# Uterine volume assay after gonadotoxic therapies in childhood, adolescence, and young adulthood: A systematic review and Bayesian network meta-analysis

Eloïse Fraison, Stephanie Huberlant, Mathilde Cavalieri, Aurore Gueniffey, Justine Riss, Christine Rousset-Jablonski, Blandine Courbiere

<figure><img src="image_1.png" /></figure>

## To cite this version:

Eloïse Fraison, Stephanie Huberlant, Mathilde Cavalieri, Aurore Gueniffey, Justine Riss, et al. Uterine volume assay after gonadotoxic therapies in childhood, adolescence, and young adulthood: A systematic review and Bayesian network meta-analysis. Acta Obstetricia et Gynecologica Scandinavica, 2025, 104 (9), pp.1616-1626. 10.1111/aogs.70003. hal-05136395

HAL Id: hal-05136395

https://hal.science/hal-05136395v1

Submitted on 18 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Uterine volume assay after gonadotoxic therapies in childhood, adolescence, and young adulthood: A systematic review and Bayesian network meta-analysis

Eloïse Fraison<fnref n="1" />,<fnref n="2" />,<fnref n="3" /> ID
Justine Riss<fnref n="8" />

Stephanie Huberlant<fnref n="4" />,<fnref n="5" />
Christine Rousset-Jablonski<fnref n="9" />,<fnref n="10" />,<fnref n="11" />

Mathilde Cavalieri<fnref n="6" />
Blandine Courbiere<fnref n="12" />,<fnref n="13" />

Aurore Gueniffey<fnref n="7" />

## Abstract

**Introduction:** Uterine damage after pelvic radiotherapy or total-body irradiation is well described, with decreased uterine volume and high obstetrical morbidity. Some recent studies have reported a smaller uterus in child, adolescent, and young adult cancer survivors treated with chemotherapy only. This systematic review investigated the long-term effects of gonadotoxic therapy on uterine volume during childhood, adolescence, and young adulthood.

**Material and Methods:** Data sources were Medline, Embase, and the Cochrane Library databases from 1990 to April 2023 searched using the following search terms: cancer survivors, bone marrow transplantation, chemotherapy, radiotherapy, and uterine volume. Study selection and synthesis: Only comparative studies reporting uterine volume in adult women who had received chemotherapy and/or radiotherapy during childhood, adolescence, or young adulthood (<25 years) were included. Two independent reviewers performed study selection, bias assessment using the ROBINS-I tool, and data extraction. The main outcome was uterine volume (mL). A Bayesian network meta-analysis with meta-regression for parity and serious risk of bias was performed using a random-effects model.

**Results:** After reviewing 2847 abstracts, four studies were selected for the meta-analysis. Uterine volume data were available for 225 women after chemotherapy, 153 women after chemoradiotherapy, and 257 control women without cancer. Uterine volume was significantly lower in the chemoradiotherapy group than in the control group (-29.2 mL [-49.1, -12.5]). Uterine volume was significantly decreased in the chemoradiotherapy group compared to the chemotherapy group (-20.9 mL [-39.1, -0.3]).

**Abbreviations:** AYA, adolescents and young adults; CAYA, childhood, adolescence, and young adulthood; HSCT, hematopoietic stem cell transplantation; NMA, network meta-analysis; SUCRA, surface under the cumulative ranking curve.

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs License](https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2025 The Author(s). *Acta Obstetricia et Gynecologica Scandinavica* published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

<footnote n="1">¹Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital of Lyon, Lyon, France</footnote>

<footnote n="2">²UMR, CNRS 5558, Laboratory of Biometry and Evolutionary Biology (LBBE), Villeurbanne, France</footnote>

<footnote n="3">³Claude Bernard University, Lyon, France</footnote>

<footnote n="4">⁴Department of Gynaecology-Obstetric and Reproductive Medicine, University Hospital of Nimes, Nimes, France</footnote>

<footnote n="5">⁵IBMM, CNRS, ENSCM, Polymers for Health and Biomaterials, University of Montpellier, Montpellier, France</footnote>

<footnote n="6">⁶Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital François Mitterrand, Dijon, France</footnote>

<footnote n="7">⁷Clinique Belledonne, Saint-Martin-d'Hères, France</footnote>

<footnote n="8">⁸Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital of Strasbourg, Strasbourg, France</footnote>

<footnote n="9">⁹Oncology and Surgery Department, Centre Léon Bérard, Lyon, France</footnote>

<footnote n="10">¹⁰Department of Gynecology-Obstetric, Hôpital Femme Mère Enfant, Bron, France</footnote>

<footnote n="11">¹¹EA 7425 HESPER- Health Services and Performance Research, University of Lyon, Lyon, France</footnote>

<footnote n="12">¹²Department of Gynecology-Obstetric and Reproductive Medicine, AP-HM, Hôpital La Conception, Marseille, France</footnote>

<footnote n="13">¹³IMBE, Aix-Marseille Univ, Avignon Univ, CNRS, IRD, Marseille, France</footnote>
**Correspondence**

Eloïse Fraison, Department of
Gynaecology-Obstetric and Reproductive
Medicine, University Hospital of Lyon, 69
boulevard Pinel 69500, Bron, France.

Email: eloise.fraison@chu-lyon.fr

**Funding information**

Gedeon Richter France

The difference in the mean uterine volume between the control and chemotherapy groups was 8.2mL [-11.8, 34.2] and was not significant.

**Conclusions:** Our meta-analysis confirms the well-known data on chemoradiotherapy-induced uterine damage. Although some studies have suggested the potential impact of high doses of chemotherapy on uterine volume, this meta-analysis did not find any significant decrease in uterine volume after chemotherapy. This result could help counsel age-reproductive women and physicians who perform assisted reproductive technologies in long-term CAYA Cancer survivors.

**KEYWORDS**

cancer survivor, CAYA, chemotherapy, meta-analysis, radiotherapy, systematic review, uterine volume

# 1 | INTRODUCTION

Uterine damage has already been well described after pelvic radiotherapy or total-body irradiation, independently of ovarian effects. The consequences are decreased uterine volume, damage to the endometrial architecture, and impairment of uterine vascularization, leading to higher obstetrical morbidity.¹ Recent studies have suggested that chemotherapy alone in adolescents and young adults (AYA) may also be responsible for uterine damage. Indeed, Van de Loo et al. observed that uterine volume was significantly smaller in a group of childhood cancer survivor women exposed to chemotherapy compared to healthy women (odds ratio [OR] 2.61, 95% confidence interval [CI], 1.15–5.91).² In a population of women treated during childhood with hematopoietic stem cells transplantation (HSCT), Beneventi et al. reported that uterine volume was significantly reduced by 81.9% (95% CI, 71.8–87.8) after total-body irradiation and by 67.4% (95% CI, 58.5–75.6) after a conditioning regimen with a high dose of alkylating agents.³ Courbiere et al. observed similar results after HSCT with a significant uterine volume reduction of 43.1% (28.8–57.4) after alkylating agent-based conditioning compared to a control group of healthy women.⁴ Many hypotheses could explain the pathophysiology of reduced uterine volume after chemotherapy; however, none have been confirmed as of yet. These include fibrotic damage induced by high-dose chemotherapy,⁵ the impact of hormonal deprivation around puberty, and a lack of compliance with hormonal replacement therapy.⁶ Importantly, the reduced uterine volume could be responsible for adverse pregnancy outcomes, such as spontaneous abortion, preterm birth, low birth weight, or small for gestation age birth.¹

The objective of this systematic review and meta-analysis was to assess the long-term impact of exposure to gonadotoxic therapies during childhood, adolescence, and young adulthood (CAYA) on uterine volume.

**Key message**

Recent studies have suggested the potential impact of high doses of chemotherapy on uterine volume, but this meta-analysis did not find any significant decrease in uterine volume after chemotherapy.

# 2 | MATERIAL AND METHODS

## 2.1 | Eligibility criteria, information sources, and search strategy

The study protocol was prospectively registered in PROSPERO (CRD42023440219), and the reporting of this systematic review and meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analysis (PRISMA-NMA) guidelines. We only included comparative studies published as full-text papers involving female cancer survivors or women who underwent HSCT, were aged over 18 years, and had received chemotherapy and/or radiotherapy during childhood (<15 years), adolescence, or young adulthood (15–25 years). Studies were included if they reported uterine volume and compared two or more of the following groups: chemotherapy alone, radiotherapy, chemoradiotherapy, and controls. Radiotherapy was defined as total-body or pelvic irradiation. We excluded animal studies, as well as studies involving women treated for cancer or receiving HSCT after the age of 25 years, displaying results only for age, or with a median age exceeding 20 years. Additionally, studies that included radical trachelectomy only for cervical cancer, anticancer treatments involving hysterectomy, or chemotherapy for gestational trophoblastic neoplasia were excluded.
Uterine volume was defined as the volume of the uterus assessed using abdominal or pelvic ultrasonography or magnetic resonance imaging (MRI).

The Cochrane Library, Embase, and PubMed databases were searched from inception until April 30, 2023. The search was limited to articles published in English or French. We used a combination of Medical Subject Heading terms and text words, including "cancer survivors," "bone marrow transplantation," "chemotherapy," "radiotherapy," and "uterine volume." The full search strategy for each database is described in detail in the appendix. Relevant reviews identified in the search were screened to identify additional relevant citations (Supporting Information Appendix S1).

## 2.2 | Study selection

Two independent reviewers conducted the initial screening of the titles and abstracts of all articles without information on the authors, institutions, journal titles, and study results. The full texts of the potentially relevant articles were independently retrieved and assessed for inclusion by two reviewers. The reasons for the exclusion of ineligible studies were documented. Methodological validity was also assessed before inclusion in the review using the adapted Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies.⁷ Any discrepancies or uncertainties were resolved through discussions among the reviewers to reach a consensus.

## 2.3 | Data extraction

Pairs of reviewers independently extracted data from the included articles using a data-extraction form designed by the authors. The following details were collected for all included studies: country, study design, study type, inclusion and exclusion criteria, study period, cancer and therapy characteristics, age at main therapy, follow-up duration, age at examination, parity, comorbidities, and outcomes.

For articles published after 2013 that included women under the age of 25 years, the authors of the original studies were contacted to collect any pertinent missing data if the primary outcome was reported overall but not specifically for each treatment group.

## 2.4 | Assessment of risk of bias

Two independent reviewers assessed the methodological quality of the selected studies. The risk of bias was assessed using the ROBINS-I tool.⁸

## 2.5 | Data analysis

Box-Cox, quantile estimation, and method for unknown non-normal distribution (MLN) approaches were used to estimate the

sample mean and standard deviation (SD) when not documented in an article.⁹,¹⁰ No other replacements for missing data were performed.

A Bayesian NMA was performed to quantify the relative association of each therapy with uterine volume adjusted for parity, assuming similarity and transitivity.¹¹ Articles with uterine volume documented by parity were split into nulliparous and parous and were considered independent articles in the NMA. However, if the results for a given therapy were reported in several groups (other than parity), then only the group with the highest number of subjects was included in the NMA (e.g., Ref. [3]). Convergence was assessed using Gelman-Rubin diagnostic statistics, plots, and autocorrelation plots.¹² After generating the network geometry, local inconsistency was estimated by comparing the direct and indirect evidence using the node-splitting method. Heterogeneity and global inconsistencies were assessed using the Q-test and I² statistic.¹¹ To better control for heterogeneity across studies, random-effect models were used under the assumption of consistency.

The relative effect size was presented as the difference in means (MD) with 95% credible intervals.

Model fit was assessed using the overall residual deviance (Dbar) and leverage plots. Dbar plots were used to detect outliers.

Therapies were ranked using the surface under the cumulative ranking curve (SUCRA).¹³ Funnel plots could not be used to evaluate publication bias because only a few studies were included in the NMA.

In the second step, because the intensity of the relative association of each therapy with uterine volume possibly varied with parity, a frequentist NMA was performed independently in parous and nulliparous women. The relative effect size was presented as MD with 95% CI.

Heterogeneity and global inconsistencies were assessed using the Q statistic, tau², and I². Direct and indirect evidence were split using a back-calculation method and compared.

Sensitivity analyses were performed using the mean and SD estimates of each approach, fixed-effects models, exclusion of possible outliers, and exclusion of articles with a serious risk of bias.

Statistical analyses were performed using R (version 4.3.2), the R package estmeansd (version 1.0.1) to derive estimations of means and SD not documented in articles, bnma (version 1.6.0) using the Markov Chain Monte Carlo engine JAGS (version 4.2) for Bayesian NMA, and netmeta (version 2.9.0) for frequentist NMA.⁹,¹⁴,¹⁵

The quality of evidence for each outcome was determined through the grading of recommendations, assessment, development, and evaluation working group methodology.

## 3 | RESULTS

Our search strategy revealed 2847 reports, of which 519 were duplicates. After screening the titles and abstracts, 158 reports were
<figure><img src="image_3.png" /><figcaption>FIGURE 1 PRISMA flow diagram of study selection.</figcaption></figure>

potentially eligible and retrieved in full text (Figure 1). Four articles were included in this meta-analysis.²⁻⁴,¹⁶ Uterine volume was assessed using ultrasonography in three articles and MRI in one article. All studies were published in English, and their main characteristics are summarized in Table 1 (Table S1 for excluded studies).

Most studies were classified as having a low-to-moderate risk of bias. Two studies had a moderate risk of participant selection bias owing to a lack of detailed information about the patient selection process.²,³ For intervention classification, two studies had a moderate risk of bias because the chemotherapy protocols lacked sufficient detail.²,¹⁶ Regarding deviation from the intervention, one article was classified as having a moderate risk of bias because the

description of the intervention was not clear.² For missing data, one study was classified as having a moderate risk of bias because the number of patients differed between the table and text.

## 3.1 | Synthesis of the results

### 3.1.1 | Results using the Bayesian method, including parity as a covariate

Uterine volume data were available for 225 women after chemotherapy, 153 women after chemoradiotherapy, and 257 women
<table><caption>TABLE 1 Main characteristics of studies included in the systematic review and network meta-analysis.</caption><thead><tr><th>First author, year</th><th>Country</th><th>Type of study</th><th>Study design</th><th>Study population</th><th>Study control</th><th>Recruitment period</th></tr></thead><tbody><tr><td>Larsen, 2004</td><td>Denmark</td><td>Cohort study</td><td>Prospective</td><td>Inclusion/exclusion criteria: female survivors diagnosed and treated for a noncentral nervous system childhood cancer (malignant hematologic disease, solid tumor); ≤15 years old at the time of diagnosis, treated with radiotherapy and/or chemotherapy; off treatment for at least 1 year at study inclusion; in complete remission, ≥ 18 years old at study inclusion.<br>Exclusion criteria: lost to follow-up, previous hysterectomy, institutionalized mental disorders</td><td>No healthy control group for this study. The chemotherapy group was compared to the chemoradiotherapy one.</td><td>Treatment: January 1970–December 1996</td></tr><tr><td>Beneventi, 2015</td><td>Italie</td><td>Matched exposed/ non-exposed</td><td>Prospective</td><td>Inclusion criteria: women survivors of childhood malignancies and patients who have received SCT for thalassemia major or sickle cell anaemia.<br>Exclusion criteria: N/A</td><td>Controls were healthy volunteers of similar age as the cases who were recruited among women attending a cytologic screening and human papillomavirus vaccination center of our department.</td><td>Treatment: 1984–2011<br>Assessment: January 2010–December 2012</td></tr><tr><td>Courbiere, 2023</td><td>France</td><td>Cohorte study</td><td>Prospective</td><td>Inclusion criteria: women &gt;18 years old participating in the LEA cohort; those who underwent HSCT during childhood or adolescence for acute leukemia and after an MAC regimen including either TBI or an alkylating agent-based regimen; who agreed with undergoing pelvic magnetic resonance imaging (MRI) to assess their uterine volume.<br>Exclusion criteria: N/A</td><td>Inclusion criteria: women enrolled in the radiology department of the principal investigator for pelvic MRI during the study period, aged between 18 and 40 years, without any uterine pathology who underwent pelvic MRI during the study period.<br>Exclusion criteria: controls were excluded in case of uterine pathology, such as adenomyosis or fibroids</td><td>November 2017–June 2021</td></tr><tr><td>van de Loo, 2019</td><td>The Netherlands</td><td>Cohort study</td><td>Retrospective</td><td>Inclusion criteria: adult women treated for a cancer before the age of 18 years who survived for at least five years after diagnosis and were at least 18 years old at study entry with two inclusion criteria:<ul><li>they had a transvaginal ultrasound scan performed and a blood sample taken</li><li>their former childhood cancer treatment included external beam RT to a field that certainly (total-body irradiation and pelvic RT) or most likely (low-abdominal and lower spinal RT) involved part of the uterus</li></ul>Exclusion criteria:<ul><li>Childhood cancer survivors without a uterus or with uterine fibroids</li><li>Childhood cancer survivors without ultrasonographic data not stored</li></ul></td><td>Controls were women from the general population invited through their general practitioners, all of whom had a blood sample taken and a transvaginal ultrasound scan performed as part of the DCOG LATER-VEVO study.</td><td>Treatment: 1963 and 2002<br>Assessment: January 2008–July 2014</td></tr></tbody></table>
<figure><img src="image_4.png" /><figcaption>FIGURE 2 Uterine volume: Bayesian NMA Forest plot, with parity as a dummy variable (mL).</figcaption></figure>

without cancer (controls). The results with random and fixed effects
were similar; therefore, only random results were presented.

Uterine volume was significantly lower in the chemoradiother-
apy group than in the control group (-29.2 mL [-49.1 to -12.5]) and
compared to the chemotherapy group (-20.9 mL [-39.1 to -0.3]).
The MD in uterine volume between the control and chemotherapy
groups was 8.2 mL [-11.8-34.2] and not significant (Figure 2). The
results were similar after the exclusion of outliers—e.g., the control
group in the study by Van de Loo et al. and the parous chemotherapy
group in the study by Courbiere et al. reinforcing the same differ-
ences and trends (Figures 3 and 4).

SUCRA for the control, chemotherapy, and chemoradiother-
apy groups were 0.91, 0.57, and 0.01, respectively (Table 2). One
study did not display data by parity (n = 165), had a serious risk
of bias, and was excluded from the sensitivity analysis. SUCRA
showed the same ranking, and sensitivity analyses led to the same
conclusions.

<figure><img src="image_5.png" /><figcaption>FIGURE 3 Uterine volume: Bayesian NMA network graph after the exclusion of outliers (mL).</figcaption></figure>

3.1.2 | Results according to parity

Only three studies reported results according to parity, including
387 nulliparous and 103 parous women.

In nulliparous women, NMA showed moderate heterogeneity
or inconsistency (τ² = 72.6, I² = 51.6% [0%; 84%]). There was no sig-
nificant difference in uterine volume between the chemotherapy
and control groups (-2.4 mL; [-19.1-14.3]). The uterine volume in
the chemoradiotherapy group was significantly lower than in the

control group (-21.6 mL; [-39.5 to -3.7]) and the chemotherapy
group (-19.2 mL; [-31.6 to -6.7]) (Figures 5 and 6, Table 3).

SUCRA for the control, chemotherapy, and chemoradiotherapy
groups were 0.8, 0.7, and 0.006, respectively (Table 4).

In parous women, the NMA was performed and showed
high heterogeneity or inconsistency (τ² = 496.1, I² = 55.4% [0%;
85.2%]). There was no significant difference in uterine volume
<figure><img src="image_6.png" /><figcaption>FIGURE 4 Uterine volume: Bayesian NMA Forest plot, with parity as a dummy variable without outlier (mL).</figcaption></figure>

<table><caption>TABLE 2 Uterine volume, SUCRA, Bayesian (mL).</caption><thead><tr><td>Therapy</td><td>SUCRA (result)</td></tr></thead><tbody><tr><td>Treatment Chemotherapy</td><td>0.5723</td></tr><tr><td>Treatment control group</td><td>0.9144</td></tr><tr><td>Treatment Radio+Chemo</td><td>0.0132</td></tr></tbody></table>

Note: SUCRA: surface under the cumulative ranking distribution defined in Salanti et al. (2011). Order according to surface, with first rank corresponding to the highest surface.

between the chemotherapy and control groups (-16.9 mL; [-57.5-23.6]) and the chemoradiotherapy and control groups (-31.4 mL; [-71.9-9]). Moreover, in parous women, there was no significant difference between the chemoradiotherapy and the chemotherapy groups in uterine volume (-14.5 mL; [-47.3-18.3]) (Figures 7 and 8, Table 5).

SUCRA for the control, chemotherapy, and chemoradiotherapy groups were 0.81, 0.68, and 0.005, respectively (Table 4).

4 | DISCUSSION

In this meta-analysis, a significantly lower uterine volume was observed in the chemoradiotherapy group compared to the control group. However, no significant difference in uterine volume was observed between the chemotherapy and control groups, even after adjustment for parity.

The negative impact of chemoradiotherapy on the uterus is already well documented¹ and our results align with those reported in cohort studies of cancer survivors.²⁻⁴,¹⁶ However, recent studies have raised a negative impact of high-dose chemotherapy alone with a significant reduction of uterine volume.²⁻⁴ For instance, Courbiere et al. observed a significant decrease in uterine volume in a homogeneous cohort of acute leukemia female survivors exposed during childhood and adolescence to standardized conditioning regimens with high doses of alkylating agents.⁴ However, it remained difficult to determine whether the significant reduction in uterine volume observed with high-dose alkylating chemotherapy was due to the direct cytotoxicity of the alkylating agents themselves or whether it was an indirect consequence of chemotherapy-induced ovarian damage and subsequent hypoestrogenism. Van de Loo et al.'s study also reported that the uterine volume of nulliparous women exposed to chemotherapy was lower compared to the control groups, with a median of 48.1 mL (35.7-61.8 mL) versus 61.3 mL (49.1-75.5 mL). Nevertheless, after having corrected the analyses using the alkylating agent dose score, they did not observe a significant risk of having a small uterine volume in chemotherapy-exposed nulliparous childhood cancer survivors (1.34, 95% CI 0.52-3.70). Parous women also did not show differences between the exposed groups in the risk of having a small uterine volume (<63.1 mL). Notwithstanding, uterine volumes were 68.1 mL (47.3-84.9 mL) and 90.2 mL (66.6-106.4 mL) in the post-chemotherapy and control groups, respectively, and the threshold of 63.1 mL for defining a small uterus was an arbitrary
<figure><img src="image_7.png" /><figcaption>FIGURE 5 Uterine volume, Nulliparous: Forest plot of direct and indirect evidence and network (random effect, ref. = control group, mln estimates, frequentist NMA).</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>FIGURE 6 Uterine volume, Nulliparous: Forest plot of direct and indirect evidence and network (random effect, ref. = chemotherapy only, mln estimates, frequentist NMA).</figcaption></figure>

<table><caption>TABLE 3 Uterine volume in nulliparous: League table (mln estimates, fréquentiste NA, random-effects model).</caption><tr><td>Chemotherapy</td><td>-6.8 [-24.4; 10.8]</td><td>18.8 [6.4; 31.2]</td></tr><tr><td>Control Group</td><td>-2.4 [-19.1; 14.3]</td><td>16.0 [-4.6; 36.6]</td></tr><tr><td>Radiotherapy+Chemotherapy</td><td>19.2 [6.7; 31.6]</td><td>21.6 [3.7; 39.5]</td></tr></table>

Note: Data are difference in Means (MD) of UV with 2-sided 95% confidence interval. Pairwise comparisons of the therapy in the column versus the therapy in the row in the lower triangle and row versus column in the upper triangle. Estimates from network meta-analysis in the lower triangle and the direct treatment estimates from pairwise comparisons in the upper triangle.

<table><caption>TABLE 4 Uterine volume, SUCRA value (mln estimates, frequentist NMA).</caption><thead><tr><th rowspan="2">Therapy</th><th colspan="2">Random</th><th colspan="2">Common</th></tr><tr><th>Nulliparous</th><th>Parous</th><th>Nulliparous</th><th>Parous</th></tr></thead><tbody><tr><td>Control group</td><td>0.799</td><td>0.8125</td><td>0.892</td><td>0.8955</td></tr><tr><td>Chemotherapy</td><td>0.695</td><td>0.6830</td><td>0.608</td><td>0.6045</td></tr><tr><td>Radiotherapy+Chemotherapy</td><td>0.006</td><td>0.0045</td><td>0.000</td><td>0.0000</td></tr></tbody></table>

threshold. These results led us to perform our metanalysis, and we observed that when the data were pooled, no significant differences were found between the control and chemotherapy groups regarding uterine volume.

The major strength of our study was its rigorous methodology, with a strict selection of included studies. We only included studies

with a control group because the estimation of uterine volume can vary depending on the operator, imaging technique, and mathematical equations used. Therefore, volume data from cohort studies without a control group are likely to introduce excessive bias. The risk of assessment bias was determined by using the Cochrane ROBINS-I tool. Sensitivity analyses were performed when required.
<figure><img src="image_9.png" /><figcaption>FIGURE 7 Uterine volume, Parous: Forest plot of direct and indirect evidence and network (random effect, ref. = control group, MLN estimates, frequentist NMA).</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>FIGURE 8 Uterine volume, Parous: Forest plot of direct and indirect evidence and network (random effect, ref. = chemotherapy only, MLN estimates, frequentist NMA).</figcaption></figure>

<table><caption>TABLE 5 Uterine volume in parous: League table (mln estimates, fréquentiste NA, random-effects model).</caption><tr><td>Chemotherapy</td><td>-20.3 [-62.9; 22.4]</td><td>12.6 [-20.5; 45.6]</td></tr><tr><td>-16.9 [-57.5; 23.6]</td><td>Control group</td><td>24.7 [-18.6; 67.9]</td></tr><tr><td>14.5 [-18.3; 47.3]</td><td>31.4 [-9.0; 71.9]</td><td>Radiotherapy+Chemotherapy</td></tr></table>

Note: Data are difference in means (MD) of UV with 2-sided 95% confidence interval. Pairwise comparisons of the therapy in the column versus the therapy in the row in the lower triangle and row versus column in the upper triangle. Estimates from network meta-analysis in the lower triangle and the direct treatment estimates from pairwise comparisons in the upper triangle.

The study population was homogeneous in terms of age because we selected studies that focused on AYA.

However, this study has some limitations. First, the measurement of uterine volume was not homogeneous, as it was assessed through ultrasonography in three articles²,³,¹⁶ and through MRI in one.⁴ Only four articles could be included, which was sufficient to perform a meta-analysis. However, with this heterogeneity of measurement and the low number of included articles, the results should be interpreted with caution. Moreover, we had to adapt the results to those of other studies. Only Courbiere et al. presented the results using means, whereas the other three studies showed medians. Therefore, we had to convert the medians into means to be able to perform a meta-analysis. In some of the included articles, we had to divide the effectiveness to ascertain

the gonadotoxic treatment received in each group of patients. This division reduced the number of included patients in each group and, therefore, the strength of our study. Finally, regarding the comparison of the chemotherapy and control groups, only three publications had a specific group treated with chemotherapy alone that could be compared to healthy women, and the article by Van de Loo et al. held more weight than the others.²⁻⁴ In this study, female patients were treated for a primary malignancy before 18 years of age, and the included population was heterogeneous, with numerous types of cancer and chemotherapy regimens. Among them, 78% of the patients had been exposed to chemotherapy before menarche, and only 61% were exposed to alkylating agents. This heterogeneity of the main study included in the meta-analysis also led us to carefully interpret the results.
Finally, when we look at the results according to parity, the small sample size included in the subgroup analysis again did not allow for any definitive conclusion regarding the influence of chemotherapy on uterine volume.

## 5 | CONCLUSION

Our meta-analysis confirmed the well-known data on the damage caused by chemoradiotherapy to the uterus but did not find any significant impact of chemotherapy alone on uterine volume. Our results contradicted some recent studies that reported a reduction in uterine volume after high-dose chemotherapy. Sunguc et al. reported an increased risk of prematurity in a cohort of female survivors of adolescent and young adult cancer for all chemotherapy types.¹⁷ Based on this study and the observations by Meirow et al. on the effect of cyclophosphamide on ovarian stroma, we hypothesize that chemotherapy could also damage the uterus despite a maintained uterine volume.⁵ Moreover, studies in mice have shown damage to the skeletal muscle with muscle mass atrophy after cisplatin treatment.¹⁸ Chemotherapy-induced damage to the myometrium has never been studied in humans, and its effect on uterine muscle has never been demonstrated. It could be interesting to follow pediatric cohorts with homogeneous groups of female patients (e.g., type of cancer, type of chemotherapy, doses of chemotherapy, hormonal follow-up, and treatment) to provide insights into uterine and obstetrical impacts. Gathering the data between countries to provide specific answers for each oncological protocol with good statistical power could be valuable.

## AUTHOR CONTRIBUTIONS

Eloïse Fraison: designed the work, selected the studies, extracted the data, wrote the manuscript. Stephanie Huberlant: designed the work, selected the studies, extracted the data. Mathilde Cavalieri, Aurore Gueniffey, Justine Riss, and Christine Rousset-Jablonski: extracted the data. Blandine Courbiere: designed the work, corrected the manuscript. All authors analyzed the results and approved the final version of the manuscript.

## ACKNOWLEDGMENTS

The authors would like to thank Mathilde Chabut and Alina Zgardau for providing additional data about their initial publications: "Ovarian Function and Spontaneous Pregnancy After Hematopoietic Stem Cell Transplantation for Leukemia Before Puberty: An L.E.A. Cohort Study" and "Obstetrical and Perinatal Outcomes in Female Survivors of Childhood and Adolescent Cancer: A Population-Based Cohort Study," respectively. The authors also thank Solène Linguille (Monitoring Force Group, Maison-Laffitte), who developed the search strategy, and Dr. Bernadette Darné (Monitoring Force Group, Maison-Laffitte), who performed the statistical analyses and provided statistical expertise for the manuscript.

## FUNDING INFORMATION

The study was funded by an unrestricted grant from GEDEON RICHTER, France.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

## ORCID

Eloïse Fraison https://orcid.org/0000-0001-8083-1346

## REFERENCES

1. Griffiths MJ, Winship AL, Hutt KJ. Do cancer therapies damage the uterus and compromise fertility? *Hum Reprod Update*. 2020;26:161-173.

2. Van De Loo LEXM, Van Den Berg MH, Overbeek A, et al. Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors. *Fertil Steril*. 2019;111:372-380.

3. Beneventi F, Locatelli E, Giorgiani G, et al. Adolescent and adult uterine volume and uterine artery Doppler blood flow among subjects treated with bone marrow transplantation or chemotherapy in pediatric age: a case-control study. *Fertil Steril*. 2015;103:455-461.

4. Courbiere B, Drikes B, Grob A, et al. The uterine volume is dramatically decreased after hematopoietic stem cell transplantation during childhood regardless of the conditioning regimen. *Fertil Steril*. 2023;119:663-672.

5. Meirow D, Dor J, Kaufman B, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. *Hum Reprod*. 2007;22:1626-1633.

6. Vergier J, Reynaud R, Michel G, Auquier P, Courbiere B. Misconceptions and beliefs around hormone replacement therapy after childhood hematopoietic stem cell transplantation: a qualitative study among women leukemia survivors. *PLoS One*. 2023;18:e0283940.

7. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. *Eur J Epidemiol*. 2010;25:603-605.

8. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. *BMJ*. 2016;355:i4919.

9. McGrath S, Zhao X, Steele R, et al. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. *Stat Methods Med Res*. 2020;29:2520-2537.

10. Cai S, Zhou J, Pan J. Estimating the sample mean and standard deviation from order statistics and sample size in meta-analysis. *Stat Methods Med Res*. 2021;30:2701-2719.

11. Chapter 11: undertaking network meta-analyses.

12. Gelman A, Rubin DB. Inference from iterative simulation using multiple sequences. *Stat Sci*. 1992;7:457-472.

13. Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. *J Clin Epidemiol*. 2011;64:163-171.

14. Balduzzi S, Rücker G, Nikolakopoulou A, et al. netmeta: an R package for network meta-analysis using frequentist methods. *J Stat Softw*. 2023;106(2):1-40. https://doi.org/10.18637/js.s.v106.i02

15. Seo M, Schmid C. bnma: Bayesian network meta-analysis using 'JAGS'. 2024. R package version 1.6.0 https://CRAN.R-project.org/package=bnma

16. Larsen EC, Schmiegelow K, Rechnitzer C, Loft A, Müller J, Nyboe Andersen A. Radiotherapy at a young age reduces uterine volume of childhood cancer survivors. *Acta Obstet Gynecol Scand*. 2004;83:96-102.

17. Sunguc C, Winter DL, Heymer EJ, et al. Risks of adverse obstetric outcomes among female survivors of adolescent and young adult
cancer in England (TYACSS): a population-based, retrospective co-
hort study. *Lancet Oncol.* 2024;25:1080-1091.

18. Courbiere B, Fraison E, Cavalieri M, et al. Reduced uterine volume after children, adolescent, and young adult chemotherapy exposure. A systematic review and Bayesian network meta-analysis. *Hum Reprod.* 2024;39(Supplement 1, P-348):i357.

SUPPORTING INFORMATION

Additional supporting information can be found online in the
Supporting Information section at the end of this article.

**How to cite this article:** Fraison E, Huberlant S, Cavalieri M, et al. Uterine volume assay after gonadotoxic therapies in childhood, adolescence, and young adulthood: A systematic review and Bayesian network meta-analysis. *Acta Obstet Gynecol Scand.* 2025;104:1616-1626. doi:[10.1111/aogs.70003](https://doi.org/10.1111/aogs.70003)