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Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial.
Hum Reprod. 2021 Jan 01; 36(1):70-81.HR

Abstract

STUDY QUESTION

Are the long-term reproductive outcomes following recurrent dilatation and curettage (D&C) for miscarriage in women with identified and treated intrauterine adhesions (IUAs) comparable to women without IUAs.

SUMMARY ANSWER

Reproductive outcomes in women with identified and treated IUAs following recurrent D&C for miscarriage are impaired compared to women without IUAs; fewer ongoing pregnancies and live births are achieved with a prolonged time to a live birth.

WHAT IS KNOWN ALREADY

The Prevention of Adhesions Post Abortion (PAPA) study showed that application of auto-crosslinked hyaluronic acid (ACP) gel, an absorbable barrier in women undergoing recurrent D&C for miscarriage resulted in a lower rate of IUAs, 13% versus 31% (relative risk 0.43, 95% CI 0.22 to 0.83), lower mean adhesion score and significant less moderate to severe IUAs. It is unclear what the impact is of IUAs on long-term reproductive performance.

STUDY DESIGN, SIZE, DURATION

This was a follow-up of the PAPA study, a multicenter randomized controlled trial evaluating the application of ACP gel in women undergoing recurrent D&C for miscarriage. All included women received a diagnostic hysteroscopy 8-12 weeks after randomization to evaluate the uterine cavity and for adhesiolysis if IUAs were present. Here, we present the reproductive outcomes in women with identified and treated IUAs versus women without IUAs, 46 months after randomization.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Between December 2011 and July 2015, 152 women with a first-trimester miscarriage with at least one previous D&C, were randomized for D&C alone or D&C with immediate intrauterine application of ACP gel. Participants were approached at least 30 months after randomization to evaluate reproductive performance, obstetric and neonatal outcomes and cycle characteristics. Additionally, the medical files of all participants were reviewed. Main outcome was ongoing pregnancy. Outcomes of subsequent pregnancies, time to conception and time to live birth were also recorded.

MAIN RESULTS AND THE ROLE OF CHANCE

In women pursuing a pregnancy, 14/24 (58%) ongoing pregnancies were recorded in women with identified and treated IUAs versus 80/89 (90%) ongoing pregnancies in women without IUAs odds ratio (OR) 0.18 (95% CI 0.06 to 0.50, P-value <0.001). Documented live birth was also lower in women with IUAs; 13/24 (54%) with versus 75/89 (84%) without IUAs, OR 0.22 (95% CI: 0.08 to-0.59, P-value 0.004). The median time to conception was 7 months in women with identified and treated IUAs versus 5 months in women without IUAs (hazard ratio (HR) 0.84 (95% CI 0.54 to 1.33)) and time to conception leading to a live birth 15 months versus 5.0 months (HR 0.54 (95% CI: 0.30 to 0.97)). In women with identified and treated IUAs, premature deliveries were recorded in 3/16 (19%) versus 4/88 (5%) in women without IUAs, P-value 0.01. Complications were recorded in respectively 12/16 (75%) versus 26/88 (30%), P-value 0.001. No differences were recorded in mean birth weight between the groups.

LIMITATIONS, REASONS FOR CAUTION

In the original PAPA study, randomization was applied for ACP gel application. Comparing women with and without IUAs is not in line with the randomization and therefore confounding of the results cannot be excluded. IUAs, if visible during routine hysteroscopy after randomization were removed as part of the study protocol; the influence of IUAs on reproductive outcome may therefore be underestimated. Women undergoing a recurrent D&C for miscarriage were included, a specific group likely to generate clinically significant adhesions. The findings should therefore not be generalized to all women undergoing D&C for miscarriage.

WIDER IMPLICATIONS OF THE FINDINGS

As IUAs have an impact on reproductive performance, even after hysteroscopic adhesiolysis, primary prevention is essential. Expectative and medical management should therefore be considered as serious alternatives for D&C in women with a miscarriage. In case D&C is necessary, application of ACP gel should be considered.

STUDY FUNDING/COMPETING INTEREST(S)

The original PAPA study (NTR 3120) was an investigator initiated study that was funded by the Foundation for scientific investigation in Obstetrics and Gynaecology of the Saint Lucas Andreas Hospital (currently renamed OLVG Oost), SWOGA. The syringes containing ACP gel were received from Anika Therapeutics, the manufacturer of Hyalobarrier® Gel Endo. The current follow-up study was also an investigator-initiated study without funding. The funder and sponsor had no role in the design of this follow-up study, data collection, data analysis, data interpretation, trial design, patient recruitment, writing of the report or any aspect pertinent to the study. ABH, RAL, JAFH and JWRT have no conflict to declare. HAMB reports being a member of safety board research Womed.

TRIAL REGISTRATION NUMBER

Netherlands Trial Register NTR 3120.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Zaans Medical Center, Zaandam, the Netherlands. Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands.Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands.Department of Epidemiology and Biostatistics, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands.Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands.Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33320197

Citation

Hooker, Angelo B., et al. "Reproductive Performance of Women With and Without Intrauterine Adhesions Following Recurrent Dilatation and Curettage for Miscarriage: Long-term Follow-up of a Randomized Controlled Trial." Human Reproduction (Oxford, England), vol. 36, no. 1, 2021, pp. 70-81.
Hooker AB, de Leeuw RA, Twisk JWR, et al. Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial. Hum Reprod. 2021;36(1):70-81.
Hooker, A. B., de Leeuw, R. A., Twisk, J. W. R., Brölmann, H. A. M., & Huirne, J. A. F. (2021). Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial. Human Reproduction (Oxford, England), 36(1), 70-81. https://doi.org/10.1093/humrep/deaa289
Hooker AB, et al. Reproductive Performance of Women With and Without Intrauterine Adhesions Following Recurrent Dilatation and Curettage for Miscarriage: Long-term Follow-up of a Randomized Controlled Trial. Hum Reprod. 2021 Jan 1;36(1):70-81. PubMed PMID: 33320197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial. AU - Hooker,Angelo B, AU - de Leeuw,Robert A, AU - Twisk,Jos W R, AU - Brölmann,Hans A M, AU - Huirne,Judith A F, PY - 2020/05/09/received PY - 2020/08/04/revised PY - 2020/12/16/pubmed PY - 2020/12/16/medline PY - 2020/12/15/entrez KW - Asherman syndrome KW - conception KW - dilatation and curettage KW - hyaluronic acid KW - intrauterine adhesions KW - miscarriage KW - pregnancy KW - reproductive outcome SP - 70 EP - 81 JF - Human reproduction (Oxford, England) JO - Hum Reprod VL - 36 IS - 1 N2 - STUDY QUESTION: Are the long-term reproductive outcomes following recurrent dilatation and curettage (D&C) for miscarriage in women with identified and treated intrauterine adhesions (IUAs) comparable to women without IUAs. SUMMARY ANSWER: Reproductive outcomes in women with identified and treated IUAs following recurrent D&C for miscarriage are impaired compared to women without IUAs; fewer ongoing pregnancies and live births are achieved with a prolonged time to a live birth. WHAT IS KNOWN ALREADY: The Prevention of Adhesions Post Abortion (PAPA) study showed that application of auto-crosslinked hyaluronic acid (ACP) gel, an absorbable barrier in women undergoing recurrent D&C for miscarriage resulted in a lower rate of IUAs, 13% versus 31% (relative risk 0.43, 95% CI 0.22 to 0.83), lower mean adhesion score and significant less moderate to severe IUAs. It is unclear what the impact is of IUAs on long-term reproductive performance. STUDY DESIGN, SIZE, DURATION: This was a follow-up of the PAPA study, a multicenter randomized controlled trial evaluating the application of ACP gel in women undergoing recurrent D&C for miscarriage. All included women received a diagnostic hysteroscopy 8-12 weeks after randomization to evaluate the uterine cavity and for adhesiolysis if IUAs were present. Here, we present the reproductive outcomes in women with identified and treated IUAs versus women without IUAs, 46 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between December 2011 and July 2015, 152 women with a first-trimester miscarriage with at least one previous D&C, were randomized for D&C alone or D&C with immediate intrauterine application of ACP gel. Participants were approached at least 30 months after randomization to evaluate reproductive performance, obstetric and neonatal outcomes and cycle characteristics. Additionally, the medical files of all participants were reviewed. Main outcome was ongoing pregnancy. Outcomes of subsequent pregnancies, time to conception and time to live birth were also recorded. MAIN RESULTS AND THE ROLE OF CHANCE: In women pursuing a pregnancy, 14/24 (58%) ongoing pregnancies were recorded in women with identified and treated IUAs versus 80/89 (90%) ongoing pregnancies in women without IUAs odds ratio (OR) 0.18 (95% CI 0.06 to 0.50, P-value <0.001). Documented live birth was also lower in women with IUAs; 13/24 (54%) with versus 75/89 (84%) without IUAs, OR 0.22 (95% CI: 0.08 to-0.59, P-value 0.004). The median time to conception was 7 months in women with identified and treated IUAs versus 5 months in women without IUAs (hazard ratio (HR) 0.84 (95% CI 0.54 to 1.33)) and time to conception leading to a live birth 15 months versus 5.0 months (HR 0.54 (95% CI: 0.30 to 0.97)). In women with identified and treated IUAs, premature deliveries were recorded in 3/16 (19%) versus 4/88 (5%) in women without IUAs, P-value 0.01. Complications were recorded in respectively 12/16 (75%) versus 26/88 (30%), P-value 0.001. No differences were recorded in mean birth weight between the groups. LIMITATIONS, REASONS FOR CAUTION: In the original PAPA study, randomization was applied for ACP gel application. Comparing women with and without IUAs is not in line with the randomization and therefore confounding of the results cannot be excluded. IUAs, if visible during routine hysteroscopy after randomization were removed as part of the study protocol; the influence of IUAs on reproductive outcome may therefore be underestimated. Women undergoing a recurrent D&C for miscarriage were included, a specific group likely to generate clinically significant adhesions. The findings should therefore not be generalized to all women undergoing D&C for miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: As IUAs have an impact on reproductive performance, even after hysteroscopic adhesiolysis, primary prevention is essential. Expectative and medical management should therefore be considered as serious alternatives for D&C in women with a miscarriage. In case D&C is necessary, application of ACP gel should be considered. STUDY FUNDING/COMPETING INTEREST(S): The original PAPA study (NTR 3120) was an investigator initiated study that was funded by the Foundation for scientific investigation in Obstetrics and Gynaecology of the Saint Lucas Andreas Hospital (currently renamed OLVG Oost), SWOGA. The syringes containing ACP gel were received from Anika Therapeutics, the manufacturer of Hyalobarrier® Gel Endo. The current follow-up study was also an investigator-initiated study without funding. The funder and sponsor had no role in the design of this follow-up study, data collection, data analysis, data interpretation, trial design, patient recruitment, writing of the report or any aspect pertinent to the study. ABH, RAL, JAFH and JWRT have no conflict to declare. HAMB reports being a member of safety board research Womed. TRIAL REGISTRATION NUMBER: Netherlands Trial Register NTR 3120. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/33320197/Reproductive_performance_of_women_with_and_without_intrauterine_adhesions_following_recurrent_dilatation_and_curettage_for_miscarriage:_long_term_follow_up_of_a_randomized_controlled_trial_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/deaa289 DB - PRIME DP - Unbound Medicine ER -
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