when medications are indicated physicians should use the benzodiazepines that have long safety records and should prescribe a benzodiazepine as monotherapy at the lowest effective dosage for the shortest possible duration. Furthermore, high peak concentrations of the drugs should be avoided by dividing the daily dosage into at least two doses. Finally, the best means of monitoring the safety and efficacy of therapy should be determined. 
From the viewpoint of the fetus, SSRI is recommended for preventive therapy for panic disorder during pregnancy. When a benzodiazepine is indicated for the treatment of an acute panic disorder in the pregnant patient, shorter half-life agents such as oxazepam, temazepam, lormetazepam are preferred during pregnancy to longer-acting diazepam and clonazepam. According to some lorazepam is preferred over alprazolam for preventive therapy, because it has a somewhat longer duration of action, it lacks active metabolites, and it does not seem to be associated with an immediate and as severe a withdrawal syndrome in the neonate. 
An SSRI is recommended first line for the treatment of OCD during pregnancy with adequate risk-benefit assessment. 
Clinical evidence from India in the estimation of risk following exposure to psychotropic drugs in general and antidepressants or anxiolytics and hypnotics, in particular, is very scarce. Probably, it is due to the nonmaintenance of pregnancy register in the country that the adverse drug exposures fail to be reported.
Sethi and Manchanda  analyzed all the neonates with one or more congenital abnormality during the 15-month period at the Queens Mary Hospital, KGMC Lucknow. Retrospective inquiry into the antenatal period of the mothers was conducted to gain information for the psychotropic drug history during pregnancy. Of 3825 births during 15 months, congenital abnormalities were observed in 58 neonates (incidence, 1.5%). 41 (70.7%) had a single defect and 17 (29.3%) had more than one defect. Of the drugs reportedly used during pregnancy, history of diazepam and chlorpromazine was available in one patient each during the second and third trimester only. History of other drugs in first trimester included hormonal preparations (5), analgesics (3), antiemetics (2), benzathine penicillin (1), ergot (1), Ayurvedic and Homeopathic compounds (1 each).
Other studies ,, done even earlier reported regarding the incidence of congenital malformations with varied molecules not limited to psychotropics. Some studies reported an incidence of 2-4%, while others of 1.4%.
This area has been relatively little explored thereafter. The reasons could be many ranging from ethical concerns regarding the designs of the study to poor recording and reporting of adverse outcomes due to lack of pregnancy register. The gap in the knowledge is huge, especially when the work done across the globe has improvised significantly both in terms of awareness of the psychiatric comorbidities in pregnancy and design of the prospective longitudinal studies which are methodologically sound to answer the clinical conundrums associated with decision making in this high-risk population.
| Section 2|| |
Issues related to psychotropic use during lactation
Maternal and neonatal pharmacokinetics
According to Buist et al.,  psychotropic drug exposure during lactation involves three distinct processes: The pharmacokinetics of the mother, transport of the drug into breast milk, and the pharmacokinetics of the developing infant.
Maternal factors include ionization fraction, protein binding of the drugs, dosage, frequency of drug administration, and the absorption of the dose by the mother. Blood flow to the breast, breast metabolism of the drug and milk composition also exert an influence. 
Neonatal absorption is influenced by pH of the breast milk; distribution is affected by differing fat/muscle/extracellular and total body water ratios. As well, neonates have less plasma protein and lipolysis occurring shortly after birth that brings about an increase in free fatty acids which compete with the drugs for protein binding. 
Neonates have a reduced capacity to metabolize and excrete drugs and drug metabolites can accumulate in the infant's system and though only a very small amount of drug may cross from mother to infant at any one feed, over time this may lead to potentially toxic levels. Hepatic metabolic processes of oxidation and glucuronidation are usually impaired in neonates. Finally, the process of breastfeeding itself can influence how much drug enters the infant's system. Suckling, time on each breast, amount consumed per feed, feeding intervals, and the interval between drug consumption and feeding all need to be considered. 
Antidepressants exposure during lactation
There is extensive literature focusing on antidepressants exposure in nursing mothers. The available database in this respect is provided in [Table 2].
|Table 2: Maternal dose, infant plasma concentrations of antidepressants after breast milk excretion and observed effects on infants|
Click here to view
Guidelines for antidepressant use in lactation
The data tabulated above have been synthesized by many comprehensive reviews and practice guidelines by some scientific organizations ,,,,,,,, which provide some recommendations in clinical decision making.
Basic recommendation of risk-benefit analysis is always upheld and the pointers for consideration include risk of untreated maternal illness for the mother and the infant, the risk/benefit of the specific treatment for the mother and the infant, the risk/benefit of being breastfed or not for the infant, the possible maternal risks of renouncing breastfeeding, and the mother's desire to breastfeed.
Nonpharmacological interventions such as psychotherapy should be considered, particularly for mild to moderate depression but for moderate to severe depression and in some cases also with an anxiety disorder, pharmacotherapy is indicated. Moreover, for women with previous postpartum depression or women who have been treated with antidepressants during pregnancy, antidepressants are the preferred mode of treatment in the prophylaxis or new episodes/relapses.
It is usually recommended that paroxetine and sertraline should be preferred over other SSRIs due to the low infant exposure for these drugs. When possible, fluoxetine and citalopram should be avoided or used with caution due to the higher infant plasma levels than for other drugs and the possible risk of adverse effects in the infant. ,, However, in case of prior effective treatment with fluoxetine or citalopram, or if the mother has used one of these drugs during pregnancy, it could also be used in the postpartum period. , Berle and Spigset  suggest that when antidepressant treatment is indicated in the postpartum period, the women should generally not be advised to discontinue breastfeeding.
Scarce data exist for drugs such as fluvoxamine, venlafaxine, duloxetine, reboxetine, bupropion, and mirtazapine and should not be considered as first-line therapies, but they can be used in special cases. ,,
Some of the reviews and guidelines recommend infant monitoring, particularly if the infant is sick, premature or has a low body weight. ,,
Routine breast milk and/or infant serum sampling for drug concentration analysis are generally not recommended. ,, It can, however, be helpful if the infant has signs that may be indicative of drug exposure. 
Pumping and discarding breast milk to reduce the exposure has been suggested to be of little value. It is important to reinforce the importance of breastfeeding and its benefits but not at all costs; we need to present a balanced view.
Limitations of the studies estimating drug concentrations in infant
There is no definitive consensus as to the best means to monitor the nursing infant's antidepressant exposure in the clinical setting. Monitoring infant serum concentrations is poorly reliable due to the fact that the laboratory assays do not have the sensitivity required to detect the typical serum concentrations of breastfeeding infants, further, in the absence of meaningful clinical correlation, even a detectable infant serum concentration is uninterpretable.  Mathematical models to forecast risk exposure via lactation are available but are derived from the collection of a single random breast milk sample and ignore pharmacokinetics of medications in the fetus. 
Gentile  recently proposed a specific safety index for antidepressant use in breastfeeding mothers. The index is expressed as the ratio between the reported number of infants with adverse events after exposure to an antidepressant through milk and the reported total number of exposed infants for the same antidepressant, multiplied by 100. It is suggested that a value <2 indicates that the drug is relatively safe; a value of 2.1-10 indicates that the drug should be used with great caution, and a value above 10 indicates that the drug should be contraindicated in breastfeeding mothers. The index has some bottlenecks in terms of low reliability with less sample size, less reliable interpretations depending on the quality of raw data. ,
Benzodiazepine anxiolytics during lactation
Benzodiazepines are commonly used medications in postpartum psychiatric disorders. Well-controlled studies in this respect are lacking, and much of the evidence is based on case reports.
In one such report,  oxazepam was identified in the urine of an 8-day-old breastfed infant whose mother had received diazepam 30 mg/day for 3 days. The child became lethargic, lost weight, and showed electroencephalogram changes consistent with a sedative drug. In another study,  oxazepam has been measured in the breast milk of a 33-year-old patient who received 30 mg/day of the drug for 3 days. Samples of oxazepam determination were collected each morning and evening and then 10 and 34 h after the final dose. In both plasma and milk, the half-life was 12 h, and the milk plasma ratio was between 0.1 and 0.3 throughout the sampling period. It was calculated that a suckling baby would be exposed to <1/1000 th of the maternal dose. Other studies ,, show excretion data as low as 1% with oxazepam and up to 8% with alprazolam.
Erkkola and Kanto  estimated diazepam and its major metabolite, N-desmethyldiazepam, in the milk and the infants' plasma of three women who received 30 mg/day of diazepam for 6 days after parturition. While there was an increase in the concentration of parent drug and metabolite from day 4 to 6 in the mothers' milk and plasma, the concentration in the infants' plasma declined which was attributed to the maturation of the infants' drug metabolizing capacity. A similar type of study was conducted by Brandt  and the metabolite levels (N-desmethyldiazepam) always exceeded those of the parent drug which was explained by the difference in the protein binding between two compounds.
Studies ,, have also shown the passage of lorazepam, lormetazepam, and quazepam into breast milk.
Whitelaw et al.  examined the effects of lorazepam on the children born to 51 women treated for up to 5 days after delivery with either an oral (n = 35) or an intravenous (n = 16) preparation. Plasma, cord blood, and urine samples were measured in 26 deliveries and breast milk samples in one patient. Neonatal excretion of lorazepam was gradual. Elimination in preterm babies was much slower than in full-term children. According to these authors, the low concentrations of drug involved were not associated with obvious adverse effects except for sedation lasting about 48 h.
The hypnotics such as nitrazepam and flunitrazepam have also been observed to be distributed into milk. ,
Two small studies , have suggested that the nonbenzodiazepine hypnotics zolpidem and zaleplon are safe in nursing.
Guidelines for benzodiazepine use in lactation
In general, short-term, low-dose use of benzodiazepines is considered fairly safe during lactation. No long-term adverse effects have been reported in exclusively breastfed children whose mothers were taking benzodiazepines on a regular basis,  but there have been a few case reports  of transient sedation in breastfed infants, which improved on cessation of breastfeeding. In cases where high doses are to be used or repeated administration will be needed then breastfeeding should probably be discontinued. The shorter-acting benzodiazepines (alprazolam, lorazepam) are favored over those with longer half-lives (clonazepam, diazepam). Moreover, the minimum dosage required for symptom relief should be used, and the infant should be monitored regularly. Single doses of benzodiazepines do not require any limitation on breastfeeding.
Work done in India
The literature in this field is again sparse, and the authors did not come across any study that attempted to address this issue. The literature worldwide is deficient in many ways to guide clinical decision making in cases with psychotropic use in lactation. It appears that the enlightened community in India will have to consider these research limitations and undertake steps to push for building research evidence base to make the best possible clinical judgment in these cases. The work at global level is considering elucidating the neurodevelopmental and genetic models to unearth the least exposure pathways to the fetus during lactation  and in this respect, our country seems to be at a very nascent stage where even the basic pregnancy register or even crude fetal drug estimation studies are not in place.
| Conclusions|| |
A pregnant patient with comorbid mental illness would require a careful evaluation of the risk-benefit assessment of psychotropic drug exposure leading to maternal benefit versus fetal harm and vice versa. The available evidence both during pregnancy and lactation does not report gross harm due to drug exposure in pooled data and provides some cautions concerning safety of use of some molecules. The available evidence needs to be viewed with an element of caution in the absence of well-designed controlled studies. Further, it is unlikely that such kind of studies would be forthcoming due to legal and ethical considerations. Similarly, during lactation, psychotropic drug not detected in the fetus does not completely abort the risk to the neonate and an approach of least possible drug exposure to the fetus should be followed. The guidelines that have been presented following an extensive review of the literature would help to guide clinical decision making both during pregnancy and lactation to minimize risk to the mother as well as the fetus. The research evidence in this aspect in India is miniscule, and a proper plan needs to be in place starting from the establishment of pregnancy registers to designing of studies to build an evidence base.
Future efforts at the global level include attempts to delineate the neurobiological and neurodevelopmental and pharmacogenetic avenues in exploring psychotropic drug exposure in the treated mother and information on this issue can allow further re-evaluation of risk-benefit assessment in this respect. , Attempts are also being made at the level of regulatory agencies to improvise existing drug labeling and information policies. Pregnancy labels of the future likely will address areas such as clinical considerations, summary risk assessment, and data to support the assessment. The goals of the initiative are to highlight clinical considerations relevant to making prescribing decisions for a particular medication for pregnant women, including disease risk and the risk of no treatment. This label also will include information that may assist clinicians when counseling women whose fetuses are inadvertently exposed to medications in early gestation. The summary risk assessment section may be a narrative text that articulates, as best can be determined, the risk of exposure based on animal and human data. 
Effective perinatal services in India need to start from the scratch. The attempt to gain insight into the research evidence regarding psychotropic drug exposure in pregnancy and lactation might start with a scientific and political will to establish pregnancy registers. Issues related to the ethical conduct of pregnancy registry research, including informed consent, and the timing and circumstances of outcome reporting are clearly complex, but this initiative would mark a welcome beginning in gathering clinical evidence. Further awareness and cooperation among the clinical experts including pediatricians, gynecologists, and physicians would be required for the better care of this high-risk population. The researchers in India need to develop a potential insight into developmental pharmacology and biology that can be gained through the careful study of adverse effects of drug exposure to the fetus.
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Mental Health Foundation St. Maarten, Dutch Caribbean, Ex-Faculty Central Institute of Psychiatry, Ranchi, Jharkhand
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]