Presence of intrauterine fluid in women with a large niche is not associated with a difference in endometrial thickness

A long-term complication of a Cesarean section (CS) is a Ce- sarean scar defect, or uterine niche. Over 60% of women develop a niche, and 24% of these women have a large niche (1). A niche can cause gynecological symptoms such as dysmenorrhea and spotting ( 2). Furthermore, a niche may have a negative impact on fertility. Poor outcomes in fertility treatments after CS is a concern. Women with a previous CS have a lower ‘live birth rate’ in in vitro fertilization or intracytoplasmic sperm injec- tion cycles than the women who deliver vaginally (3). In addi- tion, women with a niche have a signi ficantly lower pregnancy rate than the women without a niche; 37.5% vs. 47.6% (4). The low pregnancy rate despite equal embryo qual- ity suggests that embryo implantation may be compromised. Successful implantation of the embryo requires a recep- tive endometrium and an attachment of the embryo. Previ- ous studies show that intrauterine fluid (IUF) because of a hydrosalpinx reduces reproductive outcomes signi ficantly by affecting the thickness and composition of the endome- trium (5). A thinner endometrium is associated with reduced reproductive outcomes after in vitro fertilization or intracy- toplasmic sperm injection ( 6). As 46% of niches are associ- ated with IUF ( 2), we hypothesized that niche-related –IUF compromises the endometrial thickness and could be an in- termediate factor for the negative impact of a niche on fertility. STUDY DESIGN A prospective cohort study was performed in the Amsterdam University Medical Center (medical ethics committee numbers: 2011.297, 2018.009). All women with a large niche, defined as a residual myometrial thickness (RMT) of <3m m or an RMT <50% of the adjacent myometrial thickness, reg- ular menstrual cycle, and unexplained infertility (as de fined by the World Health Organization), who visited our out-patient clinic between 2011 and 2021 were included. Exclusion criteria were as follows: use of medication likely to influence endometrial thickness; hydrosalpinx; or intraca- vitary irregularities. During the first consultation, baseline characteristics were recorded and participants were examined by transvaginal ul- trasound performed by experienced gynecologists. Before analysis, all measurements were veri fied by reviewing the recorded sonographic evaluations by 2 researchers (S.K.M. and B.P.). If required, a third person (J.H.) was consulted and disagreements were discussed until consensus was reached. The niche was measured according to the niche measurements guideline (1). Double endometrial thickness was measured in the midsagittal plane, as the maximum distance between the 2 interfaces of endometrial–myometrial junction. The presence of adenomyosis was scored based on the Morphological Uterus Sonographic Assessment (MUSA) criteria by van den Bosch (7). When IUF was present, thickness of anterior and posterior wall endometrium was measured thereby excluding the IUF. Women with a niche and infertility were divided into 2 groups based on the presence of IUF, de fined as fluid in the uterine cavity independent of the presence of fluid located in the niche ( Fig. 1 A and B). The outcome of this study was endometrial development as measured by endometrial thickness. For statistical analysis, IBM SPSS Statistics v.26 (2019) was used. Tests were performed 2-sided and were considered statistically significant with P< .05. A linear regression anal- ysis, with adjustment for the day of the menstrual cycle, dura- tion of infertility, and RMT was performed.

A total of 141 women met the inclusion criteria. Table 1 pre- sents the baseline characteristics of 103 (73%) women without and 38 (27%) women with IUF. Baseline characteristics of both groups were comparable except for RMT and duration of infertility. The duration of infertility in the group with IUF was significantly longer; 27 months (interquartile ranges [IQRs], 19 –42) vs. 24 months (IQR, 16 –36), P¼ .02. The vol- umes of the niches were comparable in both groups. No statistically signi ficant difference in thickness of the endometrium was found between the 2 groups. The median endometrial thickness of women without IUF was 6.6 mm (IQRs, 4.5 –9.0) compared with 6.0 mm (IQRs, 4.5 –8.1) in the group with IUF, P¼ .25 (Fig. 1C). Additional linear regression analysis with adjustment, found no signi ficant relation be- tween IUF and endometrial thickness neither ( b 0.96, P¼ .53). A sub analysis of women in the luteal phase (n ¼ 62) showed a similar trend, the median endometrial thickness of women without IUF was 7.8 mm (IQR, 5.7 –10.2) compared with 7.1 mm (IQR, 4.8 –9.5), P¼ .46 (Fig. 1D). Overall, the presences of adenomyosis was not signi fi- cantly different between the groups, except for fan-shaped shadowing, which was more pronounced in the group without IUF ( Table 1 ). Possibly the presence of more pronounced fibrosis or IUF masks the typical shadowing, as there was no difference in translesional vascularity and other adeno- myosis features.

The presence of IUF in women with a niche was not associated with a signi ficant difference in endometrial thickness. How- ever, we noted a longer duration of infertility at baseline in women with a niche when IUF was present. Prospective studies of endometrial cellular composition, secretome and function as well as differences in uterine microbiome and S.J.M.K.M. has nothing to disclose. B.P. has nothing to disclose. J.V. has nothing to disclose. R.A.d.L. has nothing to disclose. E.D.P.U. has nothin g to disclose. J.A.F.H. has nothing to disclose. 322 VOL. 119 NO. 2 / FEBRUARY 2023 RESEARCH LETTER adenomyosis features in women with a large niche in relation to reproductive outcome are underway, to shed more light on niche related infertility, especially when IUF is present. Saskia J.M. Klein Meuleman, M.D. a,b Britt Post, M.D. a Jolijn Vissers, M.D. a,b Robert A. de Leeuw, M.D., Ph.D. a,b Emiel D. Post Uiterweer, M.D., Ph.D. a,c Judith A.F. Huirne, M.D., Ph.D. a,b,* a Department of Obstetrics and Gynaecology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; b Amsterdam Reproduction and Development, Amsterdam, the Netherlands; and c Department of Obstetrics and Gynaecology, University Medical Center Utrecht, Utrecht, the Netherlands *Correspondence to: Judith A.F. Huirne, M.D., Ph.D., Department of Obstetrics and Gynaecology, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail address: [email protected] https://doi.org/10.1016/j.fertnstert.2022.11.004

1. Jordans IPM, de Leeuw RA, Stegwee SI, Amso NN, Barri-Soldevila PN, van den Bosch T, et al. Sonographic examination of uterine niche in non-pregnant women: a modi fied Delphi procedure. Ultrasound Obstet Gynecol 2019;53: 107–15. 2. Vervoort A, Vissers J, Hehenkamp W, Br€olmann H, Huirne J. The effect of lapa- roscopic resection of large niches in the uterine caesarean scar on symptoms, ultrasound findings and quality of life: a prospective cohort study. BJOG 2018;125:317–25. 3. Vissers J, Sluckin TC, van Driel-Delprat CCR, Schats R, Groot CJM, Lambalk CB, et al. Reduced pregnancy and live birth rates after in vitro fertil- ization in women with previous Caesarean section: a retrospective cohort study. Hum Reprod 2020;35:595 –604. 4. Wang L, Wang J, Lu N, Liu J, Diao F. Pregnancy and perinatal outcomes of pa- tients with prior Cesarean section after a single embryo transfer in IVF/ICSI: a retrospective cohort study. Front Endocrinol (Lausanne) 2022;13:851213 . 5. Sapmaz T, G €undo/C21gdu LS, Cetin MT, Urunsak IF, Polat S. The ultrastruc- tural effects of surgical treatment of hydrosalpinx on the human endome- trium: a light and electron microscopic study. Ultrastruct Pathol 2019;43: 99–109. 6. Gao G, Cui X, Li S, Ding P, Zhang S, Zhang Y. Endometrial thickness and IVF cycle outcomes: a meta-analysis. Reprod Biomed Online 2020;40:124 –33. 7. Van den Bosch T, de Bruijn AM, de Leeuw RA, Dueholm M, Exacoustos C, Valentin L, et al. Sonographic classi fication and reporting system for diag- nosing adenomyosis. Ultrasound Obstet Gynecol 2019;53:576 –82. VOL. 119 NO. 2 / FEBRUARY 2023 323 Fertility and Sterility® FIGURE 1 (A) Image of a uterus with a niche and intrauterine fluid in midsagittal plane using transvaginal ultrasound. (B) Schematic image of the uterus with a niche and intrauterine fluid in (a), with n ¼ uterine niche (C) Distribution of endometrial thickness in women without intrauterine fluid ( blue triangles) and women with intrauterine fluid ( green dots ). ( D) Median endometrial thickness in women without intrauterine fluid ( blue) and women with intrauterine fluid (green) during the luteal phase. Klein Meuleman. Niche related intrauterine fluid. Fertil Steril 2022. 324 VOL. 119 NO. 2 / FEBRUARY 2023 RESEARCH LETTER TABLE 1 Baseline characteristics Without intrauterine fluid (n [ 103) With intrauterine fluid (n [ 38) P value Mean age (y) 34.15 (32.64 –37.11) 34.57 (32.44 –37.01) 0.71 BMI (kg/m2) 24.39 (21.78 –27.46) 25.18 (22.16 –29.39) 0.30 Smoking (n (%)) (n ¼ 101)5 (4.95) (n ¼ 36)4 (11.11) 0.24 Number of CS 1.17 /C6 0.45 1.16 /C6 0.44 0.74 Number of miscarriages 0.50 /C6 1.06 0.79 /C6 1.32 0.16 Duration of infertility (m) 24.00 (16 –36) 27.00 (19 –42) 0.02 Cycle day 14.00 (8.0 –18.00) 11.00 (7.0 –20.0) 0.43 Position of uterus (%) 0.08 AvF 43 (41.7) 22 (57.9) RvF 34 (33.0) 7 (18.4) Stretched 11 (10.7) 7 (18.4) Extreme RvF 15 (14.6) 2 (5.3) Niche volume (mm 3)( n ¼ 97) (n ¼ 38) 0.95 353.40 (192.65–861.99) 268.46 (165.40 –556.19) RMT (mm) 1.0 (0.1 –1.5) 1.50 (0.88 –2.13) 0.01 Any MUSA criterion for adenomyosis present (n ¼ 75) 40 (53.3) (n ¼ 26) 17 (65.4) 0.29 Interrupted junctional zone present, n( % ) (n ¼ 75) 8 (10.7) (n ¼ 26) 2 (7.7) 0.50 Irregular junctional zone present, n( % ) (n ¼ 75) 15 (20.0) (n ¼ 26) 3 (11.5) 0.26 Sub endometrial lines and buds present, n (%) (n ¼ 75) 18 (24.0) (n ¼ 26) 3 (11.5) 0.14 Translesional vascularity present, n( % ) (n ¼ 75) 21 (28.0) (n ¼ 26) 6 (23.1) 0.63 Fan-shaped shadowing present, n( % ) (n ¼ 75) 15 (20.0) (n ¼ 26) 1 (3.8) 0.04 Hyperechoic islands present, n (%) (n ¼ 75) 25 (33.3) (n ¼ 26) 6 (23.1) 0.33 Cysts in myometrium present, n (%) (n ¼ 75) 10 (13.3) (n ¼ 26) 5 (19.2) 0.33 Asymmetrical thickening of myometrium present, n (%) (n ¼ 75) 15 (20.0) (n ¼ 26) 7 (26.9) 0.46 Note: Data are presented as mean (/C6 SD) or median (interquartile range) or counts (%). BMI ¼ body mass index, AvF ¼ anteverted flexed, MUSA ¼ Morphological Uterus Sonographic Assessment, RvF¼ retroverted flexed, RMT ¼ residual myometrial thickness Klein Meuleman. Niche related intrauterine fluid. Fertil Steril 2022. VOL. 119 NO. 2 / FEBRUARY 2023 325 Fertility and Sterility®