Subsequent fertility, pregnancy, and gynecologic outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome compared with normal monochorionic twin gestations

Accepted Manuscript Subsequent fertility, pregnancy and gynecologic outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome compared to normal monochorionic twin gestations Simen Vergote, MD, Liesbeth Lewi, MD PhD, Willem Gheysen, MD, Luc de Catte, MD PhD, Roland Devlieger, MD PhD, Jan Deprest, MD PhD PII:

S0002-9378(18)30016-4

DOI:

10.1016/j.ajog.2018.01.013

Reference:

YMOB 12039

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 11 October 2017 Revised Date:

2 January 2018

Accepted Date: 8 January 2018

Please cite this article as: Vergote S, Lewi L, Gheysen W, de Catte L, Devlieger R, Deprest J, Subsequent fertility, pregnancy and gynecologic outcomes after fetoscopic laser therapy for twintwin transfusion syndrome compared to normal monochorionic twin gestations, American Journal of Obstetrics and Gynecology (2018), doi: 10.1016/j.ajog.2018.01.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

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TITLE: Subsequent fertility, pregnancy and gynecologic outcomes after fetoscopic laser therapy for

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twin-twin transfusion syndrome compared to normal monochorionic twin gestations

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Authors: Simen VERGOTE, MD1, Liesbeth LEWI, MD PhD1, Willem GHEYSEN, MD1, Luc DE CATTE, MD

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PhD1, Roland DEVLIEGER, MD PhD1, Jan DEPREST, MD PhD1,2

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Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven,

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Leuven, Belgium

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Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium, and Department of

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Institute for Women’s Health, University College London, London, UK

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Disclosure statement: The authors report no conflict of interest.

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Financial support: Research into complicated monochorionic twin pregnancies is funded by

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the Klinische Onderzoeks- en Opleidings Raad (KOOR) of the UZ Leuven and the starter’s

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fund of the KU Leuven (LL). RD is a fundamental clinical researcher for the Fonds

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Wetenschappelijk Onderzoek Vlaanderen (1803311N ). JDP is supported by the Great

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Ormond Street Hospital Charity Fund and the Wellcome / EPSRC funding the GIFT-Surg

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research project.

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Corresponding author:

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Jan DEPREST, MD PhD

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Department of Development and Regeneration

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Faculty of Medicine, KU Leuven, Leuven, 3000, Belgium

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Tel: +32 16 34 46 04 – Fax: +32 16 34 42 05

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E-mail: [email protected]

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Word count: Abstract 327 words; Main text 2708 words

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IMPLICATIONS AND CONTRIBUTIONS

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Fetoscopic laser coagulation is the current first line treatment for twin-to-twin transfusion

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syndrome, yet long term maternal outcomes are poorly documented. We compared

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reproductive, obstetric, gynecologic and psychological outcomes in women who previously

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underwent laser to those of women with uncomplicated monochorionic (MC) twins. No

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adverse medium-term reproductive nor gynecologic adverse events were self-reported,

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however psychological or emotional problems are more frequent than in women with

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uncomplicated MC twins. This mainly affects women who lost one or more fetuses in the

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index pregnancy. This should prompt our attention beyond the limits of the index gestation

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identification

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support

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CONDENSATION

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Patients who underwent fetoscopic laser coagulation for twin-to-twin transfusion syndrome

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do not report adverse medium-term reproductive nor gynecologic adverse events, yet more

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psychological problems.

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SHORT TITLE

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Reproductive outcomes after fetoscopic laser therapy

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ABSTRACT

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BACKGROUND: An improved survival and quality of life for neonatal survivors after

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fetoscopic laser therapy (FLC) for twin-twin transfusion syndrome (TTTS) has been reported.

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However, little is known about the medium-term maternal effects after FLC with respect to

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reproductive and gynecologic outcomes.

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OBJECTIVE: To document reproductive, obstetric, gynecologic and psychological outcomes in

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women who underwent FLC for TTTS.

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STUDY DESIGN: Monocentric controlled study on consecutive women who underwent FLC

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for TTTS between 2007 and 2013 at the University Hospitals Leuven (cases; n=198). Controls

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were women followed for an uncomplicated monochorionic diamniotic (MCDA) twin

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pregnancy and with uneventful course during the same time period (controls; n=211). All

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patients received a questionnaire enquiring on their fertility, later pregnancies and

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gynecologic outcomes.

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RESULTS: The response rate was 50.4% (cases: n=95; controls: n=109). Most baseline

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characteristics were similar across both groups. Women in the FLC group attempted more

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frequently a new pregnancy (34% (31/92) versus 21% (22/107) in controls; p<0.05) and

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became more often pregnant (100% (31/31) versus 82% (18/22); p<0.05).We observed a

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shorter inter-pregnancy interval in cases than controls (median interval: 12 (IQR 5-27) versus

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24 (IQR 15-30) months; p<0.05). This was also observed in cases who lost one or more

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fetuses or babies in the index pregnancy (median interval: 9 (IQR 3.5-25.5) months; p<0.05).

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The complication rate during subsequent pregnancies (26% (8/31); versus 11% (2/19);

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p=0.194) and at delivery (17% (5/30) versus 11% (2/19); p=0.554) were comparable. More

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women who underwent FLC reported relevant psychological symptoms (44% (40/92) versus

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21% (23/107); p<0.05). When only women were considered in whom there was a double

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surviving twin pair, there were no differences in psychological symptoms compared to

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controls (16% (15/55) versus 21% (23/107); p=0.411). Gynecologic problems were equally

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frequent in both groups (20% (18/92) versus 31% (33/107); p=0.069).

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CONCLUSION: No adverse medium-term maternal effects with respect to fertility, obstetric

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and gynecologic outcomes were observed after FLC. However, these women reported more

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psychological or emotional problems than women with MCDA without FLC.

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KEYWORDS

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fetoscopic laser coagulation / fertility / gynecologic outcome / pregnancy outcome /

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psychological outcome / twin-twin transfusion syndrome

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INTRODUCTION Monochorionic diamniotic (MCDA) twins comprise 20-30% of spontaneous and 4-5%

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of iatrogenic twin gestations. In those, the risk for perinatal complications is much greater

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than in dichorionic twins and singletons pregnancies.1,2 This is due to the presence of

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vascular anastomoses connecting the fetal circulations which are responsible for a range of

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pregnancy complications, including twin-twin transfusion syndrome (TTTS). About 10% of

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MCDA twin pregnancies are affected by TTTS, a serious complication characterized by

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unbalanced feto-fetal transfusion over the chorionic plate anastomoses.1,3–5 Because TTTS

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typically occurs in the pre-viable period, its prognosis is dismal without treatment.

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Polyhydramnios-related miscarriage or the preterm birth of two sick neonates is common, as

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well as intrauterine demise of one or both twins.4,5 Fetoscopic laser coagulation (FLC) of

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chorionic plate anastomoses combined with amnioreduction has been shown to be the best

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first line treatment for this condition.3,6

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Though a lot of research has shown improved survival and quality of life for survivors

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after fetoscopic laser surgery, there are to our knowledge no studies on their mother’s later

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reproductive, obstetrical and gynecologic outcomes. Given the likelihood of a less than

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perfect fetal or neonatal outcome, or the simple fact of increased stress by intensive follow

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up with many uncertainties, the psychological impact on individual families may be

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significant. Herein, we aimed to investigate such effects in women with monochorionic twins

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who earlier had FLC as compared to women with uncomplicated monochorionic twins.

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MATERIALS AND METHODS This was a single centre study conducted at the Fetal Medicine Unit of the University

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Hospitals Leuven. We searched our database for patients who underwent fetoscopic laser

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coagulation (FLC) for twin-twin transfusion syndrome (TTTS) between 2007 to 2013 (cases).

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As controls, we selected patients with MCDA pregnancies who, following the diagnosis of

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monochorionicity in the first trimester, were managed at our unit during the same time

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span. Furthermore, we selected those pregnancies who were not complicated by TTTS, intra-

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uterine growth restriction (IUGR), twin-anemia polycytemia syndrome (TAPS) or discordant

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anomaly and without fetal or neonatal loss.1 The medical records were searched for

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maternal age, parity prior to the index pregnancy and loss of either or both twins during the

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index pregnancy or neonatal period.

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Patients were sent an invitation to participate, with comprehensive information and

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a questionnaire (Appendix 1 and 2). Consenting patients were left the choice to either fill out

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this survey online, using LimeSurvey (version 2.00+ Build 130708, The LimeSurvey Project

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Team, Hamburg, Germany) or using a hard copy to be returned in a prepaid envelope. The

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survey was based on a questionnaire used in a previous study on patients undergoing

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fetoscopic surgery for severe congenital diaphragmatic hernia.7 That questionnaire was in

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turn based on earlier used surveys on patients undergoing open maternal fetal surgery.8 The

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survey consisted of 19 multiple choice questions (MCQ), 5 questions with a standardized

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format reply (SFR), and 11 open questions (OQ). The first segment of the survey (3 MCQ, 2

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SFR, 1 OQ) covered the desire to further conceive after the index pregnancy and the time

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interval until conception. There was also possibility to indicate whether there was a

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relationship between the problem in the index pregnancy (monochorionicity per se, or any

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of its complications) and the decision (not) to conceive again. The second segment (11 MCQ,

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4 OQ) queried the outcomes of later pregnancies (number of fetuses, gestational age at

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birth, delivery method, weight at birth, occurrence of congenital anomalies) as well as

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obstetric complications during pregnancy or labor with a specific enquiry to complications

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which could relate to the uterine scar, and fertility problems (pre-existent or new problems,

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need for assisted reproduction technology). In the third segment (1 MCQ, 1 OQ), patients

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were requested to report on psychological problems they experienced after the index

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pregnancy and on the possible relationship with that pregnancy. The fourth segment (4

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MCQ, 3 SFR, 4 OQ) asked for gynecologic problems after the index pregnancy (abnormal

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menstruations, lower abdominal pain, others). Patients also had the option to provide

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contact information of their treating physician when consenting for additional information

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being asked to their physician. The questionnaire finished by an open question (1 OQ) in

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which the patients could add any other problems that they thought might have occurred

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after the index pregnancy, yet not covered by the previous questions. The questionnaire was

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available in Dutch, French and English; translations were done by native speakers. This study

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was approved by the Ethics Committee on clinical studies of the UZ Leuven (S59805).

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The answers of the surveys were pooled in a Microsoft Excel database (Microsoft

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Corp, Redmond, WA, USA) by the primary author and analysed using SPSS (v.24; IBM

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Software, Inc., Armonk, NY, USA). All data are reported as number, percentage, median and

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interquartile range (IQR). Categorical variables were analysed by the Pearson chi-square test,

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subgroups were analysed by the Mann-Whitney U test; the numerical variables were

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analysed by the Mann-Whitney U test. Patients with missing data were excluded from

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analysis and detailed in tables. A p-value of <0.05 was considered significant.

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RESULTS We identified a total of 409 patients, 198 cases and 211 controls, in our database.

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Table 1 displays the demographic variables for cases versus controls. Per definition, controls

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experienced no fetal or neonatal loss. The interval between the index delivery and survey

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was significantly longer (+6 months) in controls than for a median interval of 74 months in

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cases. There was also a difference in geographical background. Cases were less likely to be

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further managed at our unit (69% (134/198) following FLC since they were referred back,

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whereas controls were by definition patients managed locally throughout their pregnancy

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(100% (211/211); p<0.05).

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Four patients were not invited because of insufficient contact information (two cases

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and one control) or unrelated maternal death (one control) (Figure 1). Therefore 405 women

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were eventually contacted between January 2017 and June 2017, initially by e-mail, in case

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of bounce back or missing contact, through a letter, and in the absence of a reply, by

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telephone. Ten women refused to participate in the study (6 cases and 4 controls) and were

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included in the non-responders. We received 95 surveys from cases and 109 controls by six

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months after the start of the study (response rate 50.4%).

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Table 1 displays demographic variables of respondents versus non-respondents.

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There were no significant differences except that there were more responders managed

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locally (in the University Hospitals Leuven), irrespective of their group assignment. Also the

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interval between the index delivery and survey was comparable. The response rate in

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women treated for TTTS was comparable to that of women with uncomplicated MCDA

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pregnancies (48% (95/196) versus 52% (109/209); p=0.459).

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Three surveys of cases and two of controls were eventually discarded because of

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incomplete answers or obvious inconsistencies in their answers (2% (5/204)). This left

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answers from 199 women. Table 2 displays their reproductive outcomes. Following the index

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pregnancy, cases were more likely to attempt a new pregnancy than controls (34% (31/92)

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versus 21% (22/107), respectively; p<0.05). There was no difference in parity at baseline in

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these patients. Women who were known to have lost one or two fetuses or babies following

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laser coagulation, attempted more frequently a new pregnancy compared to those who did

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not experience fetal or neonatal loss (79% (26/33) versus 7% (4/55), respectively; p<0.05).

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There were no de novo infertility problems: of those attempting to conceive, more women

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in the FLC group became pregnant (100% (31/31) versus 82% (18/22) in controls; p<0.05).

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Twelve participants became pregnant by assisted reproductive technology (ART); however,

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they required ART before. Women having undergone FLC attempted a new pregnancy earlier

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than controls (median interval 12 (IQR 5-27) versus 24 (IQR 15-30) months; p<0.05). This

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difference was also observed when only comparing cases who lost one or two fetuses or

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babies in the index pregnancy to controls (median interval 9 (IQR 3.5-25.5) months; p<0.05).

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Table 3 displays details on these 67 subsequent pregnancies (44 cases and 23

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controls). In the first gestation after the index pregnancy, there was no difference in first

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trimester losses (13% (4/31) in cases versus 16% (3/19) in controls; p=0.777). One control

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patient had an unplanned pregnancy ending in an induced abortion in the first trimester for

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social reasons. There were no second or third trimester losses observed in either groups.

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Forty-two women delivered beyond viability. There was no difference in weight at birth of

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the first baby after the index pregnancy (median 3.47 (IQR 3.12-3.65) versus 3.65 (IQR 3.29-

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3.80) kilograms; p=0.331). Fourteen women reported at least one complication during

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subsequent pregnancies or during delivery of those pregnancies, as detailed in Table 4.

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One hundred and forty-six women did not wish to conceive again (66% (61/92) in

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cases versus 79% (85/107) in controls; p<0.05). In both groups, there were as many women

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who indicated that this decision was related to events in the index pregnancy (15% (9/61)

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versus 6% (5/85); p=0.074). They reported as reasons fear for new pregnancy complications

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(5/9 cases and 0/5 controls), psychological distress persisting since the index pregnancy (4/9

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and 2/5), care for the baby or babies (1/9 and 2/5) or because of completion of the family

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(2/5 controls). Those women from both groups who chose not to conceive again were of the

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same age (median 37.4 years in cases versus 37.9 years in controls; p=0.802). One of these

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women mentioned that this was due to her age; she was in the laser group (12.5% (1/8)

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versus 0% in controls (0/5); p=0.724). There were no cases or controls who indicated that

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the need for IVF impacted their decision.

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Fifty-one women report gynaecological problems after the index pregnancy, as

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detailed in Table 4. Women from both groups did report similar rates of problems (20%

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(18/92) in cases versus 31% (33/107) in controls; p=0.069). Psychological and emotional

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problems are detailed in Table 4. They were more commonly reported by women

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undergoing laser (44% (40/92)) than by controls (21% (23/107); p<0.05). Problems most

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commonly reported were anxiety concerning the health of the index baby/babies or fear for

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repetition and feelings of guilt. Nineteen cases (20%) reported grieving the loss of a child.

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Other problems were a depressed mood and a variety of other feelings difficult to grasp in a

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single common denominator (details in Appendix 3). When only women were considered in

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whom there was a double surviving twin pair, there were no differences in psychological and

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emotional problems (16% (15/55) versus 21% (23/107); p=0.411).

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COMMENT We did not identify significant differences in subsequent fertility, pregnancy and

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gynecologic outcomes between patients who had FLC and patients with uncomplicated

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MCDA pregnancies. However, following laser surgery, psychological or emotional problems

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were more common. This coincided with the loss of either one or both twins in the index

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pregnancy. Grieving the loss of a child, anxiety and feelings of guilt seem to play an

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important role, whereas a depressed mood was evenly reported in both groups.

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Apart from the potential immediate complications of fetoscopic surgery during the

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index pregnancy, there is the theoretical concern for an impact on later reproductive life. In

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this study, almost twice as many women from the FLC group attempted another pregnancy

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and reassuringly all were successful in achieving this. Their desire to conceive again we tie to

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the loss of one or both babies due to TTTS: the vast majority of women (79% (26/33)) who

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lost one or more babies attempted another pregnancy, as compared to only 7% of women

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who did take home two babies (p<0.05). Those women who had a laser, and who

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experienced a loss, attempted to conceive even earlier than those who had a successful

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pregnancy outcome (9 vs. 12 months). Conversely, the majority of those who did not wish to

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conceive again, did not indicate this decision was related to events in the index pregnancy.

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The primary concern of open maternal-fetal surgery is uterine dehiscence (14%) and

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rupture (14%).8 This should be less after fetoscopic surgery, which essentially uses a 2.3 to 5

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mm access to the uterus.9,10 In this study using self-reported outcomes, no uterine ruptures

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were mentioned by our patients. One woman in each group indicated there was some

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problem with a uterine scar. In the control group that problem was in retrospect related to a

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caesarean section scar. One woman who underwent laser surgery indicated that the

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“fetoscopic scar led to adhesions and constipation”. However, this was an interpretation,

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and there was no indication in the medical records for this complaint to be a dehiscence or

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threatening rupture. One out of four participants reported gynecologic problems of any kind, yet without a

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different likelihood in groups. This is somewhat higher than in our previous study in

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singletons undergoing fetoscopic surgery, though patients in both studies were of

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comparable age (37 years).7 One explanation might be that caesarean deliveries are more

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often performed in twin pregnancies than in pregnancies with CDH (which are usually

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singleton pregnancies). Women who previously had a caesarean delivery report more

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frequently abdominal pain and abnormal bleeding.11,12

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Four out of ten women who underwent laser reported subsequent psychologic and

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emotional problems. This number is comparable to what we observed in women who gave

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birth to a baby with CDH.7 The most logical reason for that seems to us a problematic

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outcome in the index pregnancy. We are strengthened in this interpretation by the fact that

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this difference disappeared when comparing cases with two surviving infants to our controls

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(who per definition experienced no loss). Nevertheless, an uncomplicated monochorionic

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diamniotic pregnancy seemed to have a psychological impact as well. One in five women

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indicated such problems. Therefore, it seems that psychological support should be liberally

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offered to women with monochorionic twins, even in the absence of TTTS. Other studies

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show that multiple births often have an impact on the mental health of parents, resulting in

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depression, anxiety and parenting stress.13

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We acknowledge a number of weaknesses to our study. First, there was a difference

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in geographical background, yet this is because we perform surgery on patients who come

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from all over Europe. They may have another cultural background and cope with such

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problems differently. The majority of respondents are from Belgium, so conclusions on our

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study population may only apply locally. Second, the response rate was less than desirable,

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yet is acceptable and more than what we observed in a similar study on mothers with

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fetuses with CDH (40%).7 Third, we did not use condition specific and validated

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questionnaires. In their absence, we modified a questionnaire that was used before by

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Wilson et al for women undergoing open fetal surgery, for studying women undergoing

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endoscopic fetal surgery for CDH.7,8 Fourth, it should be noted that complications are self-

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reported and not validated by a physician. This may lead to inaccuracies of the occurrence,

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nature and severity of some medical complications. Another limitation is that many of the

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psychological problems were not categorized, as they appeared to be of variable nature.

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Given the relevance and high likelihood of a psychological impact, it would be interesting in

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future studies to use validated instruments for the assessment of the long-term

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psychological impact. Sixth, though we have a fairly high number of patients, the sample size

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might still be too low to make conclusions on rare complications or regarding events that do

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not occur in both groups. With these numbers, statistics become unreliable for very rare

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complications or for events, such as fetal losses, that are confined to one specific group

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(women who underwent FLC). Though we observed differences in psychologic impact and

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interval to next pregnancy in women with loss(es), it is possible that we underestimate its

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magnitude. Finally, there were ten women who refused to participate (6 cases and 4

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controls). That number is not insignificant. If these women would be the ones with severe

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complications, we may have underestimated the impact of fetoscopic surgery.

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Our study also has some strengths. It first provides relevant information on

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reproductive and gynecologic outcomes following fetoscopic surgery for TTTS, information

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which is to our knowledge until now almost non-existent. Second, we used an appropriate

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control group. Therefore we feel confident that fetoscopic surgery for TTTS does not have

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medium-term adverse gynaecological and reproductive effects. The psychological impact

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seems to be high due to the burden of the loss of a child. Strong support for these women is

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advocated.

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after fetoscopic surgery for congenital diaphragmatic hernia. Hum Reprod.

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2016;31(9):2024-2030. doi:10.1093/humrep/dew160.

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

16

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311

8.

Wilson RD, Lemerand K, Johnson MP, et al. Reproductive outcomes in subsequent

312

pregnancies after a pregnancy complicated by open maternal-fetal surgery. Am J

313

Obstet Gynecol. 2010;203(3). doi:10.1016/j.ajog.2010.03.029. 9.

Surg. 2010;7(2):113-125. doi:10.1007/s10397-010-0565-4.

315 316

Beck V, Pexsters A, Gucciardo L, et al. The use of endoscopy in fetal medicine. Gynecol

10.

RI PT

314

Petersen SG, Gibbons KS, Luks FI, et al. The Impact of Entry Technique and Access Diameter on Prelabour Rupture of Membranes Following Primary Fetoscopic Laser

318

Treatment for Twin-Twin Transfusion Syndrome. Fetal Diagn Ther. 2016;40(2):100-

319

109. doi:10.1159/000441915. 11.

M AN U

320

SC

317

Hannah ME, Hannah WJ, Hodnett ED, et al. Outcomes at 3 months after planned cesarean vs planned vaginal delivery for breech presentation at term: the

322

international randomized Term Breech Trial. J Am Med Assoc. 2002;287(14):1822-

323

1831. doi:10.1097/00132586-200306000-00026.

324

12.

TE D

321

Wang CB, Chiu WWC, Lee CY, Sun YL, Lin YH, Tseng CJ. Cesarean scar defect: Correlation between Cesarean section number, defect size, clinical symptoms and

326

uterine position. Ultrasound Obstet Gynecol. 2009;34(1):85-89. doi:10.1002/uog.6405.

328 329 330 331

13.

AC C

327

EP

325

Wenze SJ, Battle CL, Tezanos KM. Raising multiples: mental health of mothers and fathers in early parenthood. Arch Womens Ment Health. 2015;18(2):163-176. doi:10.1007/s00737-014-0484-x.

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

17

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TABLES

333

Table 1: Demographic variables Parameter

Cases

Controls

(n=198)

(n=211)

p-value

Responders Non(n=204)

p-value

responders

RI PT

332

(n=201)

Loss of one or more of the 69 (39%)

0 (0%)

p<0.05

pregnancy or neonatal

M AN U

perioda Women managed locally

211 (100%)

p<0.05

188 (92%)

155 (77%)

p<0.05

107 (54%)

114 (58%)

p=0.444

106 (53%)

111 (57%)

p=0.433

Median age at survey

30 (28-33)

p=0.656

30 (28-33)

30 (27-33)

p=0.243

37 (33-40)

37 (35-41)

p=0.204

37 (35-40)

37 (33-41)

p=0.398

80 (59-103)

p<0.05

77 (53-100)

77 (57-103)

p=0.193

AC C

(years)

30 (27-33)

EP

index pregnancy (years)d

TE D

pregnancy ≥ 1c Median age at delivery of

Interval between delivery

p=0.705

134 (69%)

throughout pregnancyb Parity during index

34 (19%)

SC

fetuses during index

34 (17%)

74 (54-101)

of index pregnancy and survey (months)d 334

- Data are displayed as n(%) or median (IQR)

335

- Missing values: aCases 22, Controls 0; Responders 4, Non-Responders 17; bCases 3,

336

Controls 1; Responders 1, Non-Responders 0; cCases 0, Controls 14; Responders 4, Non-

337

Responders 6; dCases 7, Controls 0; Responders 2, Non-Responders 5

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

18

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338

Table 2: Reproductive outcomes in patients who submitted completed questionnaires Parameter Cases Controls p-value (n=107)

Parity at index pregnancy ≥ 1a

47 (51%)

57 (55%)

p=0.602

Further attempt to conceive

31 (34%)

22 (21%)

p<0.05

Of those attempting to conceive Patients with ≥1 subsequent pregnancies

31 (100%)

Requiring for the first time ART

0 (0%)

Interval between delivery of index pregnancy

12 (5-27)

No further attempt to conceive

TE D

Decision related to the index pregnancy

p<0.05

SC

0 (0%)

p<0.05

10 (9-14.5)

14 (10-16)

p=0.192

61 (66%)

85 (79%)

p<0.05

9 (15%)

5 (6%)

p=0.074

M AN U

subsequent pregnancy (months)c

18 (82%)

24 (15-30.25)

and attempt at new pregnancy (months)b Interval between attempt and delivery

RI PT

(n=92)

- Data are displayed as n(%) or median (IQR)

340

- Missing values or exclusions: aCases (0 missing values), Controls (3 missing values); bCases

341

(2 missing values), Controls (0 missing values); cCases (2 missing values, 4 excluded due to

342

obvious erroneous data), controls (4 did not conceive again thus were excluded);

AC C

343

EP

339

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

19

ACCEPTED MANUSCRIPT

344

Table 3: Subsequent pregnancy outcomes Parameter

Cases

Controls

(n= 31)

(n= 19)

p-value

Subsequent pregnancy outcome

Miscarriage (loss <20 weeks)

4 (13%)

Pregnancy loss at 20-24 weeks

0

Delivery at 24-28 weeks

0

Delivery at 38-36 weeks Delivery ≥ 37 weeks Birthweight (in kilograms)a

TE D

Delivery modea Vaginal

1 (5%)

3 (16%) 0

0

0

0

27 (87%)

15 (79%)

p=0.450

3.47 (3.12-3.65)

3.65 (3.29-3.80)

p=0.331 p=0.615

20 (74%)

10 (67%)

7 (26%)

5 (33%)

8 (26%)

2 (11%)

Bleeding during pregnancy

2

0

Placental problems

1

0

Hypertension

0

0

Gestational diabetes

3

1

Othersb

3

1

EP

Caesarean delivery

Patients with ≥ 1 of the following complications during subsequent pregnancies

AC C

p=0.777

SC

0

M AN U

Termination of pregnancy <20 weeks

RI PT

Gestational age at delivery

Exact number of pregnancies with

p=0.194

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

20

ACCEPTED MANUSCRIPT 5 (17%)

2 (11%)

Problems with uterine scar

1

1

Preterm labour and/or preterm rupture of

2

0

Patients with ≥ 1 of the following complications

p=0.554

during the delivery of subsequent pregnanciesc

the membrane Othersd

2

RI PT

Exact number of pregnancies with

1

- Data are displayed as n(%) or median (IQR)

346

- Missing values or exclusions: aCases (4 pregnancy losses <20 weeks excluded), controls (3

347

pregnancy losses <20 weeks and 1 termination of pregnancy excluded); cOne case is

348

excluded due to obvious inconsistency

349

- Others: bCases (1 hydramnios, 1 ectopic pregnancy, 1 Braxton-Higgs treated medicinally),

350

controls (1 hyperemesis gravidarum); dCases (1 prolonged labour, 1 internal bleeding),

351

controls (1 urgent caesarean delivery due to an unexpected breech position)

354

M AN U

TE D

EP

353

AC C

352

SC

345

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

21

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355

Table 4: Self-reported gynecological and psychological outcomes in cases and controls. Problems Cases Controls p-value

Patients reporting ≥ 1 gynecological problem(s)

(n=92)

(n=107)

18 (20%)

33 (31%)

p=0.069

11 (12%)

Abnormal menstrual bleeding

6 (7%)

Othersa

4 (4%)

15 (14%)

p=0.667

15 (14%)

p=0.086

12 (11%)

p=0.076

SC

Abdominal pain

RI PT

after their index pregnancy

23 (21%)

p<0.05

7 (8%)

5 (5%)

p=0.386

13 (14%)

6 (6%)

p<0.05

Grieving the loss of a child

19 (20%)

0 (0%)

p<0.05

Feelings of guilt

6 (7%)

0 (0%)

p<0.05

6 (7%)

12 (11%)

p=0.250

after their index pregnancy Depressed mood

Anxiety concerning health of the baby, fear

EP

Othersb

TE D

for.repetition

40 (44%)

M AN U

Patients reporting ≥ 1 psychological problem(s)

- Data are displayed as n(%) or median (IQR)

357

- Others: aCases (1 premenstrual syndrome, 2 post-operative adhesions, 1 ovarian cyst),

358

controls (1 lasting pain caused by scar of caesarean delivery, 2 retained placental tissue, 3

359

ovarian cysts, 2 urogenital prolapses, 1 urinary incontinence, 1 mastalgia, 1 hematoma after

360

caesarean delivery, 1 uterine cysts); bSee Appendix 3

361

AC C

356

Reproductive outcomes after fetoscopic laser therapy – Vergote S. et al.

22

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FIGURE LEGENDS

364

Figure 1: Flow chart of included patients

AC C

EP

TE D

M AN U

SC

RI PT

362 363

ACCEPTED MANUSCRIPT Figure 1 Patients eligible for inclusion (n = 409)

Controls (n = 211)

RI PT

Cases (n = 198)

Exclusions due to insufficient contact information or death (n = 4)

Patients contacted by post, by email or by telephone (n =405) Controls (n = 209)

Surveys returned (n = 204)

Controls (n = 109)

TE D

Cases (n = 95)

M AN U

Cases (n = 196)

EP

Complete surveys (n = 199)

AC C

Cases (n = 92)

Controls (n = 2)

SC

Cases (n = 2)

Controls (n = 107)

Exclusions due to incomplete survey or obvious inconcistencies (n = 5) Cases (n = 3 )

Controls (n = 2)

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

ACCEPTED MANUSCRIPT

1 2

SUPPLEMENTAL DIGITAL CONTENT

3 4 5

Appendix 1: Questionnaire designed for cases

6

This questionnaire consists of 35 items. Filling it in will take around 15 minutes.

RI PT

Gynecological outcomes after fetoscopic laser therapy

7

A. Pregnancy desire

9

[1] Have you attempted to get pregnant after your pregnancy in which a twin to twin transfusion syndrome was detected?

11




Yes (Proceed to question 4)

12




No (Proceed to question 2)

M AN U

10

SC

8

[2] Is there any relationship between the problem in your pregnancy or pregnancy

14

outcome of the twin to twin transfusion syndrome and the fact that you have not

15

attempted a new pregnancy?

EP

TE D

13




Yes (Proceed to question 3)

17




No (Proceed to question 22)

18

19

AC C

16

[3] Are you willing to summarize the reason why you haven't attempted a new pregnancy?

20

21

22

(Proceed to question 22) 1

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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23

[4] How much time was there between the delivery in the pregnancy with twin to twin

24

transfusion syndrome and a new attempt to get pregnant? Months

25

[5] Have you been pregnant since your previous pregnancy with a twin to twin transfusion

27

syndrome?


Yes (Proceed to question 6)

29




No (Proceed to question 22)

SC

28

RI PT

26

[6] How much time was there between the delivery of pregnancy with twin to twin

31

transfusion syndrome and the delivery of the following pregnancy?

M AN U

30

Months

32

B. Later pregnancy outcomes

34

We would like to investigate whether there were any problems or complications during one

35

of these later pregnancies. We would like you to answer the following questions separately

36

for the first three pregnancies after the pregnancy in which a twin to twin transfusion

37

syndrome was diagnosed.

38

[7] Was it a singleton, twin or triplet?

AC C

EP

TE D

33

Singleton

Twin

Triplet

Not applicable

First pregnancy after twin to twin

2

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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transfusion syndrome Second

RI PT

pregnancy after twin to twin

SC

transfusion syndrome

M AN U

Third pregnancy after twin to

transfusion

39

EP

syndrome

TE D

twin

[8] What was the estimated gestational age at the moment of delivery? (the normal

41

gestational age is 40 weeks)

AC C

40

Miscarriage 20-24

24-28

28-36

>37

Not

weeks

weeks

weeks

weeks

applicable

or loss prior to 20 weeks of pregnancy

3

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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First pregnancy after twin to twin transfusion

RI PT

syndrome Second pregnancy after

SC

twin to twin transfusion

M AN U

syndrome Third pregnancy after twin to twin

syndrome 42

EP

[9] The delivery was

Vaginal

Caesarean delivery

Not applicable

AC C

43

TE D

transfusion

First pregnancy after twin to twin

transfusionsyndrome Second pregnancy after twin to twin

4

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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transfusionsyndrome Third pregnancy after twin to twin

RI PT

transfusionsyndrome 44

[10] What was the birth weight of your child in grammes? Please fill in 0 when not

46

applicable.

SC

45

Weight (in case of

M AN U

Weight (in grammes)

First pregnancy after twin to

Weight (in case of

twins, in

triplets, in

grammes)

grammes)

TE D

twin transfusionsyndrome

Second pregnancy after twin to

EP

twin transfusionsyndrome

AC C

Third pregnancy after twin to twin transfusionsyndrome 47

48

[11] Was there any congenital anomaly/malformation? Yes

No

Not applicable

First pregnancy after

5

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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twin to twin transfusionsyndrome Second pregnancy

RI PT

after twin to twin transfusionsyndrome Third pregnancy

SC

after twin to twin

49

50

[12] If so, what kind of anomaly?

TE D

51

M AN U

transfusionsyndrome

52

53

[13] Were there any problems or complications during your pregnancy after your

55

pregnancy with twin to twin transfusion syndrome?

AC C

EP

54

High blood

Gestational Others Not

There were

Vaginal

Placenta

no problems

bleeding

problems pressure/Pre- diabetes

or

during

applicable

eclampsia

complications your pregnancy

6

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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First pregnancy after twin to twin transfusionsyndrome

RI PT

Second pregnancy after twin to twin transfusionsyndrome

SC

Third pregnancy after twin to twin

M AN U

transfusionsyndrome 56

60

61

62

63

TE D

59

EP

58

[14] If you marked “others” in the previous question, please specify:

AC C

57

64

[15] Were there any problems/complications during labor or delivery after your pregnancy

65

with twin to twin transfusion syndrome?

7

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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There were

The

Labor

Excessive Problems

no problems

water

occured

blood

with the

or

broke

too early

loss

uterine

complications too

(before 8

during

scar of

during labor

early

months/37 delivery

or delivery

(more

weeks)

applicable

the

RI PT

than

Others Not

previous

fetoscopic surgery

SC

24

M AN U

hours before labor) First pregnancy after

Second pregnancy after twin to twin

AC C

transfusionsyndrome

EP

transfusionsyndrome

TE D

twin to twin

Third pregnancy

after twin to twin

transfusionsyndrome 66

[16] If you marked “others” in the previous question, please specify:

67

8

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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68

69

70

[17] May we contact your gynecologist to provide us detailed information about these

72

problems?


Yes

74




No

76

[18] If so, could you please give us the name and address of your gynecologist?

M AN U

75

SC

73

RI PT

71




Name :




Address :




Telephone number :

78

TE D

77

79

82

83

84

85




AC C

81

EP

80

Email address :

[19] Did you get pregnant spontaneously, i.e. without medical help? Yes

No

Not applicable

9

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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First pregnancy after twin to twin transfusionsyndrome

RI PT

Second pregnancy after twin to twin transfusionsyndrome

SC

Third pregnancy after twin to twin

M AN U

transfusionsyndrome 86

[20] If there were fertility problems, did these exist before the pregnancy in which the

88

twin to twin transfusion syndrome was diagnosed?
Yes

90


No

92

[21] What type of assisted reproduction techniques did you require?

AC C

91

EP

89

TE D

87

Medication

Artificial

IVF (In Vitro

Use of

Not

to stimulate insemination

Fertilization)/ ICSI

donor

applicable

ovulation

(using own

(Intracytoplasmic

sperm

sperm)

sperm injection)

and/or female egg

10

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

ACCEPTED MANUSCRIPT

RI PT

(oocyte).

First pregnancy after twin to twin

SC

transfusionsyndrome

M AN U

Second pregnancy after twin to twin transfusionsyndrome Third pregnancy after

TE D

twin to twin transfusionsyndrome

EP

93

C. Psychological impact

95

[22] Have you had any psychological or emotional problems related to the twin to twin

96

transfusion syndrome or the pregnancy outcome?

97

98

AC C

94

Yes

No

99 100

11

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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101

[23] Could you please describe them?

102

103

RI PT

104

105

SC

106

M AN U

107

D. Gynecological problems

109

[24] Did you have abnormal menstruations after you delivered the baby/babies of the twin

110

to twin transfusion syndrome?

111


Yes

112


No

TE D

108

[25] If so, how many months after you delivered the baby/babies of the twin to twin

114

transfusion syndrome did this problem start?

AC C

115

EP

113

Months

116

[26] What was the cause of this bleeding according to your gynecologist or general

117

practitioner?

118

119

12

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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[27] Did you have a lot of lower abdominal pain after you delivered the baby/babies of the

121

twin to twin transfusion syndrome?

122


Yes

123


No

RI PT

120

124

[28] If so, how many months after you delivered the baby/babies of the twin to twin

125

transfusion syndrome did this pain start? Months

SC

126

M AN U

127

128

[29] What was the cause of this pain according to your gynecologist or general

129

practitioner?

TE D

130

131

[30] Did you have any other gynecological problem since you delivered the baby/babies of

133

the twin to twin transfusion syndrome?

135 136


Yes

AC C

134

EP

132


No

137

[31] If so, how many months after you delivered the baby/babies of the twin to twin

138

transfusion syndrome did these problems start?

139

Months

140 13

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

ACCEPTED MANUSCRIPT

141

[32] Which problem occurred and what was the cause according to your gynecologist or

142

general practitioner?

143

RI PT

144

[33] May we contact your gynecologist to provide us detailed information about these

146

problems?
Yes

148


No

M AN U

147

SC

145

149

[34] Could you please give us the name and address of your gynecologist or general

150

practitioner?


Name




Address




Telephone number

TE D

151

154

155

156

157




AC C

153

EP

152

Email address

158 159 160 14

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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E. Other

162

[35] If you experienced other medical problems after your surgery for twin to twin

163

transfusion syndrome or if you have any other remarks regarding this questionnaire,

164

please write these in the box below:

RI PT

161

165

SC

166 167

M AN U

168

169

TE D EP

171

Thank you very much for your participation.

AC C

170

15

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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Appendix 2: Questionnaire designed for controls

174

Subsequent fertility, pregnancy and gynecological outcomes in women with

175

monochorionic twins

176

This questionnaire consists of 35 items. Filling it in will take around 15 minutes.

177

A. Subsequent pregnancy desire

178

[1] Have you attempted to get pregnant after your identical twin pregnancy? Yes (Proceed to question 4)

180




No (Proceed to question 2)

SC




M AN U

179

RI PT

172 173

181

[2] Is there any relationship between a problem in your previous identical twin pregnancy

182

or its outcome and the fact that you have not attempted a new pregnancy?


Yes (Proceed to question 3)

184




No (Proceed to question 22)

187

188

EP

186

[3] Are you willing to summarize the reason why you haven't attempted a new pregnancy?

AC C

185

TE D

183

189

(Proceed to question 22)

190

[4] How much time was there between the delivery of the identical twins and a new

191

attempt to get pregnant?

16

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Months

192 193

[5] Have you been pregnant since your previous identical twin pregnancy?

195




Yes

196




No

RI PT

194

[6] How much time was there between the delivery of the twins and the delivery of the

198

following pregnancy? Months

M AN U

199

SC

197

200

B. Later pregnancy outcomes

202

We would like to investigate whether there were any problems or complications during one

203

of these later pregnancies. We would like you to answer the following questions separately

204

for the first three pregnancies after the previous identical twin pregnancy was detected.

205

[7] Was it a singleton, twin or triplet?

EP

TE D

201

Twin

Triplet

Not applicable

AC C

Singleton

First pregnancy after identical

twin pregnancy Second pregnancy after

17

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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identical twin pregnancy Third pregnancy

RI PT

after identical twin pregnancy 206

[8] What was the estimated gestational age at the moment of delivery? (the normal

208

gestational age is 40 weeks)

M AN U

SC

207

Miscarriage 20-24

24-28

28-36

>37

Not

weeks

weeks

weeks

weeks

applicable

or loss prior to 20

TE D

weeks of pregnancy

after the identical

AC C

twins

EP

First pregnancy

Second pregnancy after the identical twins Third pregnancy after the identical

18

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

ACCEPTED MANUSCRIPT

twins 209

[9] The delivery was Vaginal

Caesarean delivery

First pregnancy

SC

after the

Not applicable

RI PT

210

identical twins

M AN U

Second pregnancy after the identical

TE D

twins Third pregnancy after the

EP

identical twins

AC C

211

212

[10] What was the birth weight of your child in grammes? Please fill in 0 when not

213

applicable.

Weight (in

Weight (in case of

Weight (in case of

grammes)

twins, in grammes)

triplets, in grammes)

First pregnancy after the

19

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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identical twins Second pregnancy after the identical twins

the identical twins 214

215

[11] Was there any congenital anomaly/malformation? No

M AN U

Yes First pregnancy after the

after the

Third

AC C

identical twins

EP

pregnancy

Not applicable

TE D

identical twins Second

SC

RI PT

Third pregnancy after

pregnancy after the

identical twins 216

[12] If so, what kind of anomaly?

217 20

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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218

219

220

RI PT

221

[13] Were there any problems or complications during your pregnancy after your

223

pregnancy with identical twins? Vaginal

Placenta

High blood

Gestational

problems or

bleeding

problems

pressure/pre-

diabetes

complications

during

identical twins Second pregnancy

eclampsia

EP

after the

applicable

AC C

pregnancy

Others Not

TE D

pregnancy

M AN U

There were no

your

First

SC

222

after the identical twins

21

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

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Third pregnancy after the identical

RI PT

twins 224

[14] If you marked “others” in the previous question, please specify:

SC

225

M AN U

226 227

228

TE D

229

230

233

234

235

AC C

232

EP

231

236

[15] Were there any problems/complications during labor or delivery after your pregnancy

237

with identical twins?

22

Reproductive outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome – Vergote S. et al.

ACCEPTED MANUSCRIPT

There were no

The

Labor

Excessive

Problems

problems or

water

occurred too

blood loss

with the

complications

broke

early (before

during

uterine scar

during labor or

too early

8 months/37

delivery

in case of an

delivery

(more

weeks)

delivery

SC

before

M AN U

labor) First pregnancy after the

identical twins

EP

after the

AC C

pregnancy

TE D

identical

Second

earlier

caesarean

hours

twins

applicable

RI PT

than 24

Other Not

Third pregnancy after the

23

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ACCEPTED MANUSCRIPT

identical twins 238

[16] If you marked “others” in the previous question, please specify:

RI PT

239

240

SC

241

M AN U

242

[17] May we contact your gynecologist to provide us detailed information about these

244

problems?

245




Yes

246




No

248

[18] Could you please give us the name and address of your gynecologist?


Name :

EP

247




251

252

AC C

249

250

TE D

243

Address :




Telephone number :




Email address :

253

254

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255

256

[19] Did you get pregnant spontaneously, i.e. without medical help? Yes

No

RI PT

First pregnancy after the

SC

identical twins Second

M AN U

pregnancy after the identical twins

identical twins

EP

257

TE D

Third pregnancy after the

Not applicable

[20] If there were fertility problems, did these exist before the pregnancy of the identical

259

twins?

260




261




262

AC C

258

Yes No

[21] What type of assisted reproduction techniques did you require?

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Medication

Artificial

IVF (In Vitro

Use of

Not

to stimulate

insemination

Fertilization)/ ICSI

donor sperm applicable

ovulation

(using own

(Intracytoplasmic

and/or

sperm)

sperm injection)

female egg

RI PT

(oocyte).

First pregnancy

SC

after the identical twins

M AN U

Second pregnancy after the identical twins

TE D

Third pregnancy after the identical twins

EP

263

C. Psychological impact

265

[22] Have you had any psychological or emotional problems related to complications

266

during the pregnancy of the identical twins or the pregnancy outcome?

AC C

264

267




Yes

268




No

269

[23] If so, could you please describe them?

26

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270

271

272

RI PT

273

274

SC

275

D. Gynecological problems

277

[24] Did you have abnormal menstruations after you delivered the baby/babies of your

278

identical twin pregnancy?


Yes

280




No

TE D

279

M AN U

276

[25] If so, how many months after you delivered of the baby/babies of your identical twin

282

pregnancy did this problem start?

284

Months

AC C

283

EP

281

285

[26] What was the cause of this bleeding according to your gynecologist or general

286

practitioner?

287

288

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[27] Did you have a lot of lower abdominal pain after you delivered the baby/babies of

290

your identical twin pregnancy?

291




Yes

292




No

RI PT

289

293

[28] If so, how many months after you delivered the baby/babies of your identical twin

294

pregnancy did this pain start?

SC

Months

295

[29] What was the cause of this pain according to your gynecologist or general

297

practitioner?

M AN U

296

298

TE D

299

300

[30] Did you have any other gynecological problem since you delivered the baby/babies of

302

your identical twin pregnancy?


304




Yes

AC C

303

EP

301

No

305

[31] How many months after you delivered the baby/babies of your identical twin

306

pregnancy did these problems start?

307

Months

308

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309

[32] Which problem occurred and what was the cause according to your gynecologist or

310

general practitioner?

311

RI PT

312

313

[33] May we contact your gynecologist to provide us detailed information about these

315

problems?


Yes

317




No

M AN U

316

SC

314

[34] Could you please give us the name and address of your gynecologist or general

319

practitioner?

320




Name :




Address :

TE D

318

323

324




325 326




AC C

322

EP

321

Telephone number :

Email address :

327

328 29

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E. Others

330

[35] If you experienced other medical problems after your identical twin pregnancy or if

331

you have any other remarks regarding this questionnaire, please write these in the box

332

below:

RI PT

329

333

SC

334 335

M AN U

336

337

TE D EP

339

Thank you very much for your participation.

AC C

338

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Appendix 3: Other psychological and emotional problems Cases (6):

342

- Emotional pregnancy

343

- Emotional period after operation

344

- Feelings of emptiness

345

- Loss of energy

346

- Not specified

347

- Care for survivor

348

Controls (12):

349

- Hard time taking care for twins (3)

350

- Emotional period after pregnancy (3)

351

- Emotional pregnancy, exhausted

352

- Hard to process that twins were premature

353

- Burn out, care for twins

354

- Unplanned pregnancy, divorce

355

- Missed career opportunity due to care for twins

356

- Exhausted, nervous

SC M AN U

TE D

EP

AC C

357

RI PT

340 341

31