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Atypical antipsychotics in pregnancy: between the need to control symptomatic psychosis and avoiding harmful effects on the fetus/Antipsihoticele atipice in sarcina: intre necesitatea de a controla simptomatologia psihotica si evitarea efectelor nocive ale medicatiei asupra fatului.

INTRODUCTION

Antipsychotics are used extensively and effectively to treat schizophrenia. The first generation which, at first, were used in the treatment of schizophrenia in usual manner, caused a significant decrease in fertility. Atypical antipsychotics don't have this dominant side effect. According to studies, the most commonly used atypical antipsychotics in pregnancy are Olanzapine, Risperidone, Quetiapine, Aripiprazole and Clozapine.

The fertility rate of women with schizophrenia or other persisting psychiatric disorders increased exponentially as a direct result of the appearance of atypical antipsychotics, of desinstitutionalization, of the availability of sexual partners, as well as of changing conceptions about serious mental illnesses. Also, the increase in prescribing atypical antipsychotics, unless Risperidone or Amisulprid, which induce hyperprolactinemia, have also helped to improve fertility.

Unplanned and unwanted pregnancies occur more frequently in mothers with schizophrenia than in the general population. Studies show that, in women with schizophrenia, the psychotic symptoms get worse often during pregnancy, with serious consequences on the quality of life to both mother and fetus.

There are numerous uncertainties related to prescribing atypical antipsychotics in pregnancy; the physician must be able to weigh the risks of the mental illness itself and the potential fetal toxicity associated with pharmacological exposure. Although there is little evidence to the teratogenic effects of atypical antipsychotics, there are reports on the fetal growth disturbances associated with this therapy administered to pregnant women (1, 2, 11).

Discussion about the harmful effects of atypical antipsychotics on the mother and fetus

It is widely accepted that the use of atypical antipsychotics alter body weight homeostasis, resulting in significant weight gain and accumulation of fat in the viscera, or complex mechanisms that can cause neural tube defects (spina bifida, anencephaly, encephalocele). The consequences of neural tube defects depend on the severity of tissue damage and, also, on the protective structures in the brain and spinal cord. Many of the children born with this defect are experiencing learning disorders and delay in psychomotor development.

This phenomenon is independent of the low level of folate that is recognized as a key factor that causes neural tube defects. However, it was demonstrated that patients treated with antipsychotics have a low intake of folate resulting in a lower serum concentrations (1, 10).

Weight gain varies depending on antipsychotic use, between 2 and 25 pounds and can affect about 60 % of patients after 3-12 months of treatment. According to studies, the treatment of pregnant women with atypical antipsychotics is associated with an increased incidence of both fetuses with low birth weight and also macrosomia, compared to the general population. Since these consequences are risk factors for the development of metabolic syndrome in postnatal life, children exposed in utero to antipsychotic drugs have a significant risk of developing obesity. However, for ethical reasons, no human studies have yet been randomized, to test this hypothesis and the mechanisms by which antipsychotics may affect fetal growth.

Data on fetal growth abnormalities are contradictory. For example, some studies have reported an increased risk of low birth weight in fetuses of mothers who were treated with Olanzapine, Quetiapine, Risperidone and Clozapine. In contrast, other studies have reported an increased risk of high birth weight in fetuses of mothers who were treated with Amisulprid, Clozapine, Olanzapine, Quetiapine or Risperidone.

In addition, there is hard evidence in favor of the idea that atypical antipsychotics lead to an increased risk of diabetes type 2. There is one study that reports that treatment with atypical antipsychotics during pregnancy increases the risk of developing pregnancy diabetes (4). These pathological changes of the carbohydrate metabolism may explain the increased incidence of fetuses with high birth weight, born to women who were treated with atypical antipsychotics during pregnancy. High birth weight and pregnancy diabetes are the main fetal complications when the mother has impaired fasting glucose or pre-existing diabetes (3).

Weight gain and fat the accumulation of mother under treatment with atypical antipsychotics may be the result of disruption of food intake (hyperphagia and decreased satiety), the direct effect of drugs on adipocytes, leading to alterations in lipogenesis and lipolysis, leading to accumulation of lipids or the effect on peripheral tissues which results in insulin resistance. Insulin resistance, combined with increased gluconeogenesis and decreased insulin secretion by pancreatic [beta] cells, is responsible for the increasing incidence of type 2 diabetes consecutive to atypical antipsychotics.

Another problem is related particularly to treating pregnant women with Clozapine, that can cause agranulocytosis to the fetus, and requires weekly monitoring of blood counts, namely the white line in the first 6 months of baby's life (1, 8, 9).

The effect of atypical antipsychotics on the placenta

It is well known that atypical antipsychotics act especially on dopamine and serotonin receptors. Recent studies (5) show the presence of 5HT2A serotonin receptor in trophoblast cell lines that have a fundamental importance in the development and function of the placenta. In other cell types, the 5HT2A receptors affect the differentiation, proliferation and cell migration, which is essential to trophoblast cell function. These phenomena become more relevant, because serotonin is synthesized de novo in human trophoblast cells, which play an important endocrine, paracrine, and autocrine role in the proper functioning of the placenta. The use of serotonin on trophoblast cultures cause an increase in aromatase activity, an effect which may result in an alteration of estrogen biosynthesis. Control of this biosynthesis is important for successful implantation of the blastocyte and for regulating the expression of leptin, which is closely related to fetal growth (6, 7).

Also, dopamine D1, D2, D4 receptors, another target of atypical antipsychotics, are present in human placental trophoblast cells. They are related to hormonal regulation of human placental lactogen by inhibiting the release (hPL) from trophoblastic cells. This hormone is similar to growth hormone, altering the metabolic status of the mother during pregnancy to help her optimize the energy reserves of the fetus.

The absence of antipsychotic treatment in women with schizophrenia

Choosing not to treat the psychiatric disorders during pregnancy is associated with increased risk for the mother and can lead to self harm or suicide, to low compliance in pre/postnatal care, lack of creating a link between mother and child and even infanticide. Current guidelines and studies highlight the need for initiation or continuation of antipsychotic treatment to vulnerable mothers, because the recurrence of psychotic symptoms is a medical emergency and a potential obstetric emergency. The switch from one antipsychotic to another during pregnancy is not indicated, because it can leave the patient on nontherapeutic doses for a period of time. In case of necessity, a therapeutic option is to increase the dosage or to add another antipsychotic. In the absence of adequate treatment with atypical antipsychotics, pregnancy can be exposed to numerous dangers caused by the mother's negligence with uncontrolled schizophrenia (malnutrition, episodes of domestic or sexual violence, gynecological infectious diseases and other unhealthy behaviors) (1, 12).

CONCLUSIONS

Current studies provide insufficient data about the effects of atypical antipsychotics on the fetus in utero and postnatal development, given the ethical limitations of the achievement of extensive studies on human subjects and, in particular, on pregnant women. However, most studies recommend the use of atypical antipsychotics during pregnancy in mothers with schizophrenia, in spite of their potential side effects by balancing the benefits and risks, both for them and for fetuses. Although the most common side effects of atypical antipsychotics are lipid metabolism disorders and weight gain, and they have severe repercussions in terms of neural tube development, and also the increase or decrease of the fetal body itself in terms of development, it has been shown that a mother's correct diet accompanied by adequate folate intake and a good pre and postnatal education can optimally control these problems.

Dania Andreea Radu--M. D., Drd., "Gr. T. Popa" University of Medicine and Pharmacy, Iasi; Resident in psychiatry, "Socola" Clinical Psychiatric Hospital, Iasi, Romania

Roxana Chirita--M. D., Ph. D., Professor, Department of Psychiatry, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi; Senior Psychiatrist, "Socola" Clinical Psychiatric Hospital, Iasi, Romania

Ilinca Untu--M. D., Drd., "Gr. T. Popa" University of Medicine and Pharmacy, Iasi; Resident in psychiatry, "Socola" Clinical Psychiatric Hospital, Iasi, Romania

Vasile Chirita--M. D., Ph. D., Professor, Department of Psychiatry, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi; Senior Psychiatrist, "Socola" Clinical Psychiatric Hospital, Iasi; Member of Romanian Academy of Medical Sciences, Iasi, Romania

Anamaria Ciubara--M. D., Ph. D., Assistant Professor, "Gr. T. Popa" University of Medicine and Pharmacy, Department of Psychiatry, Psychiatrist, "Socola" Clinical Psychiatric Hospital, Iasi, Romania

Lucian Stefan Burlea--M. D., Ph. D., Postdoctoral researcher, Assistant Professor, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi, Romania

ACNOWLEDGEMENTS AND DISCLOSURE

The authors declare that they have no potential conflicts of interest to disclose.

REFERENCES

(1.) Raha, Sandeep, Taylor, Valerie H., Holloway, Alison C., Effect of Atypical Antipsychotics on Fetal Growth: Is the Placenta Involved?, J Pregnancy. 2012; 2012: 315203, Published online Jul. 11, 2012.doi: 10.1155/2012/315203

(2.) McKenna, K., Koren, G., Tetelbaum, M. et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. Journal of Clinical Psychiatry. 2005; 66(4):444-449

(3.) Newham, J. J., Thomas, S. H., MacRitchie, K., McElhatton, P. R., McAUister-Williams, R. H. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. British Journal of Psychiatry. 2008; 192(5):333-337

(4.) Reis, M., Kallen, B. Maternal use of antipsychotics in early pregnancy and delivery outcome. Journal of Clinical Psychopharmacology. 2008; 28(3): 279-288

(5.) Viau, M., Lafond, J., Vaillancourt, C. Expression of placental serotonin transporter and 5-HT2A receptor in normal and gestational diabetes mellituspregnancies. Reproductive Biomedicine Online. 2009; 19(2):207-215

(6.) Gambino, Y. P., Maymo, J. L., Perez, Perez A., Calvo, J. C., Sanchez-Margalet, V., Varone, C. L. Elsevier Trophoblast Research Award lecture: molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression. Placenta. 2012; 33:S63-S70

(7.) Mise, H., Yura, S., Itoh, H. et al. The relationship between maternal plasma leptin levels and fetal growth restriction. Endocrine Journal. 2007;54(6):945-951

(8.) Vesga-Lopez, O., Blanco, C., Keyes, K., Olfson, M., Grant, B. F., Hasin, D. S. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry. 2008; 65(7):805-815

(9.) Michielsen, Laura A., van der Heijden, Frank MMA, Janssen, Paddy K. C., Kuijpers, Harold J. H. Effects of maternal psychotropic drug dosage on birth outcomes, Neuropsychiatr Dis Treat. 2014; 10: 13-18. Published online Dec. 10, 2013

(10.) Gideon, Koren, M. D., F.A.C.M.T., F.R.C.P.C.; Cohn, Tony, M. B., Ch. B.; Chitayat, David, M. D., F.R.C.P.C.; Bhushan, Kapur, Ph. D.; Remington, Gary, M. D., Ph. D.; Myles Reid, Diane, M. Sc.; Robert B. Zipursky, M. D., F.R.C.P.C., Use of Atypical Antipsychotics During Pregnancy and the Risk of Neural Tube Defects in Infants, Am J Psychiatry 2002;159:136-137. doi:10.1176/ appi. ajp.159.1.136

(11.) Gentile, Salvatore. Antipsychotic Therapy During Early and Late Pregnancy. A Systematic Review, Schiyophr Bull. May 2010; 36(3): 518-544, Published online Sep. 11, 2008. doi: 10.1093/schbul/sbn107

(12.) Kulkarni, J., Worsley, R., Gilbert, H., Gavrilidis, E., Van Rheenen, T. E., Wang, W., McCauley, K., Fitzgerald, P., A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies, PLoS One. 2014 May 2;9(5):e94788. doi: 10.1371/journal.pone.0094788. eCollection 2014

Correspondence:

ROXANA CHIRITA

"Socola" Clinical Psychiatric Hospital

No. 36 Sos. Bucium, code 700282, Iasi, Romania

Phone: +40 232 430 920/int.185

E-mail: d.stigma@gmail.com

Date of Submission: December, 04, 2013

Acceptance: January, 13, 2014

INTRODUCERE

Antipsihoticele sunt utilizate in mod extins si eficient pentru tratarea schizofreniei. Cele de prima generatie, care, la inceput, erau folosite, in mod uzual, in tratarea schizofreniei, determinau o scadere semnificativa a fertilitatii. Antipsihoticele atipice nu au acest efect advers dominant. Conform studiilor, cele mai frecvent utilizate antipsihotice atipice in sarcina sunt Olanzapina, Risperidona, Quetiapina, Aripiprazolul si Clozapina.

Rata fertilitatii femeilor cu schizofrenie sau alte tulburari psihice persistente a crescut exponential, ca rezultat direct al aparitiei antipsihoticelor atipice, al dezinstitutionalizarii, al disponibilitatii partenerilor sexuali, precum si al schimbarii conceptiilor cu privire la bolile psihice grave. Totodata, cresterea prescrierii antipsihoticelor atipice, mai putin a Risperidonei si a Amisulpridului care induc hiperprolactinemie a contribuit, de asemenea, la imbunatatirea fertilitatii.

Sarcinile nedorite si neplanificate apar mai frecvent la mamele schizofrene decat in ansamblul populatiei generale. Studiile arata ca la femeile cu schizofrenie, simptomatologia de aspect psihotic se agraveaza de cele mai multe ori in perioada sarcinii, avand consecinte grave asupra calitatii vietii mamei si fiind, astfel, amenintatoare la adresa fatului.

Exista numeroase incertitudini legate de prescrierea antipsihoticelor atipice la gravide, medicul trebuind sa puna in balanta riscurile pe care le implica boala psihica in sine si potentiala toxicitate fetala asociata expunerii farmacologice. Cu toate ca sunt putine dovezi care sa ateste efectele teratogene ale antipsihoticelor atipice, exista si raportari privind tulburarile de crestere fetala asociata acestei terapii administrate la femeia gravida (1, 2, 11).

Discutii cu privire la efectele nocive ale antipsihoticelor atipice asupra gravidei si produsului de conceptie

Este unanim acceptat faptul ca uzul de antipsihotice atipice altereaza homeostazia greutatii corporale, rezultand o crestere ponderala semnificativa si acumulare de grasime intre viscere, ceea ce poate cauza, prin mecanisme complexe, defecte de tub neural (spina bifida, anencefalie, encefalocel). Urmarile defectelor de tub neural depind de severitatea afectarii tesuturilor protectoare si a structurilor de la nivelul creierului si a maduvei spinarii. Multi dintre copiii nascuti cu acest defect se confrunta cu tulburari de invatare si intarziere in dezvoltarea psihomotorie.

Acest fenomen este independent de nivelul scazut al folatilor, recunoscut ca fiind un factor-cheie ce determina defecte de tub neural. Cu toate acestea, s-a demonstrat ca pacientele tratate cu antipsihotice prezinta un aport scazut de folati, ceea ce duce la concentratii serice mici ale acestora (1, 10).

Cresterile ponderale variaza in functie de antipsihoticul utilizat, intre 2 si 25 de kilograme, putand afecta aproximativ 60 % dintre pacienti dupa 3-12 luni de tratament. Conform studiilor, tratarea gravidei cu antipsihotice atipice se asociaza cu o incidenta crescuta atat a fetilor cu greutate mica la nastere, cat si a celor macrosomi, fata de populatia generala. De vreme ce aceste consecinte constituie factori de risc pentru dezvoltarea unui sindrom metabolic in viata postnatala, copiii expusi medicatiei antipsihotice in utero prezinta un risc semnificativ de a dezvolta obezitate. Cu toate acestea, din considerente etice, nu s-au facut inca studii umane randomizate, care sa testeze aceasta ipoteza, iar mecanismele prin care antipsihoticele pot afecta cresterea fetala urmeaza a fi pe deplin elucidate (2).

Datele privind anomaliile de crestere fetala sunt contradictorii. De exemplu, unele studii au raportat un risc crescut de greutate mica la nastere la fetii mamelor care au urmat tratament cu Olanzapina, Quetiapina, Risperidona sau Clozapina. In contrast, alte studii au raportat risc crescut de greutate mare la nastere la fetii mamelor care au urmat tratament cu Amisulprid, Clozapina, Olanzapina, Quetiapina sau Risperidona.

In plus, exista dovezi palpabile in favoarea ideii ca antipsihoticele atipice expun la un risc major de DZ tip 2. Exista, in acest sens, un studiu care a raportat faptul ca tratamentul cu antipsihotice atipice pe timpul sarcinii creste riscul de a dezvolta diabet gestational (4). Aceste modificari patologice ale metabolismului glucidelor pot explica, in parte, incidenta crescuta a fetilor cu greutate mare la nastere, nascuti de femei care au urmat tratament cu antipsihotice atipice pe parcursul sarcinii. Greutatea mare la nastere si diabetul gestational reprezinta principalele complicatii fetale, atunci cand mama are glicemie bazala modificata sau diabet zaharat preexistent (3).

Cresterea ponderala si acumularea de grasimi la mama aflata sub tratament cu antipsihotice atipice poate fi rezultatul unor perturbari ale aportului alimentar (hiperfagie si satietate scazuta), al efectului direct al medicamentelor asupra adipocitelor, care duce la alterarea lipogenezei si a lipolizei, determinand acumulare de lipide, sau al efectului asupra tesuturilor periferice, ce conduce la rezistenta la insulina. Aceasta, combinata cu cresterea gluconeogenezei si cu secretia scazuta de insulina de catre celulele [beta] pancreatice, este responsabila de cresterea incidentei diabetului zaharat tip 2, consecutiv uzului de antipsihotice atipice (1, 8, 9).

O alta problema este cea legata, in mod particular, de tratarea gravidei cu Clozapina, care implica pericol de agranulocitoza la fat, fiind necesara monitorizarea saptamanala a hemoleucogramei, si anume, a liniei albe, in primele sase luni de viata ale copilului (1).

Efectul antipsihoticelor atipice asupra placentei

Este bine cunoscut faptul ca antipsihoticele atipice actioneaza, cu predilectie, pe receptorii dopaminergici si pe cei serotoninergici. Cercetari recente (5) raporteaza prezenta receptorilor serotoninergici 5HT2a la nivelul trofoblastilor, linie celulara cu importanta fundamentala in dezvoltarea si functionarea placentei. In alte tipuri celulare, semnalizarea via receptorilor 5HT2a afecteaza diferentierea, proliferarea si migrarea celulara, fenomene care sunt indispensabile functionarii celulelor trofoblastice. Aceste fenomene devin si mai relevante datorita faptului ca serotonina este sintetizata de novo in celulele trofoblastice umane, unde joaca un important rol endocrin, paracrin, cat si autocrin in reglarea functionarii placentei. Tratarea culturilor de trofoblasti cu serotonina determina o crestere in activitatea aromatazei, efect din care poate rezulta o alterare a biosintezei estrogenului. Controlul acestei biosinteze este important atat pentru implantarea cu succes a blastocitului, cat si pentru reglarea exprimarii leptinei, aceasta fiind in stransa legatura cu cresterea fetala (6, 7).

Totodata, receptorii dopaminergici D1, D2, D4, o alta tinta a antipsihoticelor atipice, sunt prezenti in celulele trofoblastice din placenta umana. Acestia sunt relationati cu reglarea hormonala prin inhibarea eliberarii lactogenului uman placentar (hPL) din celulele trofoblastice. Acest hormon este similar hormonului de crestere, modificand statusul metabolic al mamei pe parcursul sarcinii pentru a facilita, astfel, optimizarea rezervelor energetice ale fatului.

Absenta tratamentului antipsihotic la gravidele cu schizofrenie

Netratarea bolilor psihiatrice in timpul sarcinii este asociata unui risc crescut pentru mama, putand conduce la autoagresiune sau suicid, autoneglijare, autoabandon si complianta scazuta pentru ingrijirea pre si postnatala, ca si pentru copil, putand duce la neglijenta, infanticide, lipsa crearii unei legaturi intre mama si copil. Ghidurile actuale si studiile subliniaza necesitatea initierii sau continuarii tratamentului antipsihotic la mamele vulnerabile, deoarece recurenta simptomatologiei psihotice constituie o urgenta medicala, cat si o potentiala urgenta obstetricala. Switch-ul de pe un antipsihotic pe altul, pe parcursul sarcinii, este o practica descurajata, aceasta putand lasa pacienta pe doze nonterapeutice pentru un anumit interval de timp. In caz de necesitate, o optiune terapeutica ar fi marirea dozelor sau asocierea unui alt antipsihotic. In lipsa unui tratament adecvat cu antipsihotice atipice, sarcina poate fi expusa unor numeroase pericole determinate de neglijenta inerenta a gravidei cu schizofrenie necontrolata (malnutritie, episoade de violenta domestica sau sexuala, boli infectioase ginecologice si alte comportamente nesano gene) (11, 12).

CONCLUZII

Literatura de specialitate ofera date insuficiente despre efectele antipsihoticelor atipice asupra fatului in utero, cat si asupra dezvoltarii sale postnatale, date fiind limitarile de ordin etic ale realizarii unor studii ample, pe subiecti umani si, in particular, pe gravide. Totusi, majoritatea studiilor recomanda administrarea antipsihoticelor atipice in timpul sarcinii la mamele cu schizofrenie, in pofida potentialelor efecte adverse ale acestora, prin punerea in balanta a beneficiilor si a riscurilor atat pentru acestea, cat si pentru feti. Cu toate ca cele mai frecvente efecte adverse ale antipsihoticelor atipice sunt reprezentate de tulburarile metabolismului lipidelor si cresterea ponderala, iar acestea au repercusiuni severe in ceea ce priveste dezvoltarea tubului neural, precum si cresterea corporala in sine a fatului, fie in sensul subdezvoltarii, fie in cel al supradezvoltarii ponderale, s-a demonstrat ca un regim alimentar echilibrat al mamei, insotit de un adecvat aport exogen de folati si de o educatie prenatala, cat si postnatala corespunzatoare pot controla, in mod optim, aceste probleme.

Dania Andreea Radu--M. D., Drd., Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi; Medic Rezident Psihiatru, Spitalul Clinic de Psihiatrie "Socola", Iasi, Romania

Roxana Chirita--Profesor universitar, Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi; Medic Primar Psihiatru, Spitalul Clinic de Psihiatrie "Socola", Iasi, Romania

Ilinca Untu--M. D., Drd., Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi; Medic Rezident Psihiatru, Spitalul Clinic de Psihiatrie "Socola", Iasi, Romania

Vasile Chirita--Profesor universitar, Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi; Medic Primar Psihiatru, Spitalul Clinic de Psihiatrie "Socola", Iasi, Romania

Anamaria Ciubara--M. D., Ph. D., Sef de Lucrari, Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi; Medic Specialist Psihiatru, Spitalul Clinic de Psihiatrie "Socola", Iasi, Romania

Lucian Stefan Burlea--M. D., Ph. D., Cercetator post-doctoral, Asistent universitar, Universitatea de Medicina si Farmacie "Gr. T. Popa", Iasi, Romania

MULTUMIRI SI DEVOALARI

Autorii declara ca nu au potentiale conflicte de interese de declarat in legatura cu acest articol.

BIBLIOGRAFIE

1. Sandeep, Raha, Taylor, Valerie H., Holloway, Alison C., Effect of AtypicalAntipsychotics on Fetal Growth: Is the Placenta Involved?, J Pregnancy. 2012; 2012: 315203, Published online July 11, 2012. doi: 10.1155/2012/315203

2. McKenna, K., Koren, G., Tetelbaum, M. et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. Journal of Clinical Psychiatry. 2005;66(4):444-449

3. Newham, J. J., Thomas, S. H., MacRitchie, K., McElhatton, P. R., McAUister-Williams, R. H. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. British Journal of Psychiatry. 2008;192(5):333-337

4. Reis, M., Kallen, B. Maternal use of antipsychotics in early pregnancy and delivery outcome. Journal of Clinical Psychopharmacology. 2008; 28(3):279-288

5. Viau, M., Lafond, J., Vaillancourt, C. Expression of placental serotonin transporter and 5-HT2A receptor in normal and gestational diabetes mellituspregnancies. Reproductive Biomedicine Online. 2009;19(2):207-215

6. Gambino, Y. P., Maymo, J. L., Perez, Perez A., Calvo, J. C., Sanchez-Margalet, V., Varone, C. L. Elsevier Trophoblast Research Award lecture: molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression. Placenta. 2012;33:S63-S70

7. Mise, H., Yura, S., Itoh, H. et al. The relationship between maternal plasma leptin levels and fetal growth restriction. Endocrine Journal. 2007; 54(6):945-951

8. Vesga-Lopez, O., Blanco, C., Keyes, K., Olfson, M., Grant, B. F., Hasin, D. S. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry. 2008;65(7):805-815

9. Michielsen, Laura A., van der Heijden, Frank M. M. A., Janssen, Paddy K. C., Kuijpers, Harold J. H. Effects of maternal psychotropic drug dosage on birth outcomes, Neuropsychiatr Dis Treat. 2014; 10: 13-18. Published online Dec. 10, 2013

10. Koren, Gideon, M. D., F.A.C.M.T., F.R.C.P.C.; Tony Cohn, M. B., Ch. B.; David Chitayat, M. D., F.R.C.P.C.; Bhushan Kapur, Ph. D.; Remington, Gary, M. D., Ph. D.; Myles Reid, Diane, M. Sc.; Zipursky, Robert B., M. D., F.R.C.P.C., Use of Atypical Antipsychotics During Pregnancy and the Risk of Neural Tube Defects in Infants, Am J Psychiatry 2002; 159:136-137. doi:10.1176/ appi.ajp.159.1.136

11. Gentile, Salvatore. Antipsychotic Therapy During Early and Late Pregnancy. A Systematic Review, Schizophr Bull. May 2010; 36(3): 518-544, Published online Sep. 11, 2008. doi: 10.1093/schbul/sbn107

12. Kulkarni, J., Worsley, R., Gilbert, H., Gavrilidis, E., Van Rheenen, T. E., Wang, W., McCauley, K., Fitzgerald, P., A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies, PLoS One. 2014 May 2;9(5):e94788. doi: 10.1371/journal.pone.0094788. eCollection 2014

Corespondenta:

ROXANA CHIRITA

Spitalul Clinic de Psihiatrie "Socola"

Sos. Bucium nr. 36, cod 700282, Iasi, Romania

Tel.: +40 232 430 920/int. 185

E-mail: d.stigma@gmail.com

Primit: Decembrie, 04, 2013

Acceptat: ianuarie, 13, 2014
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Author:Radu, Dania Andreea; Chirita, Roxana; Untu, Ilinca; Chirita, Vasile; Ciubara, Anamaria; Burlea, Luci
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Mar 1, 2014
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