ORIGINAL ARTICLE

Transcranial magnetic stimulation during pregnancy

Gökben Hızlı Sayar & Eylem Ozten & Evren Tufan &

Cem Cerit & Gaye Kağan & Nesrin Dilbaz & Nevzat Tarhan

Received: 18 December 2012 /Accepted: 7 November 2013# Springer-Verlag Wien 2013

Abstract The aim of the present study was to assess thesafety and effectiveness of high-frequency repetitive transcra-nial magnetic stimulation (rTMS) in pregnant patients withdepression. Thirty depressed pregnant patients received rTMSover the left prefrontal cortex for 6 days in a week, fromMonday to Saturday for 3 weeks. The rTMS intensity wasset at 100 % of the motor threshold. A 25-Hz stimulation witha duration of 2 s was delivered 20 times with 30-s intervals. Asession comprised 1,000 magnetic pulses. Depression wasrated using the 17-item Hamilton depression rating scale(HAMD) before and after treatment. Response was definedas a 50% reduction of the HAMD score. Patients with HAMDscores less than 8were considered to be in remission. ThemeanHAMD score for the study group decreased from 26.77±5.58

to 13.03±6.93 (p <0.001) after 18 sessions of rTMS. After thetreatment period, 41.4 % of the study group demonstratedsignificant mood improvements as indexed by a reductionof more than 50 % on the HAMD score. In addition,20.7 % attained remission (HAMD score<8), 34.5 %achieved a partial response, and 3.4 % had worsening inHAMD scores at the end of treatment. Treatment was welltolerated, and no significant adverse effects were reported.rTMS was well tolerated and found to be statistically andclinically effective in pregnant patients with treatment-resistant depression. This study contributed to the existingevidence of the antidepressant effect of rTMS in the treatmentof depression in pregnancy.

Keywords Repetitive transcranial magnetic stimulation .

rTMS . Pregnancy . Depression . Treatment

Introduction

The treatment of pregnant women with depression is a diffi-cult problem in the field of psychiatry. Pharmacological treat-ment during pregnancy requires balancing risks and expectedbenefits in each patient, taking the patients' history, presenta-tion, and preferences into account. The safety of antidepres-sant use during pregnancy is still under debate since studies onrisks of serious malformations, persistent pulmonary hyper-tension, and long-term effects on neurodevelopment reportconflicting results (Campagne 2007; Andrade et al. 2009).On the other hand, anxiety and depression are known tothreaten both the mother and pregnancy outcome, includingabnormal behavioral development of the infant at follow-up(Gentile 2005).

There are still a lot of controversies in the area of antide-pressant treatment in pregnant women due to the risk ofadverse effects on the fetus. However, repetitive transcranial

G. Hızlı Sayar : E. Ozten :G. Kağan :N. Dilbaz :N. TarhanNeuropsychiatry Istanbul Hospital, Uskudar University, Istanbul,Turkey

E. Oztene-mail: eozten@yahoo.com

G. Kağane-mail: gaye.kagan@uskudar.edu.tr

N. Dilbaze-mail: nesrin.dilbaz@uskudar.edu.tr

N. Tarhane-mail: ntarhan@uskudar.edu.tr

E. TufanFaculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey

C. CeritFaculty of Medicine, Kocaeli University, Kocaeli, Turkeye-mail: cemcerit@yahoo.com

G. Hızlı Sayar (*)Department of Psychiatry, Neuropsychiatry Istanbul Hospital,Uskudar University, Alemdag Caddesi Site Yolu No:29 Umraniye,Istanbul, Turkeye-mail: gokben.hizlisayar@uskudar.edu.tr

Arch Womens Ment HealthDOI 10.1007/s00737-013-0397-0

magnetic stimulation (rTMS) may be an acceptable choice forpregnant women with depression. rTMS is a new neuro-electrophysiological technique, which is developed on thebasis of transcranial magnetic stimulation (Rossi et al.2009). With its unique characteristics of being noninvasive,simple, and safe, clinical applications of rTMS have rapidlyexpanded over the last few years. In 2008, the US Food andDrug Administration approved TMS as an alternative form oftreatment for depression resistant to other treatments (Janicaket al. 2008). Many researchers stated that rTMS was effectivein treating depression, and the adverse effects were not obvi-ous (Shajahan et al. 2002). Motor cortex studies suggest thathigh- and low-frequency rTMS have opposite effects on theexcitability of neurons in the brain cortex (Avery et al.2006).There is substantial evidence from neuropsychological, lesion,and imaging studies that the left and right hemispheres havecontrasting roles in mood regulation (Avery et al. 2008).Therefore, it might be expected that low-frequency rTMS tothe right prefrontal cortex may be as likely to have antidepres-sant effects as high-frequency rTMS to the left prefrontalcortex. The stimulus frequency of rTMS was within the rangeof 5–25Hz in several studies as changes in cortical excitabilityhave been demonstrated with this range of frequency (Averyet al. 2006).

The proper treatment of mood disorders occurring duringpregnancy is a significant therapeutic problem since no antide-pressant medications have been established as safe for thedeveloping fetus. The nonpharmacological nature of rTMSeliminates concerns about fetal exposure to the potential risksof psychotropic medications. However, few scholars tried touse rTMS to treat pregnant women with depression for itsuncertain effects. In a survey of patient acceptability of rTMSduring pregnancy, Kim et al. (Kim et al. 2011a, b) found thatTMS was considered as an unacceptable treatment option byalmost all women before informational video, but afterwatching a teaching video about rTMS, increasing participantknowledge about rTMS increased its acceptability significantly.The aim of this study was to assess the safety and effectivenessof high-frequency rTMS in pregnant patients with depression.

Materials and methods

Study design

Pregnant patients who met the structured clinical interview forDSM-IV criteria for depression were eligible for the study. Allthe patients were “treatment-resistant”, which was describedas “failure to respond adequately to two successive courses ofmonotherapy with pharmacologically different antidepres-sants given in adequate doses for 4–6 weeks.” Concomitantmedication for depression was authorized, provided the doseadministered had been stable for at least 1 month before

enrollment and remained stable throughout the study. Of the30 patients, 12 were on selective serotonin reuptake inhibitor(SSRI) monotherapy (4 patients were on escitalopram 30 mg/day, 5 were on fluoxetine 20–40 mg/day, and 3 patients wereon sertraline 100 mg/day treatment). The other 18 patientswere free of medications for the treatment of depression for atleast 4 weeks. For ten of the patients, there was SSRI exposureduring some part of the first trimester, before the decision toproceed with rTMS has been made.

The study group had no psychiatric or general medicalcomorbidity. The study protocol conformed to the Helsinkideclaration; all patients were fully informed and signed con-sent forms. After obtaining informed consent, subjects had acomplete neurological and physical examination. Subjectswere also screened with a complete blood count, thyroidfunction tests, and electrolytes within 3 months of the treat-ments. Exclusion criteria included evidence of significantcentral nervous system dysfunctions. Additional exclusioncriteria included the presence of cardiac pacemakers, cochlearimplants, or other intracranial implants with the exception ofdental fillings, the presence of psychiatric symptoms of sig-nificant severity (e.g., refusal of food and medication or thepresence of psychosis) that would prevent a 3-week trial ofrTMS from being tolerated, and drug or alcohol abuse anddependence. Subjects with acute, unstable medical conditionsthat required stabilization (e.g., uncontrolled hypertension)prior to treatment, previous adverse pregnancy outcome, orcurrent pregnancy complications were also excluded. None ofthe participants were excluded due to fetal abnormalities. Anobstetrician screened and examined all patients with their fetalultrasound before initiating the study.

Stimulation

TMS was applied to all patients in an open-label manner usingthe Magstim Super Rapid stimulator (Magstim Company,Whitland, UK) with a figure-of-eight-shaped coil. The rTMSintensity was set at 100 % of the motor threshold (MT), whichwas determined by visual inspection. Stimulation was given tothe left prefrontal cortex, deemed to be located 5 cm in front ofthe cortical motor area of the abductor pollicis brevis of whichthe motor threshold was determined. The treatment schedulewas 6 days in a week, from Monday to Saturday for 3 weeks.The 25-Hz stimulation with a duration of 2 s was delivered 20times with 30-s intervals. A session comprised 1,000 magneticpulses, and a full course comprised an average of 18,000 pulseswith 1,000 pulses per day for 18 days. High-frequency rTMS tothe left prefrontal cortex has been used, as a choice influencedby positive preliminary results for this approach (Tarhan et al.2012). Imaging studies have shown evidence of reduced bloodflow in the left prefrontal cortex in patients with depression.Following rTMS in this area, the blood flow has been reportedto increase (Isenberg et al. 2005).

G. Hızlı Sayar et al.

Outcome measures

Depressive symptom changes were measured using the vali-dated Hamilton depression rating scale (HAMD) (Hamilton1960). The primary outcome parameter, the 17-item HAMD(HAMD-17) score, constitutes a valid and reliable measure ofthe severity of depressive symptoms (Akdemir et al. 1996).The HAMD-17 scores were obtained at baseline and 1 weekafter completing the course of rTMS. Secondary outcomeparameters included response and remission rates. Responsewas defined as a decrease in the HAMD-17 total score of atleast 50 %. Patients with HAMD-17 scores less than 8 wereconsidered to be in remission. Efficacy parameters wereassessed by an independent rater.

Statistical analysis

Data were analyzed using Statistical Package for Social Sci-ences 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Para-metric and nonparametric tests were applied to the data. Inde-pendent samples t test and Mann–Whiney U test were used tocompare independent groups. Paired t test and Wilcoxonsigned-rank test were used to compare dependent groups. Theresults of all items were expressed as mean±SD, assessedwithin a 95 % reliance and at a significance level of p <0.05.

Results

A total of 30 depressed pregnant patients who underwentrTMS treatment were included in the study. One patient with-drew from follow-up, leaving 29 patients (96.6 %) in the studygroup. The reason for her withdrawal was reconsideration ofthe risks and benefits of the study. After the sixth session,rTMS was stopped, and this subject went on to receive elec-troconvulsive therapy (ECT). The prospectively planned datacollection of 29 patients who completed the rTMS procedurewas retrospectively evaluated.

The mean age of the study group was 32.69±3.69 years(range, 25 to 39), while the mean gestational age at the firstrTMS session was 14.26±8.25 weeks (range, 5 to 32). Themean number of rTMS sessions was 16.46±5.15 for the studygroup.

The mean HAMD score for the study group decreasedfrom 26.77±5.58 to 13.03±6.93 (p <0.001). After an 18-daytreatment period, 12 of 29 patients (41.4 %) demonstratedsignificant mood improvements as indexed by a reduction ofmore than 50 % on the HAMD score. Six patients (20.7 %)attained remission (HAMD score<8), ten patients (34.5 %)achieved a partial response, and one patient (3.4 %) hadworsening in HAMD scores at the end of treatment.

In the study group, the magnetic stimulation was welltolerated. Patients had previously been informed about

contractions of facial muscles. Other side effects such ascognitive difficulties, seizures, headache, tinnitus, dizziness,or nausea which were observed during rTMS studies in theliterature were not reported in our study group.

Of the 29 pregnant participants, 23 gave birth to 25 healthybabies, and the newborns revealed no abnormalities. Themean birth weight of the infants was 3,135.5±4,09.38 g. Allwere born at >36 weeks of gestational age, with a mean 1-minApgar score of 8.1 and mean 5-min Apgar score of 8.8. Allinfants were discharged with their mother. Results of completephysical and neurologic examinations, screening tests forphenylketonuria and hypothyroidism, and hearing assessmentwere normal. None had congenital hip dysplasia, congenitalcardiac disease, cleft lip, or cleft palate. There were no gas-trointestinal, pulmonary, or muscular abnormalities. During amean follow-up of 24.8±18.47 months, none of the infantsshowed any further abnormalities. Six fetuses are still inintense follow-up in outpatient clinics and do not show anysign of intrauterine growth retardation.

Discussion

Treatment of depression during pregnancy is an understudiedarea because of concerns regarding the impact of the treatmenton the fetus. TMS appears to be a promising treatment optionfor pregnant women. This is the largest case series to datedescribing the use of rTMS in pregnancy for the treatment ofdepression. In the present study, pregnant patients' depressivesymptoms were significantly relieved, and all the newbornswere healthy.

The proper treatment of mood disorders occurring duringpregnancy is a major therapeutic problem since no antidepres-sant medications have been established as safe for the devel-oping fetus. Psychotherapy should be a first-line treatmentrecommendation for major depressive disorder during preg-nancy, but there is little evidence of the efficacy of psycho-therapy in the treatment of moderate to severe depression inpregnant depressed women. Unlike psychotherapeutic inter-ventions, patients receiving rTMS respond rapidly, often with-in 2–4 weeks, and the response can be sustained (O'Reardonet al. 2007).

While available research is not conclusive, light therapyremains a promising treatment for major depressive disorderin pregnancy (Oren et al. 2002). If psychotherapy or antide-pressants are not an option for a patient with a mild-to-moderate depression, a course of light therapy may be ofbenefit, with no documented risk to the fetus and perhapsspecifically for women with seasonal exacerbation of moodsymptoms (Epperson et al. 2004). But there are not enoughdata to support this as an evidence-based treatment for depres-sion during pregnancy and for patients with a moderate-to-severe depression.

Transcranial magnetic stimulation during pregnancy

Apart from antidepressants, the most commonly used bio-logical therapeutic process is ECT. We believe that similarefficacy can be achieved using rTMS as a safer option thanECT, with considerably less side effects. rTMS is a noveltechnology that noninvasively delivers focused magneticpulses to the surface of the brain (Lisanby et al. 2002;Lisanby 2002). With rTMS, this focal stimulation of theprefrontal cortex is conducted with the patient aware andnonsedated, and the continuation of daily activities is possibleimmediately after the stimulation session. To date, there areremarkably few cases in the literature concerning the use ofrTMS for the treatment of depression during pregnancy(Nahas et al. 1999; Klirova et al. 2008; Tan et al. 2008;Zhang and Hu 2009; Kim et al. 2011a, b; Gahr et al. 2012).

The ethics of conducting research in pregnant women hasbeen a topic of interest, given the increased recognition of theimportance of women's mental health issues. Classically,pregnant women were excluded from research participationprimarily based on the idea that the fetus represents a secondpatient with rights that should be considered. Therefore, preg-nant women are considered a special population in research.In the present study, 41.4 % of the study group demonstratedsignificant mood improvements and classified as responderswhile 20.7 % of the patients reached remission status. Theresponse rates obtained by other studies in the literature varyin great degree.

The most common side effects are pain or discomfortduring stimulation (owing to stimulation of scalp nerves andmuscles) and headache, although seizure, facial numbness,and hearing loss have been reported rarely (Janicak et al.2008). rTMS is not associated with any adverse cognitiveissues, making the treatment palatable for patients. In thepresent study, the magnetic stimulation was well tolerated.Cognitive difficulties, seizures, headache, tinnitus, dizziness,or nausea that was observed during rTMS studies in theliterature was not reported in our study group. In this study,TMS was well tolerated and safe. The dropout rate for anyreason from active TMS was 3.3 % (n =1), and discontinua-tion was not specifically because of side effects. This is lowerthan the discontinuation rates reported from clinical trials ofantidepressants.

Several issues should be considered concerning safety ofthe fetus. Based on known neurophysiology of the magneticfield induced by the rTMS coil, there is no reason to believethat there will be any exposure to the fetus. The maximumdepth of the magnetic field is believed to be about 5 cm, justsufficient to achieve the outer edges of the brain white matter(George et al. 2002). There is a risk of preterm labor if aseizure is induced with rTMS. In the literature, preterm birthwas described in one infant, but the mother was also takingvenlafaxine (Klirova et al. 2008). All other infants were re-ported as healthy, but no specific information about how thiswas assessed was given. In the present study, results of

complete physical and neurologic examinations, screeningtests for phenylketonuria and hypothyroidism, and hearingassessment of the infants were normal.

Physicians who provide health care for pregnant womenwith depression must consider the risk/benefit ratio for eachsingle case prior to rTMS treatment in pregnancy. Pregnantwomen acting as TMS operators should conservatively stay atleast 0.7 m away from the discharging coil (Rossi et al. 2009).

The risk of rTMS causing congenital malformations isunknown. There is a baseline risk of significant congenitalmalformations of about 3 % in the general population. It isunlikely that rTMS will increase this risk given the lowexposure of the fetus to the magnetic field. In the presentstudy, none of the newborns had congenital hip dysplasia,congenital cardiac disease, cleft lip, or cleft palate. There wereno gastrointestinal, pulmonary, or muscular abnormalities.

Although there are several limitations, such as small samplesize, this study provides a new approach for treating pregnantwomen with depression. HAMD was the only outcome mea-sure, but it is specific for depression. Higher responsiveness ofspecific rather than generic instruments should render the re-sults of this study usable for comparison with studies of othertreatment modalities for treatment-resistant depression. Themain limitation of this study is the noncontrolled design, whichlikely restricted the statistical power. Since the study lacks acontrol group, we cannot eliminate the possibility of a placeboeffect. Further studies are required to define the optimal param-eters of stimulation (site, intensity, frequency, etc.) to clarifywhich patient and treatment characteristics might lead to greaterantidepressant effect in pregnant women.

Conclusion

In conclusion, rTMS is a safe and well-tolerated treatment andmay be a worthwhile adjunctive treatment to medications inpregnant depressed patients. We believe our findings add tothe growing body of literature that suggests the effectivenessof rTMS. Despite the fact that the generalizability of theresearch findings is limited, rTMS treatment in pregnant de-pressed population is showing promising results and requiresfurther investigation.

References

Akdemir A, Orsel S, Dag I, IscanN,Ozbay H (1996) Hamilton depresyonderecelendirme ölçeğinin geçerliliği, güvenilirliği ve kliniktekullanımı. Psikiyatri Psikoloji Psikofarmakoloji Dergisi 4:251–259(Turkish)

Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J,Boudreau DM, Smith DH, Davis RL, Willy ME, Platt R (2009)Antidepressant medication use and risk of persistent pulmonary

G. Hızlı Sayar et al.

hypertension of the newborn. Pharmacoepidemiol Drug Saf 18(3):246–252

Avery DH, Holtzheimer PE 3rd, Fawaz W, Russo J, Neumaier J, DunnerDL, Haynor DR, Claypoole KH, Wajdik C, Roy-Byrne P (2006) Acontrolled study of repetitive transcranial magnetic stimulation inmedication-resistant major depression. Biol Psychiatry 59:187–194

Avery DH, Isenberg KE, Sampson MS, Janicak PG, Lisanby SH,Maixner DF, Loo C, Thase ME, Demitrack MA, George MS(2008) Transcranial magnetic stimulation in the acute treatment ofmajor depressive disorder: clinical response in an open-label exten-sion trial. J Clin Psychiatry 69(3):441–451

Campagne DM (2007) Fact: antidepressants and anxiolytics are not safeduring pregnancy. Eur J Obstet Gynecol Reprod Biol 135(2):145–148

Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS,Wisner KL (2004) Randomized clinical trial of bright light therapyfor antepartum depression: preliminary findings. J Clin Psychiatry65(3):421–425

Gahr M, Blacha C, Connemann BJ, Freudenmann RW, Schönfeldt-Lecuona C (2012) Successful treatment of major depression withelectroconvulsive therapy in a pregnant patient with previous non-response to prefrontal rTMS. Pharmacopsychiatry 45(2):79–80

Gentile S (2005) SSRIs in pregnancy and lactation: emphasis onneurodevelopmental outcome. CNS Drugs 19(7):623–633

GeorgeMS, Nahas Z, Kozel FA, Li X, Denslow S, YamanakaK,MishoryA, Foust MJ, Bohning DE (2002) Mechanisms and state of the art oftranscranial magnetic stimulation. J ECT 18:170–181

Hamilton M (1960) A rating scale for depression. J Neurol NeurosurgPsychiatry 23:56–62

Isenberg K, DownsD, Pierce K, Svarakic D, Garcia K, JarvisM,North C,Kormos TC (2005) Low frequency rTMS stimulation of the rightfrontal cortex is as effective as high frequency rTMS stimulation ofthe left frontal cortex for antidepressant free, treatment resistantdepressed patients. Ann Clin Psychiatry 17:153–159

Janicak PG, O'Reardon JP, Sampson SM, Husain MM, Lisanby SH, RadoJT,Heart KL,DemitrackMA (2008) Transcranialmagnetic stimulationin the treatment of major depressive disorder: a comprehensive sum-mary of safety experience from acute exposure, extended exposure,and during reintroduction treatment. J Clin Psychiatry 69:222–232

Kim DR, Epperson N, Paré E, Gonzalez JM, Parry S, Thase ME,Cristancho P, Sammel MD, O'Reardon JP (2011a) An open labelpilot study of transcranial magnetic stimulation for pregnant womenwith major depressive disorder. J Women's Health (Larchmt) 20(2):255–261

Kim DR, Sockol L, Barber JP, Moseley M, Lamprou L, Rickels K,O'Reardon JP, Epperson CN (2011b) A survey of patient acceptabil-ity of repetitive transcranial magnetic stimulation (TMS) duringpregnancy. J Affect Disord 129(1–3):385–390

KlirovaM, Novak T, KopecekM,Mohr P, Strunzova V (2008) Repetitivetranscranial magnetic stimulation (rTMS) in major depressive epi-sode during pregnancy. Neuroendocrinol Lett 29(1):69–70

Lisanby SH (2002) Update on magnetic seizure therapy: a novel form ofconvulsive therapy. J ECT 18:182–188

Lisanby SH, Kinnunen LH, Crupain MJ (2002) Applications of TMS totherapy in psychiatry. J Clin Neurophysiol 19:344–360

Nahas Z, Bohning DE, Molloy MA, Oustz JA, Risch SC, George MS(1999) Safety and feasibility of repetitive transcranial magneticstimulation in the treatment of anxious depression in pregnancy: acase report. J Clin Psychiatry 60(1):50–52

O'Reardon J, Solvason H, Janicak P, Sampson S, Isenberg KE, Nahas Z,McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA,George MS, Sackeim HA (2007) Efficacy and safety of transcranialmagnetic stimulation therapy in the acute treatment of major depres-sion: a multi-site randomized controlled trial. Biol Psychiatry 62:1208–1216

Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS,Terman M (2002) An open trial of morning light therapy for treat-ment of antepartum depression. Am J Psychiatry 159(4):666–669

Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMSConsensus Group (2009) Safety, ethical consideration and applica-tion guidelines for the use of TMS in clinical practice and research.Clin Neurophysiol 120(12):2008–2039

Shajahan PM, GlabusMF, Steele JD, Doris AB, Anderson K, Jenkins JA,Gooding PA, Ebmeier KP (2002) Left dorso-lateral repetitive trans-cranial magnetic stimulation affects cortical excitability and func-tional connectivity, but does not impair cognition in major depres-sion. Prog Neuropsychopharmacol Biol Psychiatry 26(5):945–954

Tan O, Tarhan N, Coban A, Baripoglu SK, Guducu F, Izgi HB, Hizli G,Ates O, Bulut H (2008) Antidepressant effect of 58 sessions ofrTMS in a pregnant woman with recurrent major depressive disor-der: a case report. Prim Care Companion J Clin Psychiatry 10(1):69–71

Tarhan N, Hızlı Sayar G, Tan O, Kagan G (2012) Efficacy of high-frequency repetitive transcranial magnetic stimulation in treatment-resistant depression. Clin EEG Neurosci 43(4):279–284

Zhang D, Hu Z (2009) rTMS may be a good choice for pregnant womenwith depression. Arch Women's Ment Health 12(3):189–190

Transcranial magnetic stimulation during pregnancy