Depression In Pregnancy? rTMS Might Be Our Most Safe Treatment
A Sunday Morning Review of the evidence for the treatment of depression in women who are pregnant.
As a parent of twins, I am here to tell you: pregnancy is terrifying. It is, of course, beautiful and might go fine. However, not all pregnancies are smooth sailing. Having another life gestate while exquisitely vulnerable to biological insults that could change the entire course of their life after birth? That is a huge deal. The whole situation can get substantially more dicey when there is depression involved. Major depressive disorder (MDD) is estimated to affect between 7% and 12% of pregnant women worldwide.1
First, a Marketing aside: I have a live-action event coming up! It’s called RAMHT ‘25 LA!
It is on May 18th, in Los Angeles! Get more info here.
To begin, depression itself can be harmful to a developing baby, as my colleague and sometimes co-author Justin Chan2 highlights:
Babies born to women with untreated depression are at risk of prematurity, low birth weight, and intrauterine growth restriction.2,3 The negative consequences of untreated maternal depression might also affect childhood development. Higher impulsivity, maladaptive social interactions, and cognitive, behavioural, and emotional difficulties have been shown to occur.4,5
This is all in addition to the harm to the mother, who will also be suffering from depression while worrying that the depression will be a problem for her baby. These risks are not trival, as Chan et. al. note:
Importantly, pregnant women with depression are more at risk of developing postpartum depression and suicidality.6 Increased hospital admissions and pregnancy complications such as preeclampsia have also been linked to untreated maternal depression.6,7
Oral medicines to treat depression can present dangers during pregnancy, too. The first risk people worry about is major birth defects, and that risk has been assessed in large samples, such as this paper published in JAMA in 2020:
In this case-control study of 30 630 mothers of infants with birth defects and 11 478 control mothers, there were previous and new associations between individual selective serotonin reuptake inhibitors, venlafaxine, and bupropion and specific birth defects…Venlafaxine was associated with more birth defects than other antidepressants, which needs confirmation; studies to assess birth defect risk among women taking antidepressants should account for the underlying condition.3
Of note, other antidepressants also led to additional birth defect risk if there were predisposing risk factors in place as well.
There are risks beyond birth defects, as well. Pregnancy-induced hypertension, with risks for mother and child, is increased in a case-control study from Canada:
use of antidepressants during pregnancy was significantly associated with increased risk of pregnancy-induced hypertension (OR 1.53, 95% CI 1.01, 2.33). In stratified analyses, use of selective serotonin re-uptake inhibitors (OR 1.60, 95% CI 1.00, 2.55), and more specifically, paroxetine (OR 1.81, 95% CI 1.02, 3.23) was associated with risk of pregnancy-induced hypertension.4
The risk of pre-term birth and low birthweight were both increased in a large sample published in JAMA Psychiatry as well:
Gestational age and preterm delivery were statistically significantly associated with antidepressant exposure (mean difference [MD] [weeks], −0.45; 95% CI, −0.64 to −0.25; P < .001; and OR, 1.55; 95% CI, 1.38 to 1.74; P < .001, respectively), regardless of whether the comparison group consisted of all unexposed mothers or only depressed mothers without antidepressant exposure. Antidepressant exposure during pregnancy was significantly associated with lower birth weight (MD [grams], −74; 95% CI, −117 to −31; P = .001);5
I could go on and address the risk of neurodevelopmental disorders and persistent pulmonary hypertension of the newborn, but you already get the point. The dangers of depression are high, and the risk of oral antidepressants are real and present. However, given the problem and the treatment both have risks, there is a real “damned if you do, damned if you don’t” quality if we assume we can never reduce the risk of depression without using a potentially toxic drug.
What we would benefit from is a different way to treat depression that is both more effective and safer for people who are pregnant and their soon-to-be kiddos.
New data suggests neuromodulation with transcranial magnetic stimulation is one such option. I know my readers are simply shocked—SHOCKED—that in this newsletter, crafted lovingly by a doctor who has treated thousands with TMS, we would suggest such a thing.
It’s not like I have a bias toward thinking brain stimulation is a good idea, as evidenced by the following brain stimulation-themed articles…
Those articles are just a small sampling of my voluminous output on the topic….not to mention an entire book—Inessential Pharmacology. (Amazon link) on the topic of drugs sucking. I have a bias; yes, I admit it!
However, new data backs this up. It’s not just me.
In the February 2025 issue of the Journal Brain and Behavior, Angeline et. al. penned:
Transcranial Magnetic Stimulation in Pregnancy: Efficacy, Safety, and Future Implications for Perinatal Mental Health Care
The authors did a systematic review of 363 publications, of which 3 met inclusion criteria for their review, only focusing on women who were pregnant at the time and had major depressive disorder. The first thing to point out, for my readers, is that only three papers on the topic were available. There are TOO FEW STUDIES on a crucial issue for women and, subsequently, all humans.
The first study by Kim, et. al.,6 was an open-label trial of depressed women treated with right-DLPFC inhibitory brain stimulation (not covered by insurance generally, and effective, but off-label from an FDA perspective). It included 20 participants, and the details I will drop in a footnote.7
This first approach in an open-label design was effective:
Notably, 70% of the patients exhibited a positive response to the treatment, which is defined as a reduction of at least 50% in their Hamilton Depression Rating Scale (HDRS) scores. Encouragingly, within this group, 30% met the criteria for remission, signifying a post-TMS HDRS score of less than 8. Furthermore, the mean HDRS scores demonstrated a substantial reduction from an average of 24.4 prior to TMS to 9.7 following TMS intervention (p = 0.005).
With a solid open-label data set, Kim et al. proceeded to move to a Randomized Controlled Trial. This RCT encompassed 22 pregnant women who were diagnosed with major depressive disorder during their second or third trimester. This study didn't find a statistically significant difference:
the mean HDRS score decreasing from 23.18 prior to TMS to 9.27 following the twentieth session. A noteworthy 81.8% of active TMS participants achieved the predefined criterion for response, characterized by a 50% reduction in HDRS scores, in contrast to 45.5% of sham TMS participants. Moreover, remission, defined as achieving HDRS scores lower than 8, was observed in 27.3% of the active TMS group and 18.8% of the sham TMS group. However, it is pertinent to note that neither the remission nor response rates achieved statistical significance, which the authors attributed to the limited sample size.
Given the small sample size, I’d be suspicious if there WERE a difference—there were less subjects in this trial than in the SNT trial by E. Cole and colleagues8, and thus, in an underpowered study, the chance that you can demonstrate a real difference is hampered. These trials are hard to do! As philosophical aside:
Not all things that are therapeutic are therapies. Not all therapies are therapeutic.
Being paid attention to can be therapeutic despite not being a therapy. That is what sham treatment in a study protocol is! When it comes to safety, however, the study did add to our evidence base in a meaningful way:
This RCT did not identify significant differences in pre- and postintervention estradiol or progesterone levels.
And beyond lab values not changing…the neonatal outcomes were excellent:
APGAR scores, birth length, and weight, fell within the normal range. Furthermore, the authors noted that only five women in the study were concurrently using psychiatric medication, and all of them were on stable doses for at least 2 weeks prior to commencing their TMS treatment.
So that, alone, is news. A third trial moved to a more traditional TMS protocol to the Left front of the brain (details in footnote9), conducted by Sayer et al.10
Notably, NONE OF THESE STUDIES used a standard or FDA-cleared TMS protocol, which seems to me like a miss. They may have had excellent science reasons to chose the approaches they did, but at least according to this review, no one has studied in an RCT any FDA-labeled TMS protocol in women who are pregnant. This, of course, means that close to 100% of the pregnant women considering this treatment in the real world and their treaters have minimal data to guide them! Moving on to the outcome of this study, which were similar to the results of the prior studies:
The results indicated a significant reduction in mean HDRS scores, which decreased from 26.77 to 13.03. Importantly, 41.4% of the patients exhibited a favorable response to the TMS intervention, defined as a reduction of 50% or more in HDRS scores, while 20.7% achieved remission.
It's working about the same as traditional TMS in regular clinical samples of other depressed people but with a dearth of randomized or large-scale trial data.
The point of this review was safety, and here, too, there were no adverse outcomes:
there were no reports of adverse neonatal outcomes in association with this TMS treatment. This underscores the safety of the intervention concerning neonatal health.
Thank goodness we have one more RCT coming this year that didn't make it into the above review because it hasn’t been done yet. The protocol was published less than a month after it was submitted! In just February of 2025, the following RCT protocol was published before the trial is concluded, which I hope will meaningfully answer more of the most important questions we have about what to do for women who are pregnant and depressed:
Effectiveness of rTMS compared to SSRI as early treatment of depression – study protocol of a randomized controlled trial (Early-TMS)
The authors will compare iTBS stimulation to SSRIs in pregnant women with depression to determine which is better11. I know which I’d be betting on, but we don’t have to rely on a gut check or hunches when we have empirical answers.
Science will move forward. The one bet I’m willing to make? The science will absolutely LAP the payment models if we don’t raise all our voices to both our employers and elected representatives.
The bottom line for today? In addition to the above controlled studies, authors have reviewed all available case studies of babies born after moms treated with TMS. They found no evidence of risk12:
The available reports provide no evidence that TMS to mother during pregnancy has detrimental effects on the fetus.
We know there is risk with oral antidepressants. Defined, and definite risk. Depression itself has risks that are likely greater than the risk from medicines that treat it. The only biological treatment that has no risk we know of? rTMS, for now.
And soon, thanks to the Early-TMS trial, we will have a direct comparison.
“More research is needed.” It can be exhausting to constantly repeat this statement, but that is where we are today.
Bennett, H. A., A. Einarson, A. Taddio, G. Koren, and T. R. Einarson. 2004. “Prevalence of Depression During Pregnancy: Systematic Review.” Obstetrics and Gynecology 103, no. 4: 698–709.
Chan J, Natekar A, Einarson A, Koren G. Risks of untreated depression in pregnancy. Can Fam Physician. 2014 Mar;60(3):242-3. PMID: 24627378; PMCID: PMC3952758.
Anderson, K. N., Lind, J. N., Simeone, R. M., Bobo, W. V., Mitchell, A. A., Riehle-Colarusso, T., ... & Reefhuis, J. (2020). Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA psychiatry, 77(12), 1246-1255.
De Vera, M. A., & Bérard, A. (2012). Antidepressant use during pregnancy and the risk of pregnancy‐induced hypertension. British journal of clinical pharmacology, 74(2), 362-369.
Ross, L. E., Grigoriadis, S., Mamisashvili, L., VonderPorten, E. H., Roerecke, M., Rehm, J., ... & Cheung, A. (2013). Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA psychiatry, 70(4), 436-443.
Kim, D. R., N. Epperson, E. Paré, et al. 2011. “An Open Label Pilot Study of Transcranial Magnetic Stimulation for Pregnant Women With Major Depressive Disorder.” Journal of Womens Health (2002) 20, no. 2: 255–261. https://doi.org/10.1089/jwh.2010.2353.
Each session consisted of transcranial magnetic stimulation delivered at a frequency of 1 Hz, with the magnetic intensity calibrated at 100% of the motor threshold. The target site for TMS application was the right dorsolateral prefrontal cortex. It is imperative to highlight that this study adopted an open-label design, thus precluding the implementation of a blinding process.
Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29. PMID: 34711062.
In this study, patients received a total of 18 TMS sessions, with each session administered daily, 6 days a week, spanning over a duration of 3 weeks. The 30 subjects were treated with 20 sessions of 25 Hz TMS to the left prefrontal cortex.
Hızlı Sayar, G., E. Ozten, E. Tufan, et al. 2014. “Transcranial Magnetic Stimulation During Pregnancy.” Archives of Women's Mental Health17, no. 4: 311–315. https://doi.org/10.1007/s00737-013-0397-0.
Becker-Sadzio, J., Brendel, B., Weller, S., Bornheimer, E., Mehlig, U., Padberg, F., ... & Plewnia, C. (2025). Effectiveness of rTMS compared to SSRI as early treatment of depression–study protocol of a randomized controlled trial (Early-TMS). European Archives of Psychiatry and Clinical Neuroscience, 1-11.
Pridmore, S., Turnier-Shea, Y., Rybak, M., & Pridmore, W. (2021). Transcranial Magnetic Stimulation (TMS) during pregnancy: a fetal risk factor. Australasian Psychiatry, 29(2), 226-229.