Maternal multiple sclerosis & health outcomes among children | CLEP

Maternal a number of sclerosis & well being outcomes amongst kids | CLEP


A number of sclerosis (MS) is one in all a number of power immune illnesses with an rising incidence,1 and the vast majority of sufferers are girls identified between the ages of 20 and 40 years. Through the previous 25 years, the therapy choices have improved, and with the introduction of disease-modifying remedy (DMT), folks dwelling with MS are actually inspired to pursue the life they wish to stay. With many females being identified at childbearing age, this may increasingly embody beginning a household.2 Questions associated to copy are naturally of nice concern within the increasing inhabitants of younger girls with MS and it has change into an essential space of scientific care and analysis. Ladies with MS traditionally have fewer kids than the overall inhabitants,3 and this can be due to durations of lively illness and coverings. Whether or not fertility is impaired continues to be debated,3,4 however it’s sure that some sufferers with a power illness make an lively selection to not have kids.5 It has progressively change into extra routine for neurologists to debate being pregnant when planning medical therapy in younger girls. Sufferers have been beforehand involved in regards to the heritability of MS, however neuroepidemiological research on this space have produced reassuring outcomes. Earlier research have advised that susceptibility to MS is a fancy interaction of heritability and setting, and the query about heritability is an ongoing analysis subject.6–9 A meta-analysis from 2012 discovered the age-adjusted threat of recurrence amongst offspring with a father or mother with MS to be 1.45% (95% CI 1.23–1.67).10

As well as, sufferers are naturally fearful in regards to the influence of MS as a illness and its corresponding drugs on the well being of their offspring, which has led to rising calls for for conception counseling. The affiliation between in utero publicity to maternal MS, with its accompanying medical remedies, and hostile short- and long-term offspring outcomes has been studied to a restricted extent amongst researchers in neurology and obstetrics over the previous twenty years.11–14

The authors are conscious of two evaluations,15,16 which, from a neurological angle, summarize proof on MS and short-term hostile start outcomes. One other overview examined the developmental trajectories of offspring and requested additional research on long-term outcomes in offspring.17 We carried out this overview as a result of there have been no different evaluations with a deal with long-term somatic well being outcomes within the offspring of girls with MS.

Materials and Strategies

Protocol and Registration

The overview protocol was registered on the Worldwide Potential Register of Systematic Opinions ( with ID quantity CRD42022338414, previous to initiation of the overview course of.

Search Technique and Eligibility Standards

A complete literature search was undertaken in Embase and Medline together with a reference screening of the included research carried out in PubMed, to pursue an entire protection of the subject. The search working dates have been 05.02.2022–06.15.2022 and all searches have been repeated on 08.23.2022, which didn’t contribute any new publications assembly the inclusion and exclusion standards. The final up-to-date search, carried out on 02.06.2023, added one new research.18 The search technique was developed by MLA along with a educated librarian on the College of Southern Denmark, making use of the PICOS format (inhabitants, intervention, comparability and outcomes of curiosity) and arranged in search blocks. For the search string, see the Supportive File. For the connections between search blocks, the Boolean operators AND and OR have been used.

The search outcomes are offered in Determine 1. Each major information assortment and research together with secondary sources of knowledge (eg claims databases, interviews with moms) have been thought of. Duplicates have been eliminated in Endnote. Abstracts, evaluations, case reviews, case sequence and spontaneous reviews have been excluded, as have been different kinds of research with no reference group. Offspring start, neonatal, childhood and adolescence somatic and psychological well being outcomes have been of curiosity. We included solely research reporting on baby outcomes with a threat estimate (absolute or relative threat estimates [hazard ratio (HR), odds ratio (OR), relative risk (RR)]). After reviewing the search outcomes, abstracts have been screened and full-text articles learn. Lastly, acceptable research have been included primarily based on the exclusion and inclusion standards. Causes for exclusion of papers have been recorded in a desk. The research have been sorted into three teams: 1) maternal MS and short-term outcomes within the offspring (start and neonatal), 2) in utero publicity to drugs used to deal with maternal MS and short-term outcomes within the offspring (start and neonatal), and three) maternal MS and long-term well being outcomes within the offspring (from 1 month to maturity).

Determine 1 Search technique and flowchart of exclusion and inclusion of research.

The eligibility standards for this overview have been as follows.

  • Publicity: Maternal MS analysis verified with the McDonald standards or by Worldwide Classification of Ailments (ICD) analysis codes.19 Comparability with wholesome controls was most popular. In research with DMT publicity, stratification on every sort of medicine was obligatory, and comparability with girls with MS however with out DMT therapy was most popular.
  • Research with information from pharmacovigilance databases managed by pharmaceutical producers have been excluded, along with research the place the contributing authors have been completely employed by the business.
  • Outcomes: In all research with the result of preterm start, this was outlined as start earlier than gestational age 37 weeks; low Apgar was outlined as an Apgar rating <7 at 5 minutes; and small for gestational age (SGA) was outlined as a start weight beneath –2 SD or <2500 g at accomplished 37 gestational weeks, in line with the WHO definition. In distinction to low start weight, SGA relates the start weight to gestational week, intercourse and singleton or a number of gestation, and is influenced by the intrauterine development situations and genetic potential.20 No standardized nomenclature was used for the result of congenital anomalies, which have been simply known as “congenital malformations”, “congenital anomalies” or “start defects”.
  • Presentation of outcomes: Danger estimates ought to be out there within the article. Research presenting solely descriptive outcomes, similar to prevalence, proportions or percentages, have been excluded.

Information Extraction

Screening was initially carried out primarily based on the title and summary, adopted by a full textual content screening by MLA. For the inclusion of information, the eligibility standards have been utilized by two reviewers (MLA and LRJ) who independently screened the information for inclusion. To extend the reproducibility and accuracy of the overview, the literature screening was carried out in accordance with the Most well-liked Reporting Objects for Systematic evaluations and Meta-Analyses (PRISMA 2020) guidelines and utilizing the web-based program on the College Library of Southern Denmark. Disagreements have been resolved by way of dialogue and consensus with a 3rd reviewer (BMN).

Information extracted from the included research are offered in Tables 1–3. The analyses encompass summarizing the dangers of hostile start, childhood and adolescence well being outcomes amongst offspring of girls with MS. We thought of a meta-analysis, however the variety of research recognized inside every group was too low, too few research reported on particular outcomes and the exposures have been too inhomogeneous. The authors have been conscious of some present systematic evaluations and meta-analyses on start outcomes amongst girls with MS and DMT from 2000–2019,21,22 and determined to conduct an up-to-date search on this subgroup of research.

Desk 1 Maternal A number of Sclerosis and the Impact on Neonatal Outcomes

Desk 2 Ladies with A number of Sclerosis Handled with Illness-Modifying Remedy and the Impact on Neonatal Outcomes

Desk 3 In Utero Publicity to Maternal A number of Sclerosis Well being Outcomes Throughout Childhood and Adolescence (1 Month to 18 Years)

The standard of the included research was assessed utilizing the Newcastle–Ottawa Scale (NOS) instrument for cohort research, evaluating the chance of bias as a result of choice, comparability and end result. A research could possibly be awarded a most of 1 star for every numbered merchandise within the choice and end result classes.23 A most of two stars could be given for comparability. A most of 9 factors could be given to research of the best high quality. Two authors (MLA and LRJ) carried out the evaluation independently. In conditions of disagreement, consensus was reached by way of dialogue. The assessments of the chance of bias are offered in Tables 1–3.


Literature Search and Examine Choice

The preliminary literature search recognized 1035 research by title, of which 944 have been exterior the scope of the overview. A complete of 91 research have been screened by summary, and 77 have been assessed in full. Solely 21 research have been included, and 5 of them have been newly printed in 2021/2022. An up-to-date search added yet one more research in group 2. Traits and abstract information from the included research are offered in Tables 1–3.

We discovered 10 research that belonged to group 1: Maternal MS and short-term outcomes within the offspring (start and neonatal). We discovered 9 research that belonged to Group 2: In utero publicity to drugs used to deal with maternal MS and short-term outcomes within the offspring (start and neonatal). We discovered 4 research that belonged to Group 3: Maternal MS and long-term well being outcomes within the offspring (from 1 month to 18 years). One research had outcomes that belonged to a couple of group.

Examine Traits

The research have been all cohort research and several other of them have been population-based cohorts, and so they represented 4 continents (North and South America, Asia and Europe). There have been 15 European research and eight of them have been primarily based on Scandinavian nationwide registers: Andersen et al studied the Danish inhabitants18,24,39,40 Dahl et al and Strom et al studied the Norwegian inhabitants,11,25,26 and Korjagina et al used information from Finland and Sweden of their register research.27 Two of the three German research have been primarily based on the identical dataset, however with totally different timeslots and exposures,28,29 and the 2 research from Italy got here from the identical registry, however with totally different timeslots.30,31 One research from the UK reported as part of the Oxford Document Linkage Examine on a cohort from 1970–1989.32 Chen et al studied the inhabitants of Taiwan12 and Soler et al studied a cohort in Chile.13 The Canadian research group of Razaz et al carried out two population-based register research from British Columbia on long-term outcomes in kids.33,34 Three research got here from the USA: two cohort research from Boston, utilizing information from the identical administrative claims database,14,35 and one research from Washington.36

Group 1 Research: Maternal MS and Quick-Time period Outcomes within the Offspring (Delivery and Neonatal)

We discovered 10 research in whole on this class. These research examined the affiliation between maternal MS identified earlier than the time of conception and start and neonatal outcomes within the offspring. The bulk centered on short-term start outcomes, together with 5-minute Apgar <7, SGA/low start weight, preterm start, congenital anomalies and stillbirth, among the many offspring of girls with MS.

Preterm Delivery

9 of the group 1 research reported on the result of preterm start. Two of those research discovered a considerably elevated threat of preterm start in girls with MS.12,14 MacDonald et al used the Truven Well being MarketScan Database (2011–2015; Truven Well being Analytics Inc, Ann Arbor, Michigan) and the Nationwide Inpatient Pattern (2007–2011) to establish start cohorts. Ladies with MS have been in contrast with the background inhabitants, and so they discovered an RR of 1.19 (95% CI 1.04–1.35) for preterm start within the Truven Database and RR 1.30 (95% CI 1.16–1.44) for preterm start within the Nationwide Inpatient Pattern.14 The primary limitation of the Truven Well being MarketScan Database was that 728,337 pregnancies (39.8%) have been excluded owing to non-continuous enrollment through the interval from 90 days earlier than the final menstrual interval to the supply date, which might introduce choice bias. Nevertheless, they’ve made a comparability of a number of the covariates on the included and excluded girls, stating them to be related beside 12 months of start. In a research by Chen et al from Taiwan, the OR for preterm start was 2.25 (95% CI 1.37–3.70).12 Comparability was made with an age-matched management group with none illnesses. From our perspective, the 2 research missed adjustment for some essential potential confounders, similar to maternal comorbidities, smoking, physique mass index (BMI) and medical therapy. Not one of the different six research reporting on preterm start as an end result had adequate statistical energy to attract conclusions on the chance of preterm start.24,25,32,36–38

SGA and Low Delivery Weight

Six research reported SGA and three of them discovered a considerably elevated threat, with OR 1.29–1.89, amongst kids of girls with MS in comparison with a reference group with out MS.12,24,25 The research by Chen et al discovered an elevated threat of SGA, with OR 1.89 (95% CI 1.29–2.70). It’s price noting that the research is classed as being nationwide and inhabitants primarily based, however the cohort consists of solely 174 girls with MS in contrast with 1392 wholesome controls, and the inhabitants of the island consists of 23 million folks.12 One should subsequently assume that the cohort constitutes solely a small proportion of the ladies on the island with MS giving start. A research by Dahl et al discovered an elevated threat of SGA, with OR 1.45 (95% CI 1.14–1.84), within the MS group in comparison with the background inhabitants.25 A research by Goldacre et al discovered an elevated threat of low start weight <2000 g, with OR 2.7 (95% CI 1.10–6.60), however primarily based on solely 5 instances within the MS group, which ought to most likely be interpreted as a random distribution.32 In distinction to those research, three different research reporting on SGA didn’t discover any important variations. Goldacre et al discovered an equal distribution, with OR 1.0 (95% CI 0.60–1.80), of their dataset from 1970–1989.32 Dahl et al discovered OR 1.20 (95% CI 0.99–1.45) of their research on a pattern of MS sufferers in Norway.25 Mueller et al reported on the result of low start weight <2500 g unadjusted for gestational age, and located RR 0.9 (95% CI 0.50–1.70).36 MacDonald et al reported on the result of poor fetal development (identified earlier than start) of their two research cohorts from totally different databases, and located OR 1.03 (95% CI 0.87–1.19) and OR 1.23 (95% CI 0.94–1.54). They didn’t current information on start weight ends in their research.14

Low Apgar Rating

Three research reported on low 5-minute Apgar rating. None of those discovered an elevated threat amongst kids of girls with MS.24,32,36 The Danish cohort research by Andersen et al reported an end result known as “indicators of asphyxia”, together with parts from the Apgar analysis along with umbilical wire blood pattern. This end result was decrease within the uncovered group of youngsters born to girls with MS, with OR 0.87 (95% CI 0.78–0.97).24

Congenital Anomalies

Six of the group 1 research reported on the result of congenital anomalies. MacDonald et al discovered OR 0.85 (95% CI 0.59–1.12) for congenital anomalies amongst offspring of girls with MS,14 however solely reported on main anomalies, whereas Weber-Schoendorfer and Schaefer reported OR 3.34 (95% CI 0.62–11.55) within the MS group, and so they counted each minor and main anomalies.37 The arrogance interval exhibits the low statistical precision, and the research was too small to offer agency conclusions. Within the largest cohort research, by Andersen et al, the OR for congenital anomalies was 1.02 (95% CI 0.87–1.19).24 Mueller et al discovered RR 0.6 (95% CI 0.10–2.30) for congenital anomalies.36 The 2 Norwegian research by Dahl et al didn’t report on the variety of congenital anomalies, however simply reported that they didn’t discover any variations concerning congenital anomalies.11,25 Soler et al in contrast girls with “pre-MS” and “post-MS”, however had no wholesome controls of their research.13 They discovered OR 0.66 (95% CI 0.30–1.14) for congenital anomalies in girls with being pregnant previous to MS analysis, in contrast with girls who grew to become pregnant after MS was identified.


Stillbirth was outlined in another way within the seven research that reported on this end result. The research by Fong et al discovered a threat of “fetal demise” within the MS group, with OR 1.6 (95% CI 0.90–3.10),38 whereas the most important research cohort, by Andersen et al (n=2930 girls with MS), discovered OR 1.17 (95% CI 0.68–2.00) for stillbirth.24 Each cohort research are, nonetheless, not giant sufficient to attract a big conclusion on this uncommon end result. Mueller et al studied a cohort of in another way insured MS sufferers giving start at non-federal hospitals in Washington State, and located OR 1.1 (95% CI 0.30–5.10) on the result “toddler loss of life”, however didn’t additional outlined whether or not loss of life was earlier than or after start.36 Goldacre et al discovered no stillbirths of their research group32 and Dahl et al reported “no distinction” on the result “perinatal mortality”, however didn’t current their outcomes as numbers.11,25 MacDonald et al discovered OR 0.82 (95% CI 0.23–1.52) and OR 0.96 (95% CI 0.50–1.48) of their two research cohorts.14,35

Group 2 Research: In Utero Publicity to Drugs to Deal with Maternal MS and Quick-Time period Outcomes within the Offspring (Delivery and Neonatal)

We discovered 9 research matching group 2 standards. Eight reported on the result of congenital anomalies and preterm start. 4 research reported on the result of SGA, low start weight or intrauterine development restriction (IUGR). Two research assembly our standards reported on the result of stillbirth. A scientific overview and meta-analysis of being pregnant and fetal outcomes amongst girls with MS and DMT was printed in 2020.21 Right here, Lopez-Leon et al included research from the interval January 2000 to August 2019 and reviewed the present literature on the influence of DMT. In distinction to this overview, research with out calculated threat estimates have been included. Of their meta-analyses, they discovered no elevated threat of preterm start after stratification in line with glatiramer acetate (two research, n=288), with RR 0.79 (95% CI 0.56–1.12), interferon-β (4 research, n=704), with RR 0.92 (95% CI 0.58–1.46), or natalizumab (two research, n=79), with RR 0.82 (95% CI 0.57–1.18). In all research, the uncovered kids have been in contrast with kids of moms with MS who didn’t take DMT earlier than or throughout being pregnant. Concerning main congenital anomalies, they discovered 4 research reporting this end result amongst kids uncovered to interferons (n=423), with RR 0.70 (95% CI 0.3–1.6), and glatiramer acetate (n=188), RR 0.58 (95% CI 0.16–2.12).

Only some extra papers have been printed on this class because the research by Lopez-Leon et al.21 Three research, printed within the interval January 2019 to February 2023, met our inclusion standards. A Swedish cohort research centered on interferon-β-exposed kids (n=718),27 and one Danish cohort research centered on teriflunomide-exposed kids (n=49)39 and one other on injectable first-line remedies, dimethyl fumarate and natalizumab-exposed kids (n=711 liveborns).18 Not one of the three research discovered important variations within the threat of hostile short-term start end result between DMT-exposed and unexposed kids.

Group 3 Research: Maternal MS and Lengthy-Time period Well being Outcomes within the Offspring (from 1 Month to 18 Years)

We included 4 research that reported on long-term outcomes in kids.26,33,34,40 Two of the research reported on psychiatric outcomes, one research reported on instructional end result and one research on neurological end result. Andersen et al studied psychological well being at age 11 years amongst kids of girls with MS and didn’t discover an affiliation with psychiatric diagnoses, in comparison with kids of moms with out MS.40 A register research by Strom et al adopted a complete of 1,360,149 Norwegian kids for a interval of two–24 years. A complete of 3575 kids have been identified with cerebral palsy within the background inhabitants (2.6 per 1000 stay births), and amongst kids of moms with MS, they discovered an elevated prevalence of three per 1000 stay births with cerebral palsy, RR 1.8 (95% CI 0.80–4.40). The outcome was not statistically important.26 Razaz et al examined vulnerability within the social improvement area in line with the Early Growth Instrument amongst 1- and 3-year-old kids of oldsters with MS. Youngsters uncovered to maternal MS had a decrease threat of vulnerability in comparison with kids of girls with out MS, OR 0.75 (95% CI 0.60–0.95).33 Razaz et al additionally examined temper and nervousness problems, starting from poor adjustment reactions and nervousness to phobic problems, obsessive–compulsive problems, affective psychoses and neurotic despair, amongst kids of oldsters with MS in one other set-up. Outcomes of curiosity have been recognized utilizing a mixture of hospital diagnoses, outpatient doctor diagnoses and prescription drug claims. In kids of girls with MS, the HR for the mixed end result “temper or nervousness problems” was 1.7 (95% CI 1.10–2.40), however it decreased when adjusting for maternal psychological comorbidity, HR 1.4 (95% CI 0.90–2.10).34


Our goal was to offer an outline of the present literature on the reproductive space of girls with MS and to establish the analysis gaps on this space. Stable information about short- and long-term baby outcomes is crucial for clinicians to adequately counsel girls with MS in reproductive issues. The research pointed in direction of an elevated threat of preterm start and SGA amongst girls with MS. When it comes to girls with MS handled with DMT previous to or throughout being pregnant, no clear conclusions could possibly be drawn. The few research on long-term baby outcomes centered primarily on neurodevelopmental and psychiatric impairments, and one research reported on the long-term threat of cerebral palsy amongst kids of girls with MS. None of those research reported any important findings. On this systematic overview, we now have highlighted the analysis gaps on the influence of maternal MS on offspring well being.

We centered on hostile offspring outcomes, similar to low start weight, SGA and preterm start, that are outcomes which might be essential predictors of neonatal and childhood morbidity and mortality, but in addition predictors for morbidities in maturity.41 Lengthy-term well being outcomes usually embody the chance of illnesses and improvement within the offspring throughout childhood, adolescence or so far as the follow-up time permits. Nevertheless, the influence of maternal MS on long-term baby outcomes has obtained minor consideration, and we discovered solely 4 research on long-term baby outcomes. One cause why that is the case could also be associated to the excessive demand for acceptable datasets with full and lengthy follow-up time on all people. We all know from the literature that kids of oldsters with MS have a minor elevated threat of growing MS themselves,42 however in any other case we all know little or no in regards to the influence of in utero publicity to maternal MS, DMT and the affect on the chance of the offspring growing illnesses within the first years of life, and through childhood and adolescence.

We discovered outcomes pointing in direction of kids of girls with MS being at greater threat of hostile start outcomes, similar to being born preterm, SGA or with low start weight, however with the proviso that the related research largely have been of mediocre high quality (NOS scores 5–8). A considerably elevated threat of congenital anomalies or stillbirth was not present in any of the current research, which have been, nonetheless, typically underpowered to review this end result. Moreover, many of the uncovered cohorts on this class have been a mix of sufferers with and with out DMT and weren’t stratified for this, which implies that the outcomes have a restricted applicability. Concerning the result of congenital anomalies, this isn’t a really well-described end result within the out there literature and, along with the result of stillbirth, no research had the required statistical energy to conclude on the calculated threat estimates. Usually, the cohorts weren’t solely uncovered to MS and never in comparison with wholesome controls both, which might be the popular research design on which to attract conclusions. We conclude that not one of the current research has the statistical energy to conclude on the chance of congenital anomalies or stillbirth with certainty.

Concerning medical therapy of younger girls with MS, there are at the moment two preparations usually acknowledged by the European Medicines Company and the American Meals and Drug Administration as potential therapy choices throughout being pregnant. These are the 2 mostly used medication for pregnant girls with MS:35,43 glatiramer acetate, which hypothetically induces Th2 cells to launch cytokines which might be capable of suppress inflammatory processes within the MS lesions, and interferon-β, which, amongst different issues, reduces the expression of adhesion molecules of the lymphocytes and thereby the passage of activated T cells throughout the blood–mind barrier. Glatiramer acetate and interferon-β don’t seem to extend the chance of hostile start outcomes and are already prescribed to be used throughout being pregnant to an excellent extent, however concerning the long-term well being penalties within the offspring there’s a vital analysis hole. These two preparations have been used for nearly 25 years, and long-term penalties after maternal use on the time of conception should have been an essential analysis space. The problem is of course an excellent concern for younger girls with MS who’re contemplating having kids. To the perfect of our information, no research has but examined the affiliation between maternal use of particular MS medicine across the time of conception and long-term well being penalties within the offspring.

Research previously decade have meant to make clear the implications within the offspring of in utero publicity to those preparations affecting the immune system, however the research have been primarily based on small cohorts, and the outcomes have been divergent and characterised by publicity and end result inhomogeneity. Subsequently, a possible damaging influence on the fetus nonetheless must be investigated. Sufferers fear in regards to the influence of MS and MS medicine on short- and long-term well being penalties within the offspring, and a few girls will select to not proceed their DMT throughout being pregnant37 or will resolve to not have kids owing to the lack of information on this space.3 The authors discovered a lot of pharmacovigilance research produced by pharmaceutical firms, however since they lack management teams, these research would not have the methodological high quality to allow security conclusions to be drawn from them. As well as, we determined to exclude research that centered on biometric measures, emotional and behavioral difficulties or instructional achievements within the offspring, as a substitute of threat estimates of illnesses in offspring of girls with MS.44–46

To have the ability to present exact outcomes on uncommon and severe outcomes similar to stillbirth and congenital anomalies, we’d like methodologically stable research primarily based on a bigger variety of kids. We are able to absolutely endorse the conclusion from the systematic overview and meta-analysis from 2020 by Lopez-Leon et al, that future research together with inside comparators are nonetheless wanted.21

The cumulative quantity of knowledge is certainly sparse and there’s a nice want for extra proof on this space. There’s nonetheless a big hole within the literature with regard to research on long-term somatic well being outcomes amongst kids of girls with MS, and just a few research exist on the affiliation between maternal MS and long-term well being outcomes within the offspring. One research reported on the result of cerebral palsy, however the remaining have been on psychological and social outcomes, which could possibly be associated to rising up in an setting with a father or mother with MS relatively than the intrauterine publicity to the illness. It’s difficult to advise sufferers in regards to the security of medicines with regard to uncovered offspring when most research on hostile penalties within the offspring solely take a look at outcomes inside the first 12 months of life.

Future research on long-term well being penalties within the offspring of moms with MS are essential for these sufferers.


This work has been supported by Area of Southern Denmark [grant no. 20/14788, 2022], Odense College Hospital [grant no. 122-A5119 and 128-A5300, 2021], Jascha Basis [grant no. 3630, 2020], Advisor Schou and Spouse Else-Marie Schou, born Wanges Basis [grant no. 85832].


Dr Mette Louise Andersen reviews grants from the Area of Southern Denmark, grants from the Jascha Basis, and grants from the Advisor Schous Basis, through the conduct of the research. The authors declare no competing pursuits.


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