Treatment Repetitive Transcranial Magnetic Stimulation to Peripartum Depression: Systematic Review

Abstract


Background
Peripartum depression (PPD) is commonly classi ed as occurrence of major depressive disorder (MDD) during pregnancy period and within 4 weeks after childbirth [1]. Even though PPD is common disorder that 10 20% of pregnant women can experience [2], you will spend expensive life time cost of 75,728 pounds not address the therapeutic effect or safety of rTMS [46]. A Ganho-Ávila study conducted a systematic literature review on patients with only postpartum depression [47]. Felipe's research was unreliable because the systematic review protocol was unclear and the number of study was only 3 [48]. J cole study did not quantitatively synthesize therapeutic effect size or safety [49].
In this study, we will evaluate the effect size and safety of rTMS on the mother's depression and whether it is a suitable method for the mother through systematic literature review and meta-analysis and reviewed the literature that received rTMS treatment from pregnancy to one year after childbirth, considering that the process of breastfeeding, etc. is affecting the growth of newborn babies [50][51][52].

Data Source And Search Strategy
We performed the search by using the literature published before June 2020 as keyword, using the EMBASE, MEDLINE, PsycINFO, and Cochrane Library database. Indication search term is not only peripartum depression but also antepartum depression, postpartum depression and pregnancy depression and the terms of treatment search were repeated transcranial magnetic stimulation, rTMS, transcranial magnetic stimulation and TMS. The detailed searching term and strategy are presented in Appendix 1. Generally, the literature used in meta-analysis is a randomized controlled trial(RCT) study, but non-randomized studies (NRS) which properly set up patients, intervention, comparison, outcome also can include in meta-analysis [53]. So in this study, NRS which were suitable through Cochrane algorithm were included. To minimize the omission of data and increase the reliability, two researchers independently reviewed the literature. But if the opinions of the researchers are different, the literature were reviewed together and reached an agreement. Following studies have been reported the major depressive disorder occurred months after childbirth, though DSM-5 states that the criteria for the peripartum depression is from gestation period to 1 month after delivery [50][51][52]. Therefore, we collected literature that treated rTMS within a year of birth, not 4 weeks, to consider not only the therapeutic effect of rTMS on the treatment of the peripartum depression, but also the effect on fetuses and newborns.
The criteria for exclusion are as follows: (1) experimental studies with animals, (2) when the depression rating scale was not Hamilton Depression Rating Scale, (3) studies were not published in English, (4) studies were not original or were grey literature, (5) when symptoms were baby blues and postpartum psychosis and (6) major depressive disorder did not occur from pregnancy to 1 year after childbirth.
The literature was selected according to the criteria set for all literature searched. After the screening process, the selected literature was extracted. The extracted data include basic information about literature, study characteristics to ensure that rTMS well designed for peripartum depression treatment and side effects, demographic and sociological characteristics to see whether proper patients screening has been performed, rTMS parameters known to affect the therapeutic effect [54] and the condition of a mother and newborn. The detailed are presented in Fig. 1.
Two evaluators independently reviewed the quality of the data and the risk of bias. RCT studies were examined using the Risk of bias 2 (ROB2) [55] and NRS were examined using the Risk of Bias Assessment tool for Nonrandomized Studies (ROBINS-I) [56]. Case reports and series were not ignored as a medical literature [57]. Therefore, we evaluating using Methodological quality tool [58]. The nal judgment on the overall risk of bias was agreed between the two evaluators.
Data analysis was conducted using CMA3 statistical software. For therapeutic effects, two group pre-post data in RCT and one group pre-post data for NRS were analyzed and for safety, Event rates both RCT and NRS were analyzed. Effect size was con rmed by Standardized Mean Deviation (SMD) 95% CI. The nal calculation results are shown in the Forest plot.

Search results
The literature search was conducted in accordance with PRISMA FLOW, and a summary of the search results is presented in Fig. 2. The total number of studies found in each database was 215. After excluding 101 studies due to duplication, 114 studies were left. Afterwards, 83 studies were excluded due to animal studies, non-original grey literature, non-English literature, and literature with unsuitable indications and treatments according to the inclusion and exclusion criteria. 31 documents were judged by the full text review whether they were suitable for our research purposes and nally, 11 literatures were suitable for identifying the effects and safety of rTMS on peripartum depression and detailed Excluded literature and the reasons are presented in Appendix 2. The original text was requested through the author's e-mail if only abstract was present. Finally, there were 11 studies suitable for qualitative synthesis and 5 studies suitable for quantitative synthesis.

Characteristics of Selected Studies
There were a total of 11 selected literature related to the e cacy and safety of rTMS for PPD, of which 2 RCT studies [59,60], 4 NRS [61][62][63][64], and 5 case studies [64][65][66][67][68]. The total number of participants are 100, 83 of whom received activee rTMS treatment. During pregnancy, 65 patients were treated with rTMS and most of them consisted of the second and third trimester of pregnancy. 17 patients were treated for postpartum depression and 2 patients were treated during pregnancy and after childbirth. The people included in the study were suffering from severe depression with HDRS scores of 17 or more point, two of which showed biopolar disorder. 20 participants were treated antidepressants [61,63,66,69] along with rTMS, 6 participants were treated on psychotropic [59,64]and 1 participant was treated on clonazepam for insomnia [62].   All of the included studies used HDRS to identify degree of depression. The correlation coe cient was 0.5 [71] and because heterogeneity was p < 0.001, I 2 = 71.933 the random effects model was applied [72]. rTMS have an effect on mitigating depression with SMD = 1.806, 95% CI: 0.920 -2.692 and the difference was  The rate of occurrence of all side effects from the included studies was determined. The heterogeneity of the studies was p = 0.112, I 2 = 46.631 so xed effect model was applied [72]. The probability of side effects was small (event rate = 0.346, Z= -2.696, p =0.007) [73].

Discussion
Mothers are reluctant to treat antidepressants because they are concerned about the disadvantages of their own side effects, as well as the disadvantages to the fetus [74,75], and in case of electroconvulsive therapy, only 1.2% of them accept them, and the majority are very negative because ECT has anesthesia process, and people worried about side effects such as post-treatment amnesia [76]. The population of this survey is public and if the population is limited to mothers, it will show lower acceptability. rTMS was also not well-received in the survey because it was not widely known as a recently re-examined treatment method, but after hearing the explanation of the treatment method, the acceptance rate of the mother for rTMS was signi cantly improved [77], as clinicians generally present the treatment effect while delivering knowledge of the treatment, so the acceptability of the mother acceptance of rTMS is positive.
The size of Therapeutic effect was SMD = 1.394 (95% CI: 0.944-1.843, Z = 6.079, p < 0.01) which was signi cant for treating depression [73]. Except for Garcia study [62] which is expected reporting bias because of selection report, SMD = 1.074 (95% CI: 0.689-1.459, Z = 5.468, p < 0.001) which is meaningful result. The literature not included in the meta-analysis and excluded literature because those are not suitable selection criteria also supprot the therapeutic effect of rTMS for PPD [64,[66][67][68][69][70][78][79][80][81][82]. In a studies included systematic review, 36% of the patients with PPD scored the same as the normal person and 66% saw their depression rating scale decrease by more than 50%. In adddtion, Brock G study showed that 14 out of 19 patients reduced their Edinburgh Postnatal Depression Scale (EPDS) below 8 [80] and Ozmut study also showed that 8 out of 15 patients reduced their EPDS scores by more than 50%. [79]. Other case-reporting [81,82] also succeeded in improving patients with PPD using rTMS. Although parameters that can affect therapeutic effects such as stimulation site, frequency, and interval time are still being studied, thare are not much research data, we have been able to con rm that there is therapeutic effect without relying on multiple parameter settings on the literature collected, and if the protocol becomes more sophisticated, we will have a higher therapetic effect.
Event rate = 0.346 for side effects, which is statistically small but affected [73]. However, the side effects of rTMS treatment on mothers were minor, such as headaches, discomfort and pain in the stimulation area, and these side effects disapeeared at the end of the treatment process. Even this was reported similarly in RCT and is seen as a common side effect of TMS devices, not as a side effect in treating PPD. Supine hypotension was unexpected event [61] but a disease caused by a posture problem during treatment and was able to prevent supine hypotension through postural correction [83]. In case of antidepressants, side effects are commonly known as dizziness, hand tremors, cold sweats, lethargy and anxiety [84]. These side effect are constantly experienced in daily life and it can have a huge impact on pregnant women and mothers who need to take care of their infants [85]. In addition, 2.5% of mothers who suffer from treatment resistant depression and these have to choose a different treatment method [86]. Another theratment ECT was much serious. A direct and indirect study of fetal effects in mothers who was given ECT showed fatal side effects on fetuses and mothers including uterine contraction and vaginal bleeding, and a 7.1% of fetal mortality rate [13]. Compared to these two treatments and based on all the research we've done so far, The side effcts of on motheres do not affect their daily lives and are safe.
All children born from mothers with rTMS treatmnet were born healthy. And In one RCT study in which the child's health condition was determined by appearance-pulse-grimace-activity-respiration scores, the difference between the two group was not signi cant [experimental group 8.36(1.50), control group 8.73(0.90) p = 0.501] [61].
There were ve premature births and brachial exus injury related to fetuses. Five percent of the participans in the study experienced premature birth, but two have already shown signs of premature birth risk in a biomedical test and the average rate of women experiencing premature births worldwide is 9.1 to 13.4% [87], it is unlikely that the causal relationship that rTMS treatment causes premature births will be established and further research is required. It was con rmed that brachial exus injury was the only side effect that occurred in newborns, including premature births, and that it was not associated with rTMS treatment [59]. There were no actual side effects in the infant. Hizil Sayer performed following study that checked child of mother treated rTMS and reported that the exposure of Rtms during pregnancy did not affect the cognitive or motor development results of the child [88]. Although the results are fully reliable due to the lack of research, the magnetic eld affecting fetal development is the lung and immune system [89] and it is also unlikely that rTMS will have a negative impact on fetal development and growth, given that magnetic is associated with diseases such as asthma at frequencies above 40 Hz [90]. Likewise, it could be safe because the maximum electromagnetic eld applicable to fetuses is 800mv/m [91], while the electromagnetic eld of the rTMS is 100mv/m [92].
In terms of treatment effectiveness and safety as well as economic e ciency, rTMS is more attractive method than other treatment methods. When comparing the economic e ciency of antidepressants and rTMS in a study using cohort model, the use of rTMS can save US$112 dollars for Quality Adjusted Life Years (QALY), which is more cost-effective [93] and In a Singapore study comparing economic e ciency with ECT, the cost of treating rTMS for one year was $1850(US$8515) cheaper than ECT [94]. rTMS treatment not only leads to neurobiological changes through brain stimulation, but also reduces anxiety about the cost which was one of the risk factor that has the greatest impact on pregnant women [95]. Consequently, socioeconomic costs of peripartum depression could be reduced.
Although the analysis showed high heterogeneity, it is assumed that the parameters that affect the treatment of rTMS are different in each study. In case of publication, funnel plot is asymmetric and p -value of Eggar regression is 0.001. However, except for Garcia's research [62], the funnel plot has a symmetrical structure and has no publication bias with Eggar regression p-value = 0.121. In order to do a more accurate study, high quality clinical trial should be conducted to identify the therapeutic effect of rTMS. How to compensate nontreatment groups is an important consideration. In addition, not only the randomization clinical trials but follow up or cohort study about the children born after treatment should also be conducted. Although many studies considered health of fetus [59,61,[63][64][65][66][67]70], only Myczkowski et al [60] considered breastfeeding, and only Eryilmaz et al [88] conducted follow up study of children. One of the main advantages of rTMS is that it has negative effect on the baby. Due to practical constraints, this paper cannot provide a comprehensive review of effect of rTMS on growing babies.
In this study, we have identi ed 11 studies to collect existing research data and use rTMS to treat peripartum depression and ve of them are suitable for quantitative synthesis. According to the analysis of the included studies, rTMS is statistically signi cant effect on the treatment of PPD and had fewer side effect that were minor. From a variety of perspectives, the treatment of PPD using rTMS can be thought to be an attractive treatment to avoid exposure of chemical ingredients to fetuses and severe side effects of ECT.