RESEARCH ARTICLE Open Access

Qualitative investigation of the factors thatgenerate ambivalent feelings in womenwho give birth after receiving negativeresults from non-invasive prenatal testingJunko Yotsumoto1* , Akihiko Sekizawa2, Satomi Inoue3, Nobuhiro Suzumori4, Osamu Samura5, Takahiro Yamada6,Kiyonori Miura7, Hideaki Masuzaki7, Hideaki Sawai8, Jun Murotsuki9, Haruka Hamanoue10, Yoshimasa Kamei11,Toshiaki Endo12, Akimune Fukushima13, Yukiko Katagiri14, Naoki Takeshita14, Masaki Ogawa15, Haruki Nishizawa16,Yoko Okamoto17, Shinya Tairaku18, Takashi Kaji19, Kazuhisa Maeda20, Keiichi Matsubara21, Masanobu Ogawa22,Hisao Osada23, Takashi Ohba24, Yukie Kawano25, Aiko Sasaki26, Haruhiko Sago26 and Japan NIPT Consortium

Abstract

Background: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find thatthey later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoingthe test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birthafter having received negative results from NIPT.

Methods: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis wasconducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. Thequalitative data gathered from the questionnaire were analyzed using the N-Vivo software package.

Results: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected thefeeling of ambivalence among pregnant women. Furthermore, pregnant women desired more informationregarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination,assuming the possibility that they were positive.

Conclusions: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting anddiscussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing thequality of decisions made by pregnant women.

Keywords: Ambivalence, Genetic counseling, NIPT, Anticipatory anxiety, Content analysis

BackgroundA prenatal test for fetal abnormalities may cause mater-nal anxiety [1, 2]. Pregnant women who made an unin-formed choice for non-invasive prenatal genetic testing(NIPT) felt deeper decisional regret associated with pro-longed anxiety [3, 4].

Women typically have two conflicting thoughts at theearly stage of pregnancy: the desire to know about theneonate via ultrasound examination and the reluctanceto receive negative news. Many women reportedly takethe NIPT to relieve their ambivalence regarding negativeresults [5]. Furthermore, certain women feel like theirpregnancy is provisional or temporary until they learnabout their NIPT results, i.e., although they may feelphysical changes, they may not acknowledge their preg-nancy until they see their results [6]. Ambivalence hasbeen identified among the attitudes of the general public

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: junko.yotsumoto@iuhw.ac.jp1Department of Genetic Counseling, Graduate School of Health and WelfareSciences, International University of Health and Welfare, 4-1-26 Minato-ku,Tokyo 107-8402, JapanFull list of author information is available at the end of the article

Yotsumoto et al. BMC Pregnancy and Childbirth (2020) 20:112 https://doi.org/10.1186/s12884-020-2763-z

regarding prenatal testing; however, the origins of theambivalence remain unclear [7, 8]. Lewis et al. reportedon the ambivalence of the women taking the NIPT hadambivalent feelings, e.g., desire for the information aboutthe baby by the test and additional anxiety whilst wait-ing, concerns around “over-testing” and “pressure by thehealth professionals” [9].. Ambivalence can be defined asthe “simultaneous existence of positive and negativeevaluations of an attitude” [10].In our previous study, we conducted an “awareness sur-

vey of NIPT in Japan”, and reported that women withnegative results had a higher NIPT rating than womenwith positive results, but with respect to the ethical aspectsof NIPT, women with negative results responded un-clearly [11]. In the presence of negative NIPT results, dis-eases other than the three chromosomal aneuploidies maybe identified during later stages of life [12] then they areexpected to have mixed feelings about the NIPT.Based on these findings, we thought that even women

with negative test results could have ambivalent feelingslater. This study aimed to investigate factors affectingambivalent feelings in pregnant women after undergoingNIPT.

MethodsDesignThe present study is based on a qualitative research meth-odology, involving content analysis using the free-form de-scription of the first year after questionnaire answered bywomen who received negative results for NIPT.

Research procedureAll pregnant women who took the NIPT were asked toparticipate in a questionnaire-based survey conducted bythe Japan NIPT Consortium. The survey was in two parts:(i) pre-and immediately after the NIPT test, from April2013 to March 2014 and (ii) a year- after the NIPT test,from April 2014 to March 2015. We have already reportedon part (i) [11], and the present study is for part (ii). Ayear-after research was conducted by a mail-in survey todetermine whether the assessment of the NIPT and gen-etic counseling was changed after the test and 1 year after.The contents of the questionnaire consisted of a one-year-after evaluation and free description for NIPT and geneticcounseling, and the question of the free description partwas an open-ended question, such as, “Please show youropinion or feedback of the NIPT.” In the present study,we conducted content analysis for 1562 respondents(20.6%) who provided the free-form description to theopen-ended question (Fig. 1).

ParticipantsPregnant women who were identified as being at an in-creased risk of chromosomal disorders due to advanced

maternal age, the results of ultrasound marker or mater-nal serum marker tests, or a family history of chromo-somal abnormalities or those who had a high risk ofbeing a translocation carrier, were eligible for NIPT. Inmost cases, the indication for NIPT was advanced ma-ternal age (96.5%). In addition, 14.4% of the womenunderwent NIPT based on a recommendation from theirfamily. Because the responses in the first year after thequestionnaire were anonymous, and it was impossible toobtain the background data, the personal background ofthe respondents was unknown; however, the availablenecessary background information of the respondentswho underwent NIPT was shown in the previous study[11] of 7740 women, whereas the present study was lim-ited to those who received negative NIPT results amongthe 7740 women, and therefore, the background datawere not same.

Data analysisThe questionnaires were subsequently mailed to a third-party NIPT data center for data entry. Qualitativemethods are required in situations warranting detailedanalysis and an understanding of the process to deter-mine the nature of the issue being investigated. Weundertook a combined content analysis (quantitative andqualitative) via text mining approaches, using N-VivoQualitative software for the free-form description part ofthe questionnaire focusing on ambivalent expressions.The advantage of computer-assisted content analysis oftextual data is the coding reliability that helps to gener-ate comparable results [13]. The text in the free-formdescription part was entered into the computer and usedas input for the N-vivo software. N-vivo was used forline-by-line coding of the texts, to identify emergingthemes. Furthermore, all the text was read, and the cod-ing process was discussed with two researchers. Thesub-categories extracted by N-vivo were assessed by tworeviewers. The code of those lower categories deter-mined after the evaluation was extracted inductively intothe above category by two reviewers. The coding processis shown below.

Step 1 Line-by-line coding with N-vivo, using an in-ductive approach.Step 2 Thematic grouping. The transversal analysisshowed new themes by two researchers.Step 3 Creating higher-level categories and evaluatingrelationships.Step 4 Reviewing these analyses. Thematic stabilization.All authors.

EthicsTo conduct this study, the participating centers obtainedapproval from their respective ethics committees.

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ResultsWe identified three primary categories generating feel-ings of ambivalence among women: (1) factors related togenetic counseling; (2) environmental factors, and (3) in-creased anticipatory anxiety. Furthermore, the formertwo factors caused the anticipatory anxiety (Table.1,Fig.2).

Factors related to genetic counselingThis category Factors related to genetic counselingcomprised two subcategories: “Lack of information” and”Lack of psychological care adapted to individual needs.”“Lack of information” further comprised two mid-levelcategories: “Inadequate support by medical staff up totaking NIPT” and “Lack of information in case of posi-tive result.” “Lack of psychological care adapted to indi-vidual needs comprised “Lack of psychological care atgenetic counseling,” and “Lack of genetic counseling atthe appropriate moment.”Regarding “Lack of information,” “support by medical

staff up to taking NIPT” referred to the lack of supportfrom the family physician during NIPT. Many familyphysicians were not only not helpful in referring theirpatient for genetic counseling, but they also themselves

were unaware of it. Owing to the limited number ofNIPT facilities for pregnant women in Japan, some re-spondents also reported receiving a reproachful responsefrom their family physician upon requesting informationregarding NIPT or referrals.Furthermore, certain women were criticized for taking

the NIPT during genetic counseling, and many womenwished that genetic counseling would be performed as-suming that NIPT could give positive results regarding“Lack of information in case of positive result.” Theywished to receive detailed information regarding themethods of terminating their pregnancy as one of the al-ternatives in case of chromosomal abnormalities in thefetus.

I don't think it hurts to take some time to explainabout the options for getting an artificial terminationof pregnancy in the case of a positive result. There isthis idea that an abortion=bad, but if the chance thatyou can love your child unconditionally is 0%, then Ibelieve that it is an important option, even though it'snot easy to discuss...

(if the pregnancy was terminated)

Fig. 1 Flowchart of the respondent selection

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However, some women who considered continuingtheir pregnancy despite receiving positive results uponNIPT were seeking information regarding the exactquality of life for individuals living with such illnessesand the social resources available for them.

What I really want to see added is what to do ifthe results do come out positive. I want to hearduring the counseling session the exact types ofsocial support that I could get if my child is bornwith Down syndrome or some other illness to helpme live with and raise the child with the illness,for example at school, daycare, at home, names oforganizations or municipal centers where I can getsupport.

(if the pregnancy was continued)

These data indicated that respondents were seeking in-formation during genetic counseling that would supportthe decision to continue or terminate their pregnancy.These women desired information regarding the dailylives of children with disabilities and other related mate-rials to guide their decision of whether they could raise achild with disabilities; furthermore, they desired follow-up support for women reporting with positive results inthe NIPT.

Environmental factorsEnvironmental factors included the comfort levels ofwomen for raising a child with disabilities; this aspectcomprised three subcategories: “Lack of awareness andeducation about diversity,” “Insecurities on raising thechild,” and “Lack of social support systems for peoplewith disabilities. “Insecurities on raising the child” com-prised “Insecurities for the future,” “Vague insecurity,”“Insecurities for the child-rearing environment,” and“Familiarity with challenges of living with a disabledperson.”

• • • The reason why many people have the image ofprenatal testing as an “immoral thing” in Japan maycome from views about ethics on this subject inJapan, or prejudice and closed-mindedness againstpeople with Down syndrome and other chromosomalabnormalities. I just sometimes wish that those whoare debating and giving their input on ethics wouldalso take part in discussing how to change Japaninto a more livable society for children with Downsyndrome and their families.

(Lack of awareness and education about diversity)

Fig. 2 The relationship between women’s ambivalent emotions andtheir factors

Table 1 Factors associated with ambivalence

Primary category Subcategory Mid-level category Lowest category

Factors related to genetic counseling (n = 191)

Lack of information (159)

Inadequate support by medical staff up to taking NIPT (69)

Lack of neutrality in genetic counseling (n = 11)

Lack of NIPT information from family physician before geneticcounseling (n = 26)

Family physician’s response (n = 33)

Lack of information in case of positive result (n = 91)

if the pregnancy was terminated (n = 14)

if the pregnancy was continued (n = 51)

follow-up support to positive result (n = 55)

Lack of psychological care adapted to individual needs (n = 48)

Lack of psychological care at genetic counseling (n = 35)

Lack of genetic counseling at the appropriate moment (n = 17)

Environmental factors (82)

Lack of awareness and education about diversity (n = 30)

Insecurities on raising the child (n = 63)

Insecurities for the future (n = 26)

After the parents’ death (n = 20)

Impact on the siblings (n = 17)

Vague insecurity (n = 20)

Insecurities for the child-rearing environment (n = 18)

Familiarity with challenges of living with disabled person (n = 9)

Lack of social support systems for people with disabilities (n = 23)

Increased anticipatory anxiety (n = 56)

Time related anxiety (n = 47)

Anxiety about test accuracy (n = 9)

Footnote: n Number of occurrences of each category. Categories maypartially overlap

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I want to give birth even if child with Down syndrome,if possible ... The word “life sorting” is not good, but wefeel that social systems are forced to do so. I think wemust create a welfare, education and social systemthat everyone can give birth and raise without worry-ing, even if a child has a disability.

(Lack of social support systems for people withdisabilities)

Regarding “Insecurities on raising the child”, older par-ents had a sense of responsibility to raise the child; theywere concerned regarding the life of the child after theirdeath owing to their age at pregnancy, and they wereconcerned regarding burdening the siblings of the childand, thus, had “Insecurities for the future.”Furthermore, certain respondents also exhibited

“Vague insecurity” because raising a disabled child isunfathomable and difficult to imagine, owing to thelack of experience. Others, however, already had “Fa-miliarity with challenges of living with a disabled per-son,” because they knew somebody or had familymembers with disabilities, thereby fostering the under-standing of the merits and demerits and having dis-cerned that it would be challenging. They also faced“Insecurities for the child-rearing environment” owingto their concern regarding an inadequate financialsupport or the social environment for raising a childwith disabilities.

As an actual mother of a child with chromosomalabnormalities • • •I’m glad that I had my baby, butraising my child is full of challenges and would beabsolutely impossible without the cooperation ofpeople around me, so it's not something that can beglossed over. I got tested for my second pregnancy,but I don't think I would've had the child if theresults were positive.

(Familiarity with challenges of living with a personwith disabilities).

Increased anticipatory anxiety

Increased anticipatory anxiety included the two sub-categories” Time-related anxiety” and “Anxiety abouttest accuracy.” Among the pregnant women who optedfor NIPT, there were some who were so anxious duringthe 2 weeks until they got the results that they could notsleep until finding out that their results were not posi-tive. Also, knowing that test accuracy of NIPT was not100%, some people were anxious that their result mightbe a false-negative, and they could not eliminate thisanxiety until the birth of the child.

Components of ambivalenceAmbivalent feeling comprised five subcategories: “Op-tions in the case of a positive result,” “Guilt towards thechild,” “Criticisms on NIPT from others,” “Denial of dis-abled people”, and “How to tell the child.”Some respondents “Stated their decision” with regard

to the course of action in case of a positive NIPT result,whereas others expressed “Difficulty stating their deci-sion” regarding continuing or terminating their preg-nancy. In both cases, respondents seemed agonized overtheir decision in the case of positive results (Fig. 3).

I had decided that if the results came out positive, Iwould not give birth to the baby. However, eventhough I now know that the results were negative, Ihaven't told my own parents that I took the test. Atthe same time that I feel negative about the ideathat we were picking and choosing who to keep if theresults were positive, I also blame myself for my lackof confidence in raising the child, even though it isbecause I have health problems myself.

(Stated their decision).

Some women seemed to have a sense of “Guilt to-wards the child” after given birth and parenting thechild, knowing that they were trying to decide the life ofthe child.

I don't think I would have taken the test if I wereyounger. Some people criticize that people take thetest too casually because it places very little stresson the mother or child. But I believe that anybodywho chose to take the test did so after putting lotsof thought into it. Looking into my child's face,sometimes I remember about when I took the test,and I can't help feeling sorry towards my child. Mybaby's life is very valuable, and I want to give allthe love it deserves.

(Guilt towards the child)

Furthermore, some women could not tell anybody thatthey took the NIPT owing to social pressure,” Criticismsfrom others on NIPT”, and others who felt guilty thathaving “Denial of disabled people” upon having childrenwith disorders, which were screened during NIPT, des-pite obtaining negative NIPT results.

When I watch documentaries on TV, etc., andhear that the majority of opinions seem to supportthat “Whether or not a life should live should notbe decided by parents, but should be treated asan independent life” “Even if my child has Down

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syndrome, I am so happy that they came to thisworld”. People who, for whatever reason decidednot to have the baby, will be burdened with guiltfor the rest of their lives. I did test negative, butwhenever I look into my child's face and see aperson with Down syndrome, I criticize myselfbecause “I decided on her life.”(Denial of disabled people)

DiscussionThe results of this study also showed that factors relatedto genetic counseling and environmental factors greatlyinfluence women’s decision-making regarding taking theNIPT. Because of the impact of factors related to adequateinformation, i.e., Factors related to genetic counselingbefore undergoing NIPT and Environmental factors,which describe an inadequate social environment whereinthe ability of independent decision making among womenis perturbed, Anticipatory anxiety is increased. Thedecision-making among pregnant women who receive aprenatal diagnosis is affected not only by individuals closeto them, e.g., family members or friends, but also by theopinions of medical staff, the social environment, and un-certainty regarding fetal health conditions [13–16].Furthermore, the guilt that women experience when

deciding to give birth or abort the fetus, or the guilt theyexperience regarding decision-making related to disabledindividuals and contrary sentiments associated withideas that promote prenatal testing and that having toface this moral opposition induces a state of Ambiva-lence among some women even 1 year after taking theNIPT, whenever the unresolved feelings associated with

the thought “What if the result had been positive • • •”resurfaced in their minds.There are problems related to genetic counseling

about assuming positive NIPT results. Genetic coun-selors themselves are concerned that talking to parentsabout Down syndrome during prenatal testing is likelyto elicit fear among them. Overly optimistic or negativeinformation from medical staff, who largely influencethe parents’ ultimate decision-making upon receivingpositive NIPT results can also introduce a bias [17, 18],similar to the genetic counselors themselves who lackthe necessary skills and knowledge [3]. Perhaps, this isfocused on avoiding any negative effects of providing in-formation while assuming a positive NIPT result on themental status of pregnant women, who seek emotionalrelief from undergoing the test. However, many womenalso seek information regarding the precise living condi-tions of children with the screened genetic disorders andregarding the types of social resources available to them.Statistics have revealed that in England, a few more

women who received positive NIPT results chose tohave an abortion compared to those who tested positiveupon amniocentesis [3]. Concurrently, in Japan, the pos-sibility of continuing the pregnancy existed among manywomen, despite obtaining positive NIPT results. Thepresent results also show that it is important to offergenetic counseling under the assumption of a potentiallypositive NIPT result.Among numerous pregnant women, the motivation to

undergo prenatal testing stems from their need to “feelrelieved [5].” However, among the women who inquireabout prenatal diagnosis, many request information

Fig. 3 Components of the ambivalence

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regarding not only about the actual test, but also regard-ing the many anxieties they may have about their chil-dren during pregnancy. Pregnant women attended NIPTgenetic counseling sessions at a time when they couldopenly speak and be listened to; hence, it is very import-ant to provide psychological support to pregnant womenin addition to information regarding testing methods ordisorders that can be screened for during the test [19].Fears regarding the potential discrimination faced by

the child, prejudice, the lack of understanding amongfamily members or other people, and the lack of soci-etal support for raising the child are some of the rea-sons that motivate women to have a “healthy” child.There is a cultural feature in Japan that is sensitive tothe surroundings and is easily affected. Furthermore,the present results suggest that the society is not veryopen and livable for individuals with disabilities. Simul-taneously, numerous individuals strongly felt the needto adapt to the social support systems for people givingbirth to children with disabilities. These results suggesta positive and supportive perspective towards disabledindividuals, fostering the hope that in the future, diver-sity will be widely accepted and that society will be wel-coming to all children, irrespective of being born withdisabilities. Many of the present study subjects weremothers with late-life pregnancies. We believe the po-tential impacts on family and siblings, societal preju-dices on disabilities, and attachment towards theunborn child were weighed after careful considerationand understanding of societal prejudices and the in-creased chance of having a child with an abnormalchromosomal number owing to their age before choos-ing to undergo NIPT.Similar to other types of prenatal testing, we believe

that NIPT may also increase the pregnant women’sworries and anxieties about the unborn child. The rateof infertility treatment was high among the women whounderwent NIPT (42.2%). Furthermore, women under-going infertility treatment have strong fears regardingchromosomal abnormalities among their children ([20]McMahon, 2013 #895, [21]); however, informing womenthat results are usually negative for 98% of older mothersmay as well reduce the anxiety among women undergo-ing infertility treatment [22, 23]. Offering detailed infor-mation to pregnant women during genetic counselingsessions to enable its juxtaposition with the mothers’ ownexperiences and values to make an informed decisionwhether or not to undergo NIPT lowers the amount ofuncertainty, stress, and anxiety they experience during thedecision-making [24, 25].The present study indicate that numerous individuals

seek detailed information regarding the survival of chil-dren with positive results upon NIPT, including socialsupport services, which indicates the lack of information

and its accuracy regarding these disorders. As such, ad-ministration of NIPT is accompanied by high levels ofstress among mothers, thereby potentially explainingtheir increased levels of anxiety until receiving the testresults or their anxieties regarding the accuracy of thetest [26].Pregnant women taking the NIPT are compelled to

gain adequate knowledge and understanding of theNIPT and the disorders screened therewith and to de-cide between continuing or terminating their pregnancyupon receiving a positive result within a very limitedtime. It is normal for all pregnant women to wish for ahealthy child, which motivates them to take the NIPT tobe “relieved [27].” However, even when they are relievedupon receiving negative results, many women were stillambivalent about their decision, feeling guilty about hav-ing tried to decide their child’s life, or having felt denialtowards individuals with disabilities, but also having toendorse the thoughts about the test. This is probablywhat made them recognize their ambivalence and in-ternal conflict at having these unresolved complexemotions.

ConclusionThe present study shows that even negative results caninduce ambivalent feelings among pregnant women, andit is important to recognize that these feelings may bedue to interrelated factors concerning genetic counsel-ing, environmental factors, and increased anticipatoryanxiety. Moreover, pregnant women have requested add-itional information regarding the detailed prognosis ofindividuals with Down syndrome or other congenitaldisorders and/or artificial abortion, assuming positiveNIPT results. Therefore, genetic counseling and appro-priate follow-up sessions are essential for the well-beingof pregnant women taking the NIPT.

Limitation and future directionThere may be some possible limitations to this study.Firstly, a possible bias due to only women filling in thefree description column of the questionnaire after 1 year;the background of these women is also not clear. Fur-ther prospective studies are needed to investigate thepsychosocial situations of women undergoing NIPT be-fore and after the examination and after the passage oftime. Even in the case of a negative NIPT result, womenmay have various conflicts and ambivalent feelings, andrecognizing the factors that elicit these feelings may helpfuture genetic counseling.

Practice implicationsTo reduce internal conflict in pregnant women dueto ambivalent feelings, it is critical to actively providethem detailed information about living with a child

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affected by one of the disorders screened for duringthe genetic counseling sessions and to discuss this in-formation, assuming a potentially positive result, in-cluding specifics regarding medical pregnancytermination. Importantly, we believe that pregnantwomen should receive personalized psychological careso that they can make independent decisions based onfactual knowledge. Thus, even if pregnant women ex-perience feelings of ambivalence, they should be reassuredand accept that undergoing NIPT was their decision aftercareful consideration, thereby reducing their potential in-ternal conflicts.

AbbreviationNIPT: Non-invasive prenatal testing

AcknowledgementsWe thank all clinical geneticists and genetic counselors who participated inthis study for making this study possible. We thank all the respondentsparticipating in this study.STUDY GROUP MEMBERS OF JAPAN NIPT CONSORTIUM.Seiji Wada, Miyuki Nishiyama (National Center for Child Health andDevelopment), Akira Namba (Saitama Medical University Hospital), HisaoOsada (Chiba University Graduate School of Medicine), Yasuyo Kasai(Japanese red Cross Medical Center), Atsushi Watanabe (Nippon MedicalSchool University Hospital), Kazufumi Haino (Yokohama City University),Naoki Hamajima (Niigata University Medical and Dental Hospital), TakeshiKanagawa (Osaka University), Hiroaki Nakamura, Jun Yoshimatsu (Osaka CityGeneral Hospital), Katsuhiko Naruse (Nara Medical University), HisashiMasuyama (Okayama University), Maki Hyodo (Hiroshima University), Rina Akaishi,Takashi Kojima, Yuka Shibata (Hokkaido University Graduate School of Medicine),Nahoko Shirato, Keiko Miyagami, Tatsuko Hirose, Atsuko Saito (Showa University),Yuri Hasegawa, Shoko Miura, Noriko Sasaki (Nagasaki University), Mako Ueda,Mariko Ushioda, Chiho Okada, Hiroyuki Tanaka, Mina Morii-Kashima (HyogoCollege of Medicine), Kyoko Kumagai, Eri Takeda, Kumiko Oseto (Nagoya CityUniversity), Wakana Abe (Oita University Hospital), Kimiko Enomoto (YokohamaCity University Medical Center), Yoshinobu Sugo, Mari Shinoda, (Yokohama CityUniversity Hospital) and Kitagawa Michihiro (Sanno Hospital).

Authors’ contributionsJY Study planning, drafting/revising the manuscript, analysis, andinterpretation of data, responsi-ble for the data review. AS (A.Sekizawa): Studyplanning, revising the manuscript, data collection, and a co-supervisor. SIStudy planning, analysis, and interpretation data, responsible for the datareview. NS Study planning, data collection, data review. OS Study planning,revising the manuscript, data review. TY, KM (K.Miura), HM, HS, JM, HH, YK(Y.Kamei), TE, AF, YK (Y.Katagiri), NT, MO (Masaki.O), HN, YO, ST, TK, KM(K.Maeda), KM (K.Matsubara), MO (Masanobu.O), HO, TO, YK (Y.Kawano), andAS (A.Sasaki): Study planning, data collection, data review. HS.: Studyplanning, data collection, data review, revising the manuscript. All authorshave read and have approved the final manuscript.

FundingJY was supported by the Grant-in-Aid for Scientific Research (C), Japan.

Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request.

Ethics approval and consent to participateSubjects have given their written informed consent.The study protocol has been approved by the ethics committee of Centerfor Maternal-Fetal, Neonatal and Reproductive Medicine, National Center forChild Health and Development (No 602), and each research institute’scommittee on human research, as follows.Ethics committee of Showa University, Ethics committee of Nagoya CityUniversity, The Ethical committee of the Jikei University School of Medicine,Nagasaki University Hospital Clinical Research Ethics Committee, The ethical

committee of Hyogo College of Medicine, Echics committee of MiyagiChildren’s Hospital, Yokohama City University Certified Institutional ReviewBoard, Ethics committee of Saitama Medical School, Ethics committee ofSapporo Medical University, Ethics committee of Iwate Medical University,The ethics committee of Toho University, Ethics committee of TokyoWomen’s Medical University Hospital, Ethics committee of the Fujita HealthUniversity, Ethics committee of Osaka Medical Center and Research Institutefor Maternal and Child Health, Ethics committee of Kobe University Hospital,Ethics committee of Tokushima University, Ethics committee of EhimeUniversity, Ethics committee of National Hospital Organization KyushuMedical Center, Ethical committee of Chiba University Hospital, Ethicscommittee of Kumamoto University, and Ethics committee of Oita University.

Consent for publicationNot applicable.

Competing interestsThe authors have no conflicts of interest to declare.

Author details1Department of Genetic Counseling, Graduate School of Health and WelfareSciences, International University of Health and Welfare, 4-1-26 Minato-ku,Tokyo 107-8402, Japan. 2Department of Obstetrics and Gynecology, ShowaUniversity School of Medicine, Tokyo, Japan. 3Medical Genetics Center,National Hospital Organization Tokyo Medical Center, Tokyo, Japan. 4Divisionof Clinical and Molecular Genetics, Department of Obstetrics andGynecology, Nagoya City University Graduate School of Medical Sciences,Nagoya, Japan. 5Department of Obstetrics and Gynecology, The JikeiUniversity School of Medicine, Tokyo, Japan. 6Clinical Genetics Unit, KyotoUniversity Hospital, Kyoto, Japan. 7Department of Obstetrics and Gynecology,Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.8Department of Obstetrics and Gynecology, Hyogo College of Medicine,Nishinomiya, Japan. 9Department of Maternal and Fetal Medicine, TohokuUniversity Graduate School of Medicine, Miyagi-Children’s Hospital, Sendai,Japan. 10Department of Clinical Genetics, Yokohama City University Hospital,Yokohama, Japan. 11Department of Obstetrics and Gynecology, SaitamaMedical University Hospital, Saitama, Japan. 12Department of Obstetrics andGynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.13Department of Clinical Genetics, School of Medicine, Iwate MedicalUniversity, Morioka, Japan. 14Department of Obstetrics and Gynecology,Faculty of Medicine, Toho University, Tokyo, Japan. 15Perinatal MedicalCenter, Tokyo Women’s Medical University Hospital, Tokyo, Japan.16Department of Obstetrics and Gynecology, Fujita Health University, Aichi,Japan. 17Department of Obstetrics, Osaka Medical Center and ResearchInstitute for Maternal and Child Health, Osaka, Japan. 18Department ofObstetrics and Gynecology, Kobe University Graduate School of Medicine,Kobe, Japan. 19Department of Obstetrics and Gynecology, The University ofTokushima Faculty of Medicine, Tokushima, Japan. 20Department ofObstetrics and Gynecology, Shikoku Medical Center for Children and Adults,Kagawa, Japan. 21Department of Obstetrics and Gynecology, EhimeUniversity School of Medicine, Ehime, Japan. 22Department of Obstetrics andGynecology, Clinical Research Institute, National Hospital OrganizationKyushu Medical Center, Fukuoka, Japan. 23Department of Maternal-fetalMedicine, Chiba University Hospital, Chiba, Japan. 24Department of Obstetricsand Gynecology, Kumamoto University, Kumamoto, Japan. 25Department ofMolecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.26Center for Maternal-Fetal, Neonatal and Reproductive Medicine, NationalCenter for Child Health and Development, Tokyo, Japan.

Received: 19 July 2019 Accepted: 23 January 2020

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