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    Abstract
   Introduction
   Section 1
   Section 2
   Conclusions
    References
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REVIEW ARTICLE  
Year : 2015  |  Volume : 57  |  Issue : 6  |  Page : 354-371
Antidepressants, anxiolytics, and hypnotics in pregnancy and lactation


1 Director, Central Institute of Psychiatry, Ranchi, Jharkhand, India
2 Department of Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand, India

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Date of Web Publication27-Jul-2015
 

   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

How to cite this URL:
Ram D, Gandotra S. Antidepressants, anxiolytics, and hypnotics in pregnancy and lactation. Indian J Psychiatry [serial online] 2015 [cited 2020 Feb 24];57, Suppl S2:354-71. Available from: http://www.indianjpsychiatry.org/text.asp?2015/57/6/354/161504



   Introduction Top


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. [1]

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. [2] 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. [3],[4],[5],[6],[7],[8]

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 Top


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. [9] 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. [9]

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. [10] In addition, some drugs tend to concentrate in the fetus, and their effects may be prolonged even after delivery. [10] 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. [8]

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 [11] 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. [8]

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. [12]

In view of such events [13] 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, [14] 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.
Table 1: FDA use-in-pregnancy ratings

Click here to view


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: [15]

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. [16] A teratogen is defined as an agent that interferes with the process of organogenesis and produces some type of organ malformation or dysfunction. [15] Exposure to a toxic agent before 2 weeks of gestation is not associated with congenital malformations. [17] 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. [18]

Neonatal toxicity

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. [15]

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. [19] 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. [20]

Preliminary data in terms of case reports [21],[22] exist that medication levels decrease as the pregnancy progresses. Other case reports [21],[22],[23],[24],[25],[26] 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. [27] 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.

Tricyclic antidepressants

Pregnancy loss

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 [8] do not support an increased risk of miscarriage following antidepressant use, but these assess SSRI risk than that of TCA.

Teratogenic potential

Three prospective and more than 10 retrospective studies [28],[29],[30],[31] 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. [15]

Neonatal toxicity

A TCA withdrawal syndrome with characteristic symptoms of jitteriness, irritability, and less commonly, the seizure has been observed. [32],[33],[34],[35],[36] Withdrawal seizures have been reported only with clomipramine. [32],[33],[4],[35],[36] 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, [37],[38],[39] 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. [40],[41],[42]

Neurobehavioral sequelae

Animal studies [43],[44] 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. [45] 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 [46] 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. [47] 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

Pregnancy loss

The evidence regarding the safety of SSRIs in pregnancy has shown a change in the findings in the literature reported before and after 2005. [39] Majority of the studies done before 2005 [48],[49],[50],[51] report no significant association of poor fetal or pregnancy outcomes with SSRIs especially fluoxetine use, however, the literature reported after 2005 [52],[53],[54],[55] have unearthed some such associations. However, several reports [12],[56] 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. [39],[57]

Teratogenic potential

Data reported earlier [49],[51],[57] 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. [49] 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. [58],[59] The post marketing surveillance registry data [30],[47] 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 [48] combining studies with exposures to TCAs and SSRIs did not demonstrate an increase in the risk of congenital malformation. One prospective study [60] 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 [61] 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. [56] 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. [62] and Louik et al. [63] 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. [64] 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, [65] congenital heart defects, and other major abnormalities [66],[67],[68],[69] with fluoxetine, omphalocele, [63],[69],[70],[71] and cardiac septal defects [63],[69],[71] with sertraline, and omphalocele [63],[69],[70],[71] congenital heart defects, [63],[69],[71] and neural tube defects [68] with citalopram. Other studies however, have not suggested an association between fluoxetine, [63],[64],[69],[70],[71],[72],[73],[74],[75],[76],[77] sertraline, [54],[66],[72],[73],[74],[75],[76],[77] or citalopram [66],[73],[74],[75],[77] and major congenital abnormalities. While the data are very limited, escitalopram has not been associated with risk of major malformation. [63],[68],[75],[78]

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 [79] which suggested an increase in cardiac malformations in infants exposed to paroxetine in utero compared with controls. Thereafter, multiple studies [54],[62],[65],[66],[68],[72],[80],[81] although not all [67],[74] 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. [82] This finding was criticized due to the limitations in the methodology of the published studies. [83] 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). [39],[81]

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. [48],[84],[85],[86] The fifth meta-analysis found an increased risk of cardiac malformations in infants exposed to paroxetine in the first-trimester. [82]

Neonatal toxicity

Case reports [87],[88],[89],[90] and prospective studies [47],[49] have described perinatal complications in fluoxetine exposed infants, including poor neonatal adaptation, respiratory distress, feeding problems, and jitteriness. Several other studies [46],[50],[51],[56] 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 [91],[92],[93],[94],[95],[96] of neonatal withdrawal in neonates exposed to paroxetine have been published. In a prospectively ascertained sample [91] 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 [97],[98],[99],[101] 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. [39] Furthermore, it is crucial to investigate other factors that modulate vulnerability to neonatal toxicity (e.g., prematurity and low birth weight). [20]

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 [49],[102],[103],[104],[105],[106] 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 [107] 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. [39]

Neurobehavioral sequelae

One study [46] 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 [108] 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 [109] 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 [110] 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 [110] 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. [111]

Monoamine oxidase inhibitors

A study [112] on 21 prenatal exposures to monoamine oxidase inhibitors (MAOIs) found a relative risk of 3.4 for congenital malformations. In contrast, a case report [113] of phenelzine use throughout pregnancy described a healthy outcome for the patient and her infant. In some of more recent studies, [66],[76] MAOI have been studied in conjunction with other SSRIs and SNRIs. One such retrospective case-control study [76] 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.

Newer antidepressants

Some efforts were made in 2006 [114] to review this issue. The data is presented below.

Venlafaxine

Only two studies have evaluated the use of venlafaxine in pregnancy. In one study, [57] venlafaxine was used in 150 women, and incidence of major malformations was similar to the expected rate of 1-3%. In the second study, [115] 10 subjects who received venlafaxine during pregnancy gave birth to healthy babies. A large prospective cohort study [74] 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 [116] also do not suggest an increased risk of congenital malformations after exposure to SNRI/NRIs. The limitations in terms of small sample confounded interpretations.

Mirtazapine

A small case series [117] (n = 7) of mirtazapine use in pregnancy found no perinatal complications or congenital malformations in the infants. In another prospective comparative study, [118] 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. [119] 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. [39]

Bupropion

In a study, [120] 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 [121] 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 [122] 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 [123] 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 [39] 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. [52]

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. [8]

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. [22] 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. [124]

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. [125]

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. [39] However, if a patient has had a positive response to any specific agent from any class of antidepressants that agent should be strongly considered. [124] 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 [124] is associated with a 75% risk of relapse during pregnancy. [119],[126] 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. [39]

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. [8]

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. [127],[128],[129] 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 [130] 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 [55],[131] 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. [114]

Neonatal effects

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. [114]

Teratogenic effects

The data regarding the teratogenic potential of benzodiazepines when pooled suggests adequate reproductive safety. [114]

Neurobehavioral toxicity

Animal studies [132],[133],[134],[135] 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. [136] Conversely, delayed motor development and mental retardation were reported in 7 of 8 children with in utero exposure to various benzodiazepines. [137]

Salient issues relevant to individual agents are as follows

Diazepam

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, [138] however, association with floppy infant syndrome and PNAS has been reported. [66],[139]

Clonazepam

Clonazepam has the longest mean elimination half-life of 23 (18-50) hours in adults. A limited surveillance study [140] 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. [141] But in most cases, clonazepam was used along with other antiepileptics like phenytoin and barbiturates. In a large study [142] 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. [114]

Lorazepam

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. [141]

Alprazolam

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. [141]

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. [141]

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. [8]

An SSRI is recommended first line for the treatment of OCD during pregnancy with adequate risk-benefit assessment. [56]

Indian contribution

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 [143] 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 [144],[145],[146] 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 Top


Issues related to psychotropic use during lactation

Maternal and neonatal pharmacokinetics

According to Buist et al., [147] 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. [147]

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. [147]

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. [130]

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 [203],[204],[205],[206],[207],[208],[209],[210],[211] 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. [204],[205],[206] 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. [204],[205] Berle and Spigset [211] 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. [204],[205],[209]

Some of the reviews and guidelines recommend infant monitoring, particularly if the infant is sick, premature or has a low body weight. [204],[205],[209]

Routine breast milk and/or infant serum sampling for drug concentration analysis are generally not recommended. [204],[205],[207] It can, however, be helpful if the infant has signs that may be indicative of drug exposure. [208]

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. [19] 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. [19]

Gentile [206] 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. [203],[204]

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, [212] 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, [213] 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 [213],[214],[215] show excretion data as low as 1% with oxazepam and up to 8% with alprazolam.

Erkkola and Kanto [216] 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 [217] 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 [218],[219],[220] have also shown the passage of lorazepam, lormetazepam, and quazepam into breast milk.

Whitelaw et al. [221] 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. [222],[223]

Two small studies [224],[225] 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, [165] but there have been a few case reports [226] 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 [227] 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 Top


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 directions

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. [19],[227] 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. [15]

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.

 
   References Top

1.
Janicak PG, Davis JM, Preskorn SH, Ayd FJ. Principles and Practice of Psychopharmacotherapy. 3 rd ed. Philadelphia: Lippincott, William and Wilkins; 2001.  Back to cited text no. 1
    
2.
Miller LJ. Clinical strategies for the use of psychotropic drugs during pregnancy. Psychiatr Med 1991;9:275-98.  Back to cited text no. 2
    
3.
Miller LJ. Pharmacotherapy during the perinatal period. The Hatherleigh Guide to Psychopharmacology. New York: Hatherleigh Press; 1999.  Back to cited text no. 3
    
4.
Wintz CJ. Difficult decisions: Women of childbearing age, mental illness, and psychopharmacologic therapy. J Am Psychiatr Nurses Assoc 1999;5:5-14.  Back to cited text no. 4
    
5.
Stowe ZN, Strader J, James R, Nemeroff CB. Psychopharmacology during pregnancy and lactation. In: Schatzberg AF, Nemeroff CB, editors. Textbook of Psychopharmacology. 2 nd ed. Washington, DC: American Psychiatric Press, Inc; 1998.  Back to cited text no. 5
    
6.
Gjere NA. Psychopharmacology in pregnancy. J Perinat Neonatal Nurs 2001;14:12-25.  Back to cited text no. 6
    
7.
Wisner KL, Perel JM, Wheeler SB. Tricyclic dose requirements across pregnancy. Am J Psychiatry 1993;150:1541-2.  Back to cited text no. 7
    
8.
Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Committee on Drugs. American Academy of Pediatrics. Pediatrics 2000;105 (4 Pt 1):880-7.  Back to cited text no. 8
    
9.
Ward RM. Pharmacology of the maternal-placental-fetal-unit and fetal therapy. Prog Pediatr Cardiol 1996;5:79-89.  Back to cited text no. 9
    
10.
Kerns LL. Treatment of mental disorders in pregnancy. A review of psychotropic drug risks and benefits. J Nerv Ment Dis 1986;174:652-9.  Back to cited text no. 10
    
11.
Shader RI, Greenblatt DJ. More on drugs and pregnancy. J Clin Psychopharmacol 1995;15:1-2.  Back to cited text no. 11
    
12.
Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 1993;269:2246-8.  Back to cited text no. 12
    
13.
Meltolan MW. Take two aspirin tablets or not? Risk of medication use during pregnancy. Mother Baby J 1999;4:25-32.  Back to cited text no. 13
    
14.
Sachdeva P, Patel BG, Patel BK. Drug use in pregnancy; a point to ponder! Indian J Pharm Sci 2009;71:1-7.  Back to cited text no. 14
    
15.
Nonacs R, Cohen LS. Assessment and treatment of depression during pregnancy: An update. Psychiatr Clin North Am 2003;26:547-62.  Back to cited text no. 15
    
16.
Centers for Disease Control and Prevention (CDC). Update on overall prevalence of major birth defects - Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep 2008;57:1-5.  Back to cited text no. 16
    
17.
Langman J. Human development-normal and abnormals. In: Langman J, editor. Medical Embryology. Baltimore: Williams and Wilkins; 1985. p. 123.  Back to cited text no. 17
    
18.
Moore K, Persaud T. The Developing Human: Clinically Oriented Embryology. Philadelphia: W.B. Saunders; 1993.  Back to cited text no. 18
    
19.
Newport DJ, Wilcox MM, Stowe ZN. Antidepressants during pregnancy and lactation: Defining exposure and treatment issues. Semin Perinatol 2001;25:177-90.  Back to cited text no. 19
    
20.
Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet 1995;28:235-69.  Back to cited text no. 20
    
21.
Altshuler LL, Hendrick VC. Pregnancy and psychotropic medication: Changes in blood levels. J Clin Psychopharmacol 1996;16:78-80.  Back to cited text no. 21
    
22.
Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: Dilemmas and guidelines. Am J Psychiatry 1996;153:592-606.  Back to cited text no. 22
    
23.
Sjoqvist F, Bergfors PG, Borga O, Lind M, Ygge H. Plasma disappearance of nortriptyline in a newborn infant following placental transfer from an intoxicated mother: Evidence for drug metabolism. Br J Clin Pharmacol 1972;80:496-500.  Back to cited text no. 23
    
24.
Heikkine T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. BJOG 2002;109:1003-8.  Back to cited text no. 24
    
25.
Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry 2003;160:993-6.  Back to cited text no. 25
    
26.
Loughhead AM, Stowe ZN, Newport DJ, Ritchie JC, DeVane CL, Owens MJ. Placental passage of tricyclic antidepressants. Biol Psychiatry 2006;59:287-90.  Back to cited text no. 26
    
27.
Giudici V, Pogliani L, Cattaneo D, Dilillo D, Zuccotti GV. Serotonin reuptake inhibitors in pregnancy: Can genes help us in predicting neonatal adverse outcome? Biomed Res Int 2014;2014:276918.  Back to cited text no. 27
    
28.
Cohen L, Altshuler L. Pharmacologic management of psychiatric illness during pregnancy and the postpartum period. In: Rosenbaum J, editor. Psychiatric Clinics of North America: Annual of Drug Therapy. Philadelphia: WB Saunders; 1997. p. 21-60.  Back to cited text no. 28
    
29.
Loebstein R, Koren G. Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: The Motherisk experience. J Psychiatry Neurosci 1997;22:192-6.  Back to cited text no. 29
    
30.
McElhatton PR, Garbis HM, Eléfant E, Vial T, Bellemin B, Mastroiacovo P, et al. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol 1996;10:285-94.  Back to cited text no. 30
    
31.
Misri S, Sivertz K. Tricyclic drugs in pregnancy and lactation: A preliminary report. Int J Psychiatry Med 1991;21:157-71.  Back to cited text no. 31
    
32.
Cowe L, Lloyd DJ, Dawling S. Neonatal convulsions caused by withdrawal from maternal clomipramine. Br Med J (Clin Res Ed) 1982;284:1837-8.  Back to cited text no. 32
    
33.
Eggermont E. Withdrawal symptoms in neonates associated with maternal imipramine therapy. Lancet 1973;2:680.  Back to cited text no. 33
    
34.
Schimmell MS, Katz EZ, Shaag Y, Pastuszak A, Koren G. Toxic neonatal effects following maternal clomipramine therapy. J Toxicol Clin Toxicol 1991;29:479-84.  Back to cited text no. 34
    
35.
Webster PA. Withdrawal symptoms in neonates associated with maternal antidepressant therapy. Lancet 1973;2:318-9.  Back to cited text no. 35
    
36.
Bromiker R, Kaplan M. Apparent intrauterine fetal withdrawal from clomipramine hydrochloride. JAMA 1994;272:1722-3.  Back to cited text no. 36
    
37.
Ter Horst PG, Jansman FG, van Lingen RA, Smit JP, de Jong-van den Berg LT, Brouwers JR. Pharmacological aspects of neonatal antidepressant withdrawal. Obstet Gynecol Surv 2008;63:267-79.  Back to cited text no. 37
    
38.
Kieviet N, Dolman KM, Honig A. The use of psychotropic medication during pregnancy: How about the newborn? Neuropsychiatr Dis Treat 2013;9:1257-66.  Back to cited text no. 38
    
39.
Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy: A critical review focused on risks and controversies. Acta Psychiatr Scand 2013;127:94-114.  Back to cited text no. 39
    
40.
Falterman CG, Richardson CJ. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr 1980;97:308-10.  Back to cited text no. 40
    
41.
Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:570-2.  Back to cited text no. 41
    
42.
Ali SF, Buelke-Sam J, Newport GD, Slikker W Jr. Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine. Neurotoxicology 1986;7:365-80.  Back to cited text no. 42
    
43.
Vorhees CV, Brunner RL, Butcher RE. Psychotropic drugs as behavioral teratogens. Science 1979;205:1220-5.  Back to cited text no. 43
    
44.
Vernadakis A, Parker KK. Drugs and the developing central nervous system. Pharmacol Ther 1980;11:593-647.  Back to cited text no. 44
    
45.
Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336:258-62.  Back to cited text no. 45
    
46.
Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry 2002;159:1889-95.  Back to cited text no. 46
    
47.
Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002;159:2055-61.  Back to cited text no. 47
    
48.
Addis A, Koren G. Safety of fluoxetine during the first trimester of pregnancy: A meta-analytical review of epidemiological studies. Psychol Med 2000;30:89-94.  Back to cited text no. 48
    
49.
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-5.  Back to cited text no. 49
    
50.
Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, Bouffard SM. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry 2000;48:996-1000.  Back to cited text no. 50
    
51.
Goldstein DJ. Effects of third trimester fluoxetine exposure on the newborn. J Clin Psychopharmacol 1995;15:417-20.  Back to cited text no. 51
    
52.
Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr 2008;153:807-13.  Back to cited text no. 52
    
53.
Källén B, Nilsson E, Olausson PO. Antidepressant use during pregnancy: Comparison of data obtained from a prescription register and from antenatal care records. Eur J Clin Pharmacol 2011;67:839-45.  Back to cited text no. 53
    
54.
Källén BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79:301-8.  Back to cited text no. 54
    
55.
Warburton W, Hertzman C, Oberlander TF. A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatr Scand 2010;121:471-9.  Back to cited text no. 55
    
56.
Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: A prospective controlled multicenter study. JAMA 1998;279:609-10.  Back to cited text no. 56
    
57.
Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, et al. Pregnancy outcome following gestational exposure to venlafaxine: A multicenter prospective controlled study. Am J Psychiatry 2001;158:1728-30.  Back to cited text no. 57
    
58.
Cohen LS, Rosenbaum JF. Fluoxetine in pregnancy [letter]. N Engl J Med 1997;336:872.  Back to cited text no. 58
    
59.
Robert E. Treatment depression in pregnancy. N Engl J Med 1996;335:1056-8.  Back to cited text no. 59
    
60.
Ericson A, Källén B, Wiholm B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503-8.  Back to cited text no. 60
    
61.
Inman W, Kobotu K, Pearce G, Wilton L. Prescription event monitoring of paroxetine. PEM Reports 1993;1206:1-44.  Back to cited text no. 61
    
62.
Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-92.  Back to cited text no. 62
    
63.
Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-83.  Back to cited text no. 63
    
64.
Wogelius P, Nørgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, et al. Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 2006;17:701-4.  Back to cited text no. 64
    
65.
Bakker MK, De Walle HE, Wilffert B, de Jong-Van den Berg LT. Fluoxetine and infantile hypertrophic pylorus stenosis: A signal from a birth defects-drug exposure surveillance study. Pharmacoepidemiol Drug Saf 2010;19:808-13.  Back to cited text no. 65
    
66.
Reis M, Källén B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: An update using Swedish data. Psychol Med 2010;40:1723-33.  Back to cited text no. 66
    
67.
Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, Di Gianantonio E, et al. Paroxetine and fluoxetine in pregnancy: A prospective, multicentre, controlled, observational study. Br J Clin Pharmacol 2008;66:695-705.  Back to cited text no. 67
    
68.
Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol 2011;118:111-20.  Back to cited text no. 68
    
69.
Oberlander TF, Warburton W, Misri S, Riggs W, Aghajanian J, Hertzman C. Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data. Birth Defects Res B Dev Reprod Toxicol 2008;83:68-76.  Back to cited text no. 69
    
70.
Kornum JB, Nielsen RB, Pedersen L, Mortensen PB, Nørgaard M. Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: Updated analysis. Clin Epidemiol 2010;2:29-36.  Back to cited text no. 70
    
71.
Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: Population based cohort study. BMJ 2009;339:b3569.  Back to cited text no. 71
    
72.
Bérard A, Ramos E, Rey E, Blais L, St-André M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: The importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007;80:18-27.  Back to cited text no. 72
    
73.
Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, Nimrod C, et al. Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol 2006;194:961-6.  Back to cited text no. 73
    
74.
Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: Results of a large prospective cohort study. Can J Psychiatry 2009;54:242-6.  Back to cited text no. 74
    
75.
Einarson A, Choi J, Koren G, Einarson T. Outcomes of infants exposed to multiple antidepressants during pregnancy: Results of a cohort study. J Popul Ther Clin Pharmacol 2011;18:e390-6.  Back to cited text no. 75
    
76.
Ramos E, St-André M, Rey E, Oraichi D, Bérard A. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychiatry 2008;192:344-50.  Back to cited text no. 76
    
77.
Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, et al. Major depression and antidepressant treatment: Impact on pregnancy and neonatal outcomes. Am J Psychiatry 2009;166:557-66.  Back to cited text no. 77
    
78.
Klieger-Grossmann C, Weitzner B, Panchaud A, Pistelli A, Einarson T, Koren G, et al. Pregnancy outcomes following use of escitalopram: A prospective comparative cohort study. J Clin Pharmacol 2012;52:766-70.  Back to cited text no. 78
    
79.
Williams M, Wooltorton E. Paroxetine (Paxil) and congenital malformations. CMAJ 2005;173:1320-1.  Back to cited text no. 79
    
80.
Cole JA, Ephross SA, Cosmatos IS, Walker AM. Paroxetine in the first trimester and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007;16:1075-85.  Back to cited text no. 80
    
81.
Wurst KE, Poole C, Ephross SA, Olshan AF. First trimester paroxetine use and the prevalence of congenital, specifically cardiac, defects: A meta-analysis of epidemiological studies. Birth Defects Res A Clin Mol Teratol 2010;88:159-70.  Back to cited text no. 81
    
82.
Bar-Oz B, Einarson T, Einarson A, Boskovic R, O′Brien L, Malm H, et al. Paroxetine and congenital malformations: Meta-analysis and consideration of potential confounding factors. Clin Ther 2007;29:918-26.  Back to cited text no. 82
    
83.
Gentile S, Bellantuono C. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of fetal major malformations: Focus on paroxetine. J Clin Psychiatry 2009;70:414-22.  Back to cited text no. 83
    
84.
Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: A meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14:823-7.  Back to cited text no. 84
    
85.
O′Brien L, Einarson TR, Sarkar M, Einarson A, Koren G. Does paroxetine cause cardiac malformations? J Obstet Gynaecol Can 2008;30:696-701.  Back to cited text no. 85
    
86.
Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: A meta-analysis of clinical trials. Reprod Toxicol 2006;22:571-5.  Back to cited text no. 86
    
87.
Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993;92:721-2.  Back to cited text no. 87
    
88.
Kwon P, Lefkowitz W. Poor neonatal adaptation in term infant. Fluoxetine toxicity. Pediatr Ann 2008;37:131-3.  Back to cited text no. 88
    
89.
Mhanna MJ, Bennet JB 2 nd , Izatt SD. Potential fluoxetine chloride (Prozac) toxicity in a newborn. Pediatrics 1997;100:158-9.  Back to cited text no. 89
    
90.
Mohan CG, Moore JJ. Fluoxetine toxicity in a preterm infant. J Perinatol 2000;20:445-6.  Back to cited text no. 90
    
91.
Stiskal JA, Kulin N, Koren G, Ho T, Ito S. Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001;84:F134-5.  Back to cited text no. 91
    
92.
Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 2002;156:1129-32.  Back to cited text no. 92
    
93.
Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry 1997;171:391-2.  Back to cited text no. 93
    
94.
Nordeng H, Lindemann R, Perminov KV, Reikvam A. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 2001;90:288-91.  Back to cited text no. 94
    
95.
Boucher N, Bairam A, Beaulac-Baillargeon L. A new look at the neonate′s clinical presentation after in utero exposure to antidepressants in late pregnancy. J Clin Psychopharmacol 2008;28:334-9.  Back to cited text no. 95
    
96.
Herbst F, Gortner L. Paroxetine withdrawal syndrome as differential diagnosis of acute neonatal encephalopathy? Z Geburtshilfe Neonatol 2003;207:232-4.  Back to cited text no. 96
    
97.
Galbally M, Lewis AJ, Lum J, Buist A. Serotonin discontinuation syndrome following in utero exposure to antidepressant medication: Prospective controlled study. Aust N Z J Psychiatry 2009;43:846-54.  Back to cited text no. 97
    
98.
Suri R, Altshuler L, Hendrick V, Rasgon N, Lee E, Mintz J. The impact of depression and fluoxetine treatment on obstetrical outcome. Arch Womens Ment Health 2004;7:193-200.  Back to cited text no. 98
    
99.
Maschi S, Clavenna A, Campi R, Schiavetti B, Bernat M, Bonati M. Neonatal outcome following pregnancy exposure to antidepressants: A prospective controlled cohort study. BJOG 2008;115:283-9.  Back to cited text no. 99
    
100.
Consortium on Safe Labor, Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419-25.  Back to cited text no. 100
    
101.
Administration. UFAD. FDA Medwatch Drug Alert on Effexor (venlafaxine HCL) and Effecor XR (venlafaxine HCL); 2004. Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154975.htm. [Last cited on 2011 Dec 22].  Back to cited text no. 101
    
102.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-87.  Back to cited text no. 102
    
103.
Källén B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2008;17:801-6.  Back to cited text no. 103
    
104.
Heritage CK, Cunningham MD. Association of elective repeat cesarean delivery and persistent pulmonary hypertension of the newborn. Am J Obstet Gynecol 1985;152:627-9.  Back to cited text no. 104
    
105.
Hernández-Díaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007;120:e272-82.  Back to cited text no. 105
    
106.
Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: Population based cohort study from the five Nordic countries. BMJ 2012;344:d8012.  Back to cited text no. 106
    
107.
Administration USFAD. FDA Drug Safety Communication: Selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies. 2011. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm. [Last accessed on 2015 Mar 07]. [12/4/11 ed].  Back to cited text no. 107
    
108.
Hallberg P, Sjöblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: A review and clinical aspects. J Clin Psychopharmacol 2005;25:59-73.  Back to cited text no. 108
    
109.
Weikum WM, Oberlander TF, Hensch TK, Werker JF. Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception. Proc Natl Acad Sci U S A 2012;109 Suppl 2:17221-7.  Back to cited text no. 109
    
110.
Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study. BMJ 2013;346:f2059.  Back to cited text no. 110
    
111.
Simpson KL, Weaver KJ, de Villers-Sidani E, Lu JY, Cai Z, Pang Y, et al. Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci U S A 2011;108:18465-70.  Back to cited text no. 111
    
112.
Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Science Group; 1977.  Back to cited text no. 112
    
113.
Gracious BL, Wisner KL. Phenelzine use throughout pregnancy and the puerperium: Case report, review of the literature, and management recommendations. Depress Anxiety 1997;6:124-8.  Back to cited text no. 113
    
114.
Grover S, Avasthi A, Sharma Y. Psychotropics in pregnancy: Weighing the risks. Indian J Med Res 2006;123:497-512.  Back to cited text no. 114
[PUBMED]  Medknow Journal  
115.
Yaris F, Kadioglu M, Kesim M, Ulku C, Yaris E, Kalyoncu NI, et al. Newer antidepressants in pregnancy: Prospective outcome of a case series. Reprod Toxicol 2004;19:235-8.  Back to cited text no. 115
    
116.
Lennestål R, Källén B. Delivery outcome in relation to maternal use of some recently introduced antidepressants. J Clin Psychopharmacol 2007;27:607-13.  Back to cited text no. 116
    
117.
Saks BR. Mirtazapine: Treatment of depression, anxiety, and hyperemesis gravidarum in the pregnant patient: A report of 7 cases. Arch Womens Ment Health 2001;4:165-70.  Back to cited text no. 117
    
118.
Djulus J, Koren G, Einarson TR, Wilton L, Shakir S, Diav-Citrin O, et al. Exposure to mirtazapine during pregnancy: A prospective, comparative study of birth outcomes. J Clin Psychiatry 2006;67:1280-4.  Back to cited text no. 118
    
119.
Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003;48:106-10.  Back to cited text no. 119
    
120.
Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: A prospective comparative study. Am J Obstet Gynecol 2005;192:932-6.  Back to cited text no. 120
    
121.
Glaxosmithkline. The Bupropion Pregnancy Registry Final Report; 2008. Available from: http://www.pregnancyregistry.gsk.com/documents/bup_report_final_2008.pdf. [Last accessed on 2015 Mar 07].  Back to cited text no. 121
    
122.
Alwan S, Reefhuis J, Botto LD, Rasmussen SA, Correa A, Friedman JM, et al. Maternal use of bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010;203:52.e1-6.  Back to cited text no. 122
    
123.
Cole JA, Modell JG, Haight BR, Cosmatos IS, Stoler JM, Walker AM. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007;16:474-84.  Back to cited text no. 123
    
124.
Berga SL, Parry BL, Moses-Kolko EL. Psychiatry and reproductive medicine. In: Saddock BJ, Saddock VA, Ruiz P, editors. Kaplan and Sadocks′s Comprehensive Text Book of Psychiatry. 9 th ed., Vol. II. New York: Lippinkot William and Wilkins; 2009. p. 2539-62.  Back to cited text no. 124
    
125.
Creasy RK, Resnik R. Maternal-Fetal Medicine: Principles and Practice. 3 rd ed. Philadelphia: WB Saunders; 1994. p. 96-7.  Back to cited text no. 125
    
126.
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: A randomized clinical trial. Biol Psychiatry 1998;44:77-87.  Back to cited text no. 126
    
127.
Cohen LS, Nonacs RM, Bailey JW, Viguera AC, Reminick AM, Altshuler LL, et al. Relapse of depression during pregnancy following antidepressant discontinuation: A preliminary prospective study. Arch Womens Ment Health 2004;7:217-21.  Back to cited text no. 127
    
128.
Singh S, Gulati S, Narang A, Bhakoo ON. Non-narcotic withdrawal syndrome in a neonate due to maternal clomipramine therapy. J Paediatr Child Health 1990;26:110.  Back to cited text no. 128
    
129.
Schimmell MS, Katz EZ, Shaag Y, Pastuszak A, Koren G. Toxic neonatal effects following maternal clomipramine therapy. J Toxicol Clin Toxicol 1991;29:479-84.  Back to cited text no. 129
    
130.
Epperson CN, Ballew J. Postpartum depression: A common complication of childbirth. In: Hendrick V, editor. Psychiatric Disorders in Pregnancy and Postpartum: Principles and Treatment. Totowa, New Jersey: Humana Press; 2006. p. 41-83.  Back to cited text no. 130
    
131.
Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: Literature review and implications for clinical applications. JAMA 2005;293:2372-83.  Back to cited text no. 131
    
132.
Brioni JD, Orsingher OA. Operant behavior and reactivity to the anticonflict effect of diazepam in perinatally undernourished rats. Physiol Behav 1988;44:193-8.  Back to cited text no. 132
    
133.
Kellogg CK. Benzodiazepines: Influence on the developing brain. Prog Brain Res 1988;73:207-28.  Back to cited text no. 133
    
134.
Deutch AY, Gruen RJ, Roth RH. The effects of perinatal diazepam exposure on stress-induced activation of the mesotelencephalic dopamine system. Neuropsychopharmacology 1989;2:105-14.  Back to cited text no. 134
    
135.
De Salvia MA, Cagiano R, Lacomba C, Cuomo V. Neurobehavioral changes produced by developmental exposure to benzodiazepines. Dev Pharmacol Ther 1990;15:173-7.  Back to cited text no. 135
    
136.
Hartz SC, Heinonen OP, Shapiro S, Siskind V, Slone D. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med 1975;292:726-8.  Back to cited text no. 136
    
137.
Laegreid L. Clinical observations in children after prenatal benzodiazepine exposure. Dev Pharmacol Ther 1990;15:186-8.  Back to cited text no. 137
    
138.
Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 4 th ed. Baltimore, MD: Williams and Wilkins; 1994.  Back to cited text no. 138
    
139.
Uzun S, Kozumplik O, Jakovljevic M, Sedic B. Side effects of treatment with benzodiazepines. Psychiatr Danub 2010;22:90-3.  Back to cited text no. 139
    
140.
Rosa FW, Baum C. Computerized on-line pharmaceutical surveillance system (COMPASS) teratology. Reprod Toxicol 1993;7:639-40.  Back to cited text no. 140
    
141.
Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002;53:39-49.  Back to cited text no. 141
    
142.
Czeizel AE, Bod M, Halász P. Evaluation of anticonvulsant drugs during pregnancy in a population-based Hungarian study. Eur J Epidemiol 1992;8:122-7.  Back to cited text no. 142
    
143.
Sethi N, Manchana M. Maternal drug histories and congenital abnormalities. Indian J Psychiatry 1978;20:191-2.  Back to cited text no. 143
  Medknow Journal  
144.
Ghosh S, Bali L. Congenital malformations in the newborn. Indian J Child Health 1963;12:448-52.  Back to cited text no. 144
    
145.
Saifullah S, Chandra RK, Pathak IC, Dhall GI. Congenital malformations in new born. A prospective longitudinal study. A preliminary report on 1000 consecutive births. Indian Pediatr 1967;4:251-61.  Back to cited text no. 145
    
146.
Sharma B, Bajpai PC, Sharma NL. Some observations on congenital malformations. Indian J Pediatr 1972;39:286-92.  Back to cited text no. 146
    
147.
Buist A, Norman TR, Dennerstein L. Breastfeeding and the use of psychotropic medication: A review. J Affect Disord 1990;19:197-206.  Back to cited text no. 147
    
148.
Erickson SH, Smith GH, Heidrich F. Tricyclics and breast feeding. Am J Psychiatry 1979;136:1483-4.  Back to cited text no. 148
    
149.
Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infant′s serum. Am J Psychiatry 1980;137:855-6.  Back to cited text no. 149
    
150.
Brixen-Rasmussen L, Halgrener J, Jørgensen A. Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology (Berl) 1982;76:94-5.  Back to cited text no. 150
    
151.
Pittard WB 3 rd , O′Neal W Jr. Amitriptyline excretion in human milk. J Clin Psychopharmacol 1986;6:383-4.  Back to cited text no. 151
    
152.
Sovner R, Orsulak PJ. Excretion of imipramine and desipramine in human breast milk. Am J Psychiatry 1979;136:451-2.  Back to cited text no. 152
    
153.
Stancer HC, Reed KL. Desipramine and 2-hydroxydesipramine in human breast milk and the nursing infant′s serum. Am J Psychiatry 1986;143:1597-600.  Back to cited text no. 153
    
154.
Kemp J, Ilett KF, Booth J, Hackett LP. Excretion of doxepin and N-desmethyldoxepin in human milk. Br J Clin Pharmacol 1985;20:497-9.  Back to cited text no. 154
    
155.
Matheson I, Pande H, Alertsen AR. Respiratory depression caused by N-desmethyldoxepin in breast milk. Lancet 1985;2:1124.  Back to cited text no. 155
    
156.
Frey OR, Scheidt P, von Brenndorff AI. Adverse effects in a newborn infant breast-fed by a mother treated with doxepin. Ann Pharmacother 1999;33:690-3.  Back to cited text no. 156
    
157.
Rees JA, Glass RC, Spome GA. Serum and breast milk concentrations of dothiepin. Practitioner 1976;217:686.  Back to cited text no. 157
    
158.
Gelenberg AJ. Single case study. Amoxapine, a new antidepressant, appears in human milk. J Nerv Ment Dis 1979;167:635-6.  Back to cited text no. 158
    
159.
Verbeeck RK, Ross SG, McKenna EA. Excretion of trazodone in breast milk. Br J Clin Pharmacol 1986;22:367-70.  Back to cited text no. 159
    
160.
Altshuler LL, Burt VK, McMullen M, Hendrick V. Breastfeeding and sertraline: A 24-hour analysis. J Clin Psychiatry 1995;56:243-5.  Back to cited text no. 160
    
161.
Mammen OK, Perel JM, Rudolph G, Foglia JP, Wheeler SB. Sertraline and norsertraline levels in three breastfed infants. J Clin Psychiatry 1997;58:100-3.  Back to cited text no. 161
    
162.
Stowe ZN, Owens MJ, Landry JC, Kilts CD, Ely T, Llewellyn A, et al. Sertraline and desmethylsertraline in human breast milk and nursing infants. Am J Psychiatry 1997;154:1255-60.  Back to cited text no. 162
    
163.
Wisner KL, Perel JM, Blumer J. Serum sertraline and N-desmethylsertraline levels in breast-feeding mother-infant pairs. Am J Psychiatry 1998;155:690-2.  Back to cited text no. 163
    
164.
Kristensen JH, Ilett KF, Dusci LJ, Hackett LP, Yapp P, Wojnar-Horton RE, et al. Distribution and excretion of sertraline and N-desmethylsertraline in human milk. Br J Clin Pharmacol 1998;45:453-7.  Back to cited text no. 164
    
165.
Birnbaum CS, Cohen LS, Bailey JW, Grush LR, Robertson LM, Stowe ZN. Serum concentrations of antidepressants and benzodiazepines in nursing infants: A case series. Pediatrics 1999;104:e11.  Back to cited text no. 165
    
166.
Dodd S, Stocky A, Buist A, Burrows GD, Norman TR. Sertraline analysis in the plasma of breast-fed infants. Aust N Z J Psychiatry 2001;35:545-6.  Back to cited text no. 166
    
167.
Epperson N, Czarkowski KA, Ward-O′Brien D, Weiss E, Gueorguieva R, Jatlow P, et al. Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs. Am J Psychiatry 2001;158:1631-7.  Back to cited text no. 167
    
168.
Hendrick V, Fukuchi A, Altshuler L, Widawski M, Wertheimer A, Brunhuber MV. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry 2001;179:163-6.  Back to cited text no. 168
    
169.
Stowe ZN, Hostetter AL, Owens MJ, Ritchie JC, Sternberg K, Cohen LS, et al. The pharmacokinetics of sertraline excretion into human breast milk: Determinants of infant serum concentrations. J Clin Psychiatry 2003;64:73-80.  Back to cited text no. 169
    
170.
Burch KJ, Wells BG. Fluoxetine/norfluoxetine concentrations in human milk. Pediatrics 1992;89 (4 Pt 1):676-7.  Back to cited text no. 170
    
171.
Lester BM, Cucca J, Andreozzi L, Flanagan P, Oh W. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry 1993;32:1253-5.  Back to cited text no. 171
    
172.
Taddio A, Ito S, Koren G. Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk. J Clin Pharmacol 1996;36:42-7.  Back to cited text no. 172
    
173.
Yoshida K, Smith B, Craggs M, Kumar RC. Fluoxetine in breast-milk and developmental outcome of breast-fed infants. Br J Psychiatry 1998;172:175-8.  Back to cited text no. 173
    
174.
Brent NB, Wisner KL. Fluoxetine and carbamazepine concentrations in a nursing mother/infant pair. Clin Pediatr (Phila) 1998;37:41-4.  Back to cited text no. 174
    
175.
Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, et al. Weight gain in infants breastfed by mothers who take fluoxetine. Pediatrics 1999;104:e61.  Back to cited text no. 175
    
176.
Kristensen JH, Ilett KF, Hackett LP, Yapp P, Paech M, Begg EJ. Distribution and excretion of fluoxetine and norfluoxetine in human milk. Br J Clin Pharmacol 1999;48:521-7.  Back to cited text no. 176
    
177.
Suri R, Stowe ZN, Hendrick V, Hostetter A, Widawski M, Altshuler LL. Estimates of nursing infant daily dose of fluoxetine through breast milk. Biol Psychiatry 2002;52:446-51.  Back to cited text no. 177
    
178.
Epperson CN, Jatlow PI, Czarkowski K, Anderson GM. Maternal fluoxetine treatment in the postpartum period: Effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs. Pediatrics 2003;112:e425.  Back to cited text no. 178
    
179.
Spigset O, Carleborg L, Norström A, Sandlund M. Paroxetine level in breast milk. J Clin Psychiatry 1996;57:39.  Back to cited text no. 179
    
180.
Begg EJ, Duffull SB, Saunders DA, Buttimore RC, Ilett KF, Hackett LP, et al. Paroxetine in human milk. Br J Clin Pharmacol 1999;48:142-7.  Back to cited text no. 180
    
181.
Ohman R, Hägg S, Carleborg L, Spigset O. Excretion of paroxetine into breast milk. J Clin Psychiatry 1999;60:519-23.  Back to cited text no. 181
    
182.
Misri S, Kim J, Riggs KW, Kostaras X. Paroxetine levels in postpartum depressed women, breast milk, and infant serum. J Clin Psychiatry 2000;61:828-32.  Back to cited text no. 182
    
183.
Hendrick V, Stowe ZN, Altshuler LL, Hostetter A, Fukuchi A. Paroxetine use during breast-feeding. J Clin Psychopharmacol 2000;20:587-9.  Back to cited text no. 183
    
184.
Stowe ZN, Cohen LS, Hostetter A, Ritchie JC, Owens MJ, Nemeroff CB. Paroxetine in human breast milk and nursing infants. Am J Psychiatry 2000;157:185-9.  Back to cited text no. 184
    
185.
Merlob P, Mor N, Litwin A. Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breastfeeding. Ann Pharmacother 1992;26:1563-5.  Back to cited text no. 185
    
186.
Jensen PN, Olesen OV, Bertelsen A, Linnet K. Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant. Ther Drug Monit 1997;19:236-9.  Back to cited text no. 186
    
187.
Spigset O, Carieborg L, Ohman R, Norström A. Excretion of citalopram in breast milk. Br J Clin Pharmacol 1997;44:295-8.  Back to cited text no. 187
    
188.
Schmidt K, Olesen OV, Jensen PN. Citalopram and breast-feeding: Serum concentration and side effects in the infant. Biol Psychiatry 2000;47:164-5.  Back to cited text no. 188
    
189.
Rampono J, Kristensen JH, Hackett LP, Paech M, Kohan R, Ilett KF. Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants. Br J Clin Pharmacol 2000;50:263-8.  Back to cited text no. 189
    
190.
Heikkinen T, Ekblad U, Kero P, Ekblad S, Laine K. Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002;72:184-91.  Back to cited text no. 190
    
191.
Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynecol 2004;190:218-21.  Back to cited text no. 191
    
192.
Wright S, Dawling S, Ashford JJ. Excretion of fluvoxamine in breast milk. Br J Clin Pharmacol 1991;31:209.  Back to cited text no. 192
    
193.
Yoshida K, Smith B, Craggs M, Kumar RC. Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-milk. J Affect Disord 1997;43:225-37.  Back to cited text no. 193
    
194.
Piontek CM, Wisner KL, Perel JM, Peindl KS. Serum fluvoxamine levels in breastfed infants. J Clin Psychiatry 2001;62:111-3.  Back to cited text no. 194
    
195.
Kristensen JH, Hackett LP, Kohan R, Paech M, Ilett KF. The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants. J Hum Lact 2002;18:139-43.  Back to cited text no. 195
    
196.
Briggs GG, Samson JH, Ambrose PJ, Schroeder DH. Excretion of bupropion in breast milk. Ann Pharmacother 1993;27:431-3.  Back to cited text no. 196
    
197.
Baab SW, Peindl KS, Piontek CM, Wisner KL. Serum bupropion levels in 2 breastfeeding mother-infant pairs. J Clin Psychiatry 2002;63:910-1.  Back to cited text no. 197
    
198.
Chaudron LH, Schoenecker CJ. Bupropion and breastfeeding: A case of a possible infant seizure. J Clin Psychiatry 2004;65:881-2.  Back to cited text no. 198
    
199.
Hendrick V, Altshuler L, Wertheimer A, Dunn WA. Venlafaxine and breast-feeding. Am J Psychiatry 2001;158:2089-90.  Back to cited text no. 199
    
200.
Ilett KF, Kristensen JH, Hackett LP, Paech M, Kohan R, Rampono J. Distribution of venlafaxine and its O-desmethyl metabolite in human milk and their effects in breastfed infants. Br J Clin Pharmacol 2002;53:17-22.  Back to cited text no. 200
    
201.
Hendrick V, Smith LM, Hwang S, Altshuler LL, Haynes D. Weight gain in breastfed infants of mothers taking antidepressant medications. J Clin Psychiatry 2003;64:410-2.  Back to cited text no. 201
    
202.
Newport DJ, Ritchie JC, Knight BT, Glover BA, Zach EB, Stowe ZN. Venlafaxine in human breast milk and nursing infant plasma: Determination of exposure. J Clin Psychiatry 2009;70:1304-10.  Back to cited text no. 202
    
203.
Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004;161:1066-78.  Back to cited text no. 203
    
204.
Lanza di Scalea T, Wisner KL. Antidepressant medication use during breastfeeding. Clin Obstet Gynecol 2009;52:483-97.  Back to cited text no. 204
    
205.
Berle JØ, Spigset O. Maternal antidepressant use and breastfeeding. Curr Med Lit Psychiatry 2008;19:33-7.  Back to cited text no. 205
    
206.
Gentile S. Use of contemporary antidepressants during breastfeeding: A proposal for a specific safety index. Drug Saf 2007;30:107-21.  Back to cited text no. 206
    
207.
Ragan K, Stowe ZN, Newport DJ. Use of antidepressants and mood stabilizers in breast-feeding women. In: Cohen LS, Nonacs RM, editors. Mood and Anxiety Disorders During Pregnancy and Postpartum.(Review of Psychiatry Series, Volume 24, Number 4; Oldham JM and Riba MB, series editors). Washington, DC: American Psychiatric Publishing; 2005. p. 105-44.  Back to cited text no. 207
    
208.
National Collaborating Centre for Mental Health. NICE Guideline on Clinical Management and Service Guidance. Antenatal and Postnatal Mental Health. No. 45; 2007. Available from: http://www.nice.org.uk/nicemedia/pdf/CG45fullguideline.pdf. [Last accessed on 2010 Jan 31].  Back to cited text no. 208
    
209.
Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #18: Use of antidepressants in nursing mothers. Breastfeed Med 2008;3:44-52.  Back to cited text no. 209
    
210.
ACOG Committee on Practice Bulletins - Obstetrics. ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol 2008;111:1001-20.  Back to cited text no. 210
    
211.
Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev 2011;7:28-34.  Back to cited text no. 211
    
212.
Patrick MJ, Tilstone WJ, Reavey P. Diazepam and breast-feeding. Lancet 1972;1:542-3.  Back to cited text no. 212
    
213.
Wretlind M. Excretion of oxazepam in breast milk. Eur J Clin Pharmacol 1987;33:209-10.  Back to cited text no. 213
    
214.
Stebler T, Guentert TW. Determination of diazepam and nordazepam in milk and plasma in the presence of oxazepam and temazepam. J Chromatogr 1991;564:330-7.  Back to cited text no. 214
    
215.
Oo CY, Kuhn RJ, Desai N, Wright CE, McNamara PJ. Pharmacokinetics in lactating women: Prediction of alprazolam transfer into milk. Br J Clin Pharmacol 1995;40:231-6.  Back to cited text no. 215
    
216.
Erkkola R, Kanto J. Diazepam and breast-feeding. Lancet 1972;1:1235-6.  Back to cited text no. 216
    
217.
Brandt R. Passage of diazepam and desmethyldiazepam into breast milk. Arzneimittelforschung 1976;26:454-7.  Back to cited text no. 217
    
218.
Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985;57:1042-3.  Back to cited text no. 218
    
219.
Hümpel M, Stoppelli I, Milia S, Rainer E. Pharmacokinetics and biotransformation of the new benzodiazepine, lormetazepam, in man. III. Repeated administration and transfer to neonates via breast milk. Eur J Clin Pharmacol 1982;21:421-5.  Back to cited text no. 219
    
220.
Hilbert JM, Gural RP, Symchowicz S, Zampaglione N. Excretion of quazepam into human breast milk. J Clin Pharmacol 1984;24:457-62.  Back to cited text no. 220
    
221.
Whitelaw AG, Cummings AJ, McFadyen IR. Effect of maternal lorazepam on the neonate. Br Med J (Clin Res Ed) 1981;282:1106-8.  Back to cited text no. 221
    
222.
Reider J, Wendt G. Pharmacokinetics and metabolism of the hypnotic nitrazepam. In: Garattini S, Mussini E, Randall LO, editors. The Benzodiazepines. New York, NY: Raven Press; 1973. p. 99-127.  Back to cited text no. 222
    
223.
Kanto J, Aaltonen L, Kangas L, Erkkola R, Pitkanen Y. Placental transfer and breast milk levels of flunitrazepam. Curr Ther Res 1979;26:539-46.  Back to cited text no. 223
    
224.
Pons G, Francoual C, Guillet P, Moran C, Hermann P, Bianchetti G, et al. Zolpidem excretion in breast milk. Eur J Clin Pharmacol 1989;37:245-8.  Back to cited text no. 224
    
225.
Darwish M, Martin PT, Cevallos WH, Tse S, Wheeler S, Troy SM. Rapid disappearance of zaleplon from breast milk after oral administration to lactating women. J Clin Pharmacol 1999;39:670-4.  Back to cited text no. 225
    
226.
Dusci LJ, Good SM, Hall RW, Ilett KF. Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam. Br J Clin Pharmacol 1990;29:123-6.  Back to cited text no. 226
    
227.
Homberg JR, Schubert D, Gaspar P. New perspectives on the neurodevelopmental effects of SSRIs. Trends Pharmacol Sci 2010;31:60-5.  Back to cited text no. 227
    

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Correspondence Address:
S Gandotra
Mental Health Foundation St. Maarten, Dutch Caribbean, Ex-Faculty Central Institute of Psychiatry, Ranchi, Jharkhand
India
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DOI: 10.4103/0019-5545.161504

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