Fertility preservation for women with ovarian endometriosis: it is time to adopt it as routine practice

Time for action- oxytocin & uterotonics are life-saving AND dangerous: a commentaryDeborah ArmbrusterUnited States Agency for International DevelopmentWashington, DC (currently based in Indonesia)Global Health Bureau/Maternal, Child and Nutrition Office/Maternal and Newborn Division+1 202 746-5453darmbruster@usaid.gov

Commentary on: LAPAROSCOPIC MYOMECTOMY USING LOOP LIGATION FOR GIANT INTRACERVICAL MYOMAS: A NOVEL SURGICAL TECHNIQUE.Authors: Shengke Wang, Dongdong Wang, Qihong Huang, Fujie Zhao.Journal: BJOG: An International Journal of Obstetrics & GynaecologyINTRACERVICAL FIBROID REMOVAL: A MYOMECTOMY REASONED ON BIOLOGICAL BASES .Dr. Andrea Tinelli, MD, Prof, PhDVeris delli Ponti Hospital, Obstetrics and Gynecology Department, Scorrano, Lecce, Italy; Laboratory of Human Physiology,Phystech BioMed School, Faculty of Biological & Medical Physics,Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russia.Tel: +39-3392074078; E-mail:andreatinelli@gmail.com; ORCID: 0000-0001-8426-8490Anatomically, uterine corpus, isthmus and cervix compose one organ, but functionally they attend different function during pregnancy and labor. The uterine cervix is mainly composed connective tissue and extracellular matrix, that allow the pregnancy to come to an end, up to the onset of labor, when cervical ripening and dilatation occur to deliver the fetus. The cervical innervations and the different neurotransmitters and neuropeptides expression involved in cervical ripening suggest that the cervix plays a key role in pregnancy maintenance, labor initiation, pain and delivery; this can also be supported by previous studies that showed that cervical ripening is also a neuroimmune-mediate inflammatory reaction involveing the hypogastric nerve [Di Tommaso S “et al”, 2017;18(2):140-148].Neuropeptides are signaling peptides that are produced by neural, endocrine and/or immune cells: all of these hormones are involved in a variety of biological processes, not only enhancing uterine contractility and modulating pain trigger, but also possessing anti-inflammatory, antioxidative stress and tumorigenic properties. Particularly, they contribute with changes in muscle contractility, uterine peristalsis and muscular healing and may be involved also in the uterine fibroids’ pathophysiology [Tinelli A “et al”; 2020;21(5):440-442].Uterine fibroids are generally distributed over the body and fundus of the uterus, they are surrounded by a fibroneurovascular network rich of neurotransmitters, the myoma pseudocapsule, a neurovascular bundle separating fibroid from the myometrium, and allowing less bleeding during myomectomy and better subsequent myometrial healing after removal [Tinelli A “et al”; Curr Protein Pept Sci. 2017;18(2):129-139]. For this reason, the correct myomectomy which enucleates fibroid inside its pseudocapsule has been called ”intracapsular” and has remarkable early and late biological - muscular advantages, during and after surgery [Tinelli A “et al”.; JSLS 2012;16(1):119-29].Cervical fibroids are infrequent, but often create significant problems during myomectomy, as, during the removal there can be intraoperative and late complications, such as massive bleeding and scarring fibrosis with all the repercussions on pregnancy and childbirth [Malvasi A “et al”; 2013;29(11):982-8.].Wang “et al” [Wang “et al”; BJOG 2021] proposed their intracervical myomectomy for large intracervical myomectomy on 12 patients, basing on biology of the myoma pseudocapsule. They performed a laparoscopic myomectomy putting a loop ligation along the junction of the pseudocapsule and cervix, pulling the loop it at this position; then, they performed a traction and enucleation within the fibroid wound cavity directly closes the fibroid cavity, with the surrounding vascular network bounded in the knot after ligation of the pseudocapsule without dead space, and preventing injury to nearby tissues.During fibroid enucleation, loop ligation of the pseudocapsule glides along the tumor body and operates within the fibroid wound cavity, with no cervical tissue involved during enucleation. The neurovascular bundles of the fibroid pseudocapsule are protected and spared during myomectomy and the side of the pseudocapsule attached to the fibroid was bound tightly in the loop to achieve hemostasis. This technique results less invasive and would promote fertility in case of cervical myomectomy, not requiring additional pelvic dissection and allowing to operate directly in the cervix sparing adjacent tissues and pseudocapsule.

Background: Biologic medications, specifically the TNF-α inhibitors, have become increasingly prevalent in the treatment of chronic inflammatory disease (CID) in pregnancy. Objective: To determine pregnancy outcomes in women with CID exposed to biologics during pregnancy. Search strategy: PubMed and EMBASE databases were searched through January 1998-July 2021. Selection criteria: Peer reviewed, English language cohort, case-control, cross-sectional studies, and case series which contained original data. Data collection and analysis: Two authors independently conducted data extraction and assessed study quality. A meta-analysis of proportions using a random-effects model was used to pool outcomes. Linear regression analysis was used to compare the mean of proportions of outcomes across exposure groups using the ‘treated’ group as the reference category. All studies were evaluated using an appropriate quality assessment tool described by McDonald et al. Main Results: 35 studies, 11172 pregnancies, were eligible for inclusion. Analysis showed pooled proportions for congenital malformations: treated 4%(95% CI 0.03-0.4) vs disease matched 4%(0.03-0.05).Preterm delivery treated 12%(0.10-0.14) vs disease matched 10%(0.09-0.12) Severe neonatal infection: treated 5%(0.03-0.07) vs disease matched 5%(0.02-0.07) Low birth weight: treated 10%(0.07-0.12) vs disease matched 8%(0.07-0.09) The pooled Miscarriage: treated 13%(0.10-0.15) vs disease matched 8%(0.04-0.11) Pre-eclampsia; treated 1%(0.01-0.02) vs disease matched 1%(0.00-0.01). No statistical differences in proportions were observed. Conclusion: We demonstrated comparable pregnancy outcomes in pregnancies exposed to biologics, disease matched controls and CID free pregnancies. Overall, women receiving biologics in pregnancy may be reassured regarding their safety.

Background Antenatal Care (ANC) is one of the key care-packages required to reduce global maternal and perinatal mortality and morbidity Objectives To identify the essential components of ANC and develop signal functions Search strategy MESH headings for databases including Cinahl, Cochrane, Global Health, Medline, PubMed, and Web of Science Selection Criteria Papers and reports on content of ANC published from 2000-2020 Data collection and Analysis Narrative synthesis of data and development of signal function through 7 consensus-building workshops with 184 stakeholders Main Results A total of 221 papers and reports are included from which 28 essential components of ANC were extracted and used to develop 15 signal functions with the equipment, medication and consumables required for implementation of each. Signal functions for the prevention and management of infectious diseases (malaria, HIV, tuberculosis, syphilis and tetanus) can be applied depending on population disease burden. Screening and management of pre-eclampsia, gestational diabetes, anaemia, mental and social health (including intimate partner violence) are recommended universally. Three signal functions adress monitoring of foetal growth and wellbeing and identification and management of obstetric complications. Promotion of health and wellbeing via education and support for nutrition, cessation of substance abuse, uptake of family planning, recognition of danger signs and birth preparedness are included as essential components of ANC. Conclusions New signal functions have been developed which can be used for monitoring and evaluation of content and quality of ANC. Country adaptation and validation is recommended.

Letter to the Editor, BJOG Title:Prophylactic negative wound pressure dressing (NWPD) after caesarean – an extended debate to include surgical aspectsRe: Hyldig N, Joergensen JS, Lamont RF, Moller S, Vinter CA. Prophylactic negative pressure wound therapy in obese women undergoing caesarean section: a commentary on new evidence that fuels the debate. BJOG 2021; https://doi.org/10.1111/1471-0528.16750.Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKEmail: s.sholapurkar@nhs.netTel: 07906620662Word count: 500Corresponding Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKStatement of interest: The author has no conflict of interest or funding to declare.

Objective To study the preferences and risk tolerance of women suffering from deep endometriosis (DE) with bowel involvement when they have to choose between conservative or surgical. Design Labelled Discrete Choice Experiment (DCE). Setting Dutch academic and non-academic hospitals and online recruitment. Population or Sample A total of 169 patients diagnosed with DE of the bowel. Methods Baseline characteristics and the fear for surgery were collected. Women were asked to rank attributes and choose between hypothetical conservative (medication) or surgical treatment in different choice sets (scenarios). Each choice set offered different levels of all treatment attributes. Data were analysed by using multinomial logistic regression. Main Outcome Measures The following attributes; effect/or risk on pain, fatigue, pregnancy, endometriosis lesions, mood swings, osteoporosis, temporary stoma and permanent intestinal symptoms were used in this DCE. Results In the ranking osteoporosis is the least important attribute, while in the DCE, a lower chance of osteoporosis is one of the most important drivers when choosing a conservative treatment. Women with previous surgery show less fear for surgery compared to women without surgery. The low anterior resection syndrome is almost equally important for patients as the chance of pain reduction. Pain reduction has higher importance than improving fertility chances even in women with a future child wish. Conclusions The risk of suffering from LARS as a result of treatment is almost equally important as the reduction of pain symptoms. Women with previous surgery experience less fear for surgery compared to women without a surgical history.

Mini commentary on BJOG-21-0235.R1The Project Appropriate Birth: significance of the Robson classification in confronting the caesarean section

Objective: To evaluate which risk factors for RhD immunization remain, despite adequate routine antenatal and postnatal RhIg prophylaxis (1000 IU RhIg) and additional administration of RhIg. Assessment of the prevalence of RhD immunizations. Design: Prospective cohort Setting: The Netherlands. Population: Two-year nationwide cohort. Methods: RhD-negative women in their first RhD immunized pregnancy and their foregoing non-immunized pregnancy. Risk factors for RhD immunization were compared with population data. Main outcomes measures: Risk factors for FMH and subsequently RhD immunization, prevalence of RhD immunizations. Results: The prevalence of newly detected RhD immunizations was 0.31% (79/25,170) of all RhD-negative pregnant women in the Netherlands. After exclusion, 193 women remained. Significant risk factors found in the group of 113 parous women (previous pregnancy >16 weeks, RhD positive child) were; caesarean section (CS) (OR 1.7, 95% CI 1.1-2.6), perinatal death (OR 3.5, 95% CI 1.1-10.9), gestational age over 42 weeks (OR 6.1, 95% CI 2.2-16.6), postnatal bleeding (>1000mL) (OR 2.0 95% CI 1.1-3.6), surgical removal of the placenta (SRP) (OR 4.3, 95% CI 2.0-9.3). The miscarriage rate in the group of women without a previous RhD positive child was significantly higher than in the Dutch population (35% vs 12.5% p<0.001). Conclusion: Complicated deliveries, including cases of major bleeding and surgical interventions (CS, SRP) need to be recognized as risk factor, requiring determination of FMH volume and adjustment of RhIg dosing. Miscarriage may be an additional risk factor for RhD immunization, requiring further studies. Funding: This research was partly funded by a grant from Sanquin Amsterdam.

Sir,We welcome Gurol‐Urganci I and Bidwell et al’s evaluation of the impact of the care bundle to reduce obstetric anal sphincter injury (OASI) published in your August edition last year.[1] The article reports much needed evidence on the efficacy of an intervention that has already taken hold in many maternity services across the country.Despite the article’s timely nature, we would like to voice our disappointment in the quality of the evidence of support for the care bundle Meulen and Thakar et al provide, and the recommendations made. The article fails to consider important evidence in this area of maternity care prompting this response. In particular, the authors miss the opportunity to contextualise the relatively low-level evidence they take from five articles – reporting three Scandinavian cohort studies and one educational intervention study on manual assistance during the final part of the second stage of labour (including gripping the baby’s chin through the perineum) - with the compelling findings from the Cochrane review on Perineal techniques during the second stage of labour for reducing perineal trauma. [2] This omission is important because the Cochrane review indicates that warm compresses have a bigger positive effect on OASI than the OASI care bundle reported by Meulen and Thakar et al’s. Furthermore, the Cochrane review provides evidence suggesting that hands off the perineum may protect women from episiotomy; an outcome which Meulen and Thakar et al acknowledge remained unchanged despite the third component in the care bundle aiming to ‘use of episiotomy when clinically indicated’. The selective nature of the evidence quoted, undermines the credibility of inferences that can be made from the findings. We suggest therefore, that caution should be taken when reading the authors conclusions.Our second concern rests upon the authors failure to account for the surprisingly small positive effect of the care bundle compared with the Scandinavian studies they quote. Meulen and Thakar et al report a 0.3% decrease in OASI compared with a 3.6% reduction;[3]3% reduction;[4] a 2.6% reduction for low risk women;[5] and a 2.1% reduction in the various observational studies [6] Such a small effect in an open trial could easily be caused by ascertainment bias. Again, the quality of the previous Scandinavian studies make interpretation difficult but the marked difference in results between Scandinavia and England suggests caution should be taken when reading the authors conclusions.Our final concern pertains to women’s experience of the care bundle. Not only is the acceptability of the intervention not considered in this evaluation – a significant oversight given the conspicuous lack of evidence on this – there are ethical issues within the evaluation that deserve attention. The intervention description in figure 1 claims that women were informed about what could be done to reduce OASI. This does not appear to be entirely true given the lack of consideration of warm compresses and hands off to protect against episiotomy. Even more unsettling is the statement ‘MPP should be used unless the woman objects’, implying little consideration for autonomy and informed consent.For the above reasons, we are not only disappointed with the BJOG article but with the professional stakeholder investment in the intervention which seems to have been widely and uncritically supported, with some support even being somewhat evangelical, despite the limited evidence for support.Signatures,

Objective: To review the effect of the COVID-19 pandemic on the presentation of Cervical cancer. Design/ Setting: Retrospective study involving the Regional Cancer Centres in the M62 Group. Methods: Data was collected for two equal time periods. All cervical cancers were included and FIGO 2018 staging was used for the data collection. P values were calculated using binomial hypothesis test for the difference in staging. Time from symptoms to diagnosis was assessed using a normal distribution test. All other calculations were performed using chi-squared test. Statistical significance was considered if p values were <0.05. Main outcome measures: Histology, stage at diagnosis, date of onset of symptoms, investigation and type of treatment. Results: A total of 406 cases of cervical cancer were reviewed; 233 from May – October 2019 (pre-COVID) and 173 between May – October 2020 (post COVID); representing a significant reduction in new cervical cancer diagnoses of 25% post COVID (p<0.001) There was a 42% increase in the delay from start of symptoms to diagnosis Post COVID. Pre COVID, 27% of patients presented with Stage 3 or 4 disease, whilst during COVID this was 38%; statistically significant (p <0.001). When we evaluated the treatments received between the two time periods, this was also statistically significant (chi-squared, p=0.0005). Conclusions: This study has demonstrated a statistically significant increase in the stage of cervical cancer at diagnosis and a change in treatment for cervical cancer following the onset of COVID-19. The implications of this are discussed.

Commentary

Background: While pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a pre-requisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. Methods: We performed a retrospective analysis of single cell data repositories. This data was then validated at both gene and protein level by performing qRT-PCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues. Findings: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels, only in the fetal intestine and kidney and is not expressed in the fetal lung. The placenta is also negative for the two proteins both during development and at term. Interpretation: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the GI tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid. Funding: This work was made possible by an MRC / UKRI COVID-19 Rapid response initiative grant (MR/V028480/1).

Objective: To evaluate the efficacy of long-term indomethacin therapy (LIT) in prolonging pregnancy and reducing spontaneous preterm birth (PTB) in patients undergoing fetoscopic laser surgery (FLS) for the management of twin-to-twin transfusion syndrome (TTTS). Design: Retrospective cohort study of prospectively collected data. Setting: Collaborative multicenter study Population: 557 consecutive TTTS cases that underwent FLS Methods: LIT was defined as indomethacin use for at least 48 hours. Log-binomial regression was used to estimate the relative risk (RR) of PTB in LIT compared to non-LIT group. Cox regression was used to evaluate the association between LIT use and FLS-to-delivery survival. Main outcome measures: gestational age (GA) at delivery Results: Among the 411 pregnancies included, a total of 180 patients (43.8%) received LIT after FLS and 231 patients (56.2%) did not. Median GA at fetal intervention did not differ between groups (20.4 weeks). Median GA at delivery was significantly higher in the LIT group (33.6 weeks) compared to the non-LIT group (31.1weeks), p<0.001. FLS-to-delivery interval was significantly longer in the LIT group (P<0.001). The risk of PTB prior to 34, 32, 28, and 26 weeks gestation were all significantly lower in the LIT group compared to the non-LIT group (RR=0.69, 0.51, 0.37, and 0.18, respectively). The number needed to treat (NNT) with LIT to prevent one PTB<32 weeks gestation was 4, and to prevent one PTB<34 weeks was 5. Conclusion: Long-term indomethacin after FLS for TTTS was found to be associated with prolongation of pregnancy and reducing the risk for PTB.

Letter to editor: “Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial “Cheng-Yang Hsu1, Ching-Hu Wu1, Cheng-Yu Long1, 21 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan2 Department of Obstetrics and Gynecology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanRunning head: Two prospective for this promising experimentWords Count: 315Corresponding Author:Dr. Cheng-Yu Long, MD, PhD, Department of Obstetrics and Gynaecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd, Kaohsiung 80708, TaiwanE-mail: urolong@yahoo.com.twDear Editor-in Chief:We read with great interest with recent publication in BJOG by Mackova et al. (1) This study describe effects of non-ablative erbium-doped: yttrium-aluminium-garnet (Er:YAG) laser on vaginal atrophy induced by iatrogenic menopause in the ewe. The ewes were randomized to three groups: vaginal Er:YAG laser application, estrogen replacement, and sham groups.In the estrogen replacement group of ewes, an estrogen implant was inserted under the skin in the inguinal region. The result showed increase in epithelia thickness in vaginal biopsies and it was significantly higher compared with the laser application and sham groups. In all groups, the lamina propria did not showed any significant differences. Also the autopsy showed the uterus of estrogen-exposed ewes weighted more.We would like to humbly comment the vaginal estrogen use and laser application in genitourinary syndrome of menopause.The vaginal estrogen application was given twice a week with the cream in currently practice of female who suffered from genitourinary syndrome of menopause (GSM). Firstly, the vaginal estrogen application was given twice a week with the cream in clinical practice of female who suffered from GSM. The administration showed improvement of the symptoms while no significant change in serum estrogen level. (2) The estrogen implant in the ewe experiment continues to release estrogen and caused sustained estrogen effect in the ewe and caused gaining weight of uterus, which was very different with our clinical practice of intermittent vaginal cream use.Second, the application in this study is Er:YAG laser, with the the lesser wave length: 2940 nm. While the CO2 laser had much longer wave length 10600 nm and had deeper effect in not only vaginal epithelium but also lamina propia. (3) Therefore the vascularization effects of lamina propia may be obvious noticeably.We thought these 2 flaws could be revised to make the ewe experiment more accurate and similar to current management in women with GSM.ReferencesMackova KA-OX, Mazzer AM, Mori Da Cunha MA-O, Hajkova Hympanova LA-O, Urbankova IA-O, Kastelein AA-O, et al. Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial. BJOG . 2021 May;128(6):1087-1096.Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women. Menopause . Sep-Oct 2006;13(5):737-43.Bhide AA, Khullar V, Swift S, Digesu GA. The use of laser in urogynaecology. Int Urogynecol J . 2019 May;30(5):683-692.

BJOG-20-1830.R3: The levonorgestrel intrauterine system versus endometrial ablation: when the choice of treatment goes beyond its efficacy Author: Sarah Maheux-LacroixEndometrial ablation and levonorgestrel intra-uterine system (LNG-IUS) are two well-established treatment options for women with heavy menstrual bleeding (Bergeron C, Hum Reprod Update 2020;26(2):302-11) that have contributed to the important decrease in hysterectomies over the last decades (Bergeron AM et al. J Obstet Gynaecol Can 2020;42(12):1469-74). Van den Brick et al. present a cost-effectiveness analysis comparing the two options, in which a treatment strategy starting with the LNG-IUS is less costly than a strategy starting with endometrial ablation. Up to now, economic analyzes mostly relied on simulation modeling and conclusions could vary depending on assumptions for efficacy and discontinuation in each arm. This study was based on actual data from an RCT with a 2-year follow-up.Despite the 43% discontinuation rate for LNG-IUS, this method was cheaper at 2 years and this conclusion stood up to sensitivity analyzes. The LNG-IUS remained superior despite the assumption of an ambulatory setting for endometrial ablation, but this analysis needs to be interpreted with caution. Data was lacking on costs of the outpatient setting and saving of only \euro111 was estimated when comparing to the inpatient setting (\euro2,241 versus \euro2,352). In other studies, the outpatient hysteroscopy was associated with substantial savings, being 2 to 4 times cheaper (Bennett A et al. J Obstet Gynaecol Can 2019;41(7) :930-41). Indeed, costs are always subject to vary from region to region with possibly different conclusions in different settings, but clearly an outpatient procedure reduces the cost difference between the two methods.Beyond 2 years, data is lacking. The two methods have been compared in RCT at up to 5 years (Bergeron C, Hum Reprod Update 2020;26(2):302-11) and we do not know if one method is superior the other to prevent longer term failures and re-interventions. The LNG-IUS requires replacement every 5 years but seems to decrease the risk of eventually requiring a hysterectomy in younger patient (Bergeron C, Hum Reprod Update 2020;26(2):302-11). Both factors could have an impact in a longer-term cost-effectiveness analysis and underline that future research should investigate the modifying effect of age.At the end of the day, the choice of treatment needs to be individualized to the patient needs and preferences. Certain characteristics lead us to favor the LNG-IUS, such as need for contraception, wish to preserve fertility, risk of endometrial neoplasia or presence of concomitant gynecologic conditions such as adenomyosis. On the other hand, some women do not tolerate or refuse potential side effects of hormones. Let’s keep in mind that both methods are effective, minimally invasive and represent substantial savings compared to a hysterectomy, but when both options are adequate for a patient, the LNG-IUS is less costly for society.

Title Page: MinicommentaryThis is a minicommentary on Reid et al. “How common are complications following polypropylene mesh, biological xenograft 3 and native tissue surgery for pelvic organ prolapse? A secondary analysis from the PROSPECT trial”.Title: Understanding Risk: a substitute for Information?Author : Swati Jha (MD, FRCOG)Consultant Gynaecologist and Honorary Senior Clinical Lecturer, Sheffield University. Subspecialist in UrogynaecologyInstitute : Department of Urogynaecology, Sheffield Teaching Hospitals NHS Foundation TrustAddress : Sheffield Teaching Hospitals, Level 4, Jessop Wing, Tree Root Walk, Sheffield. S10 2SFSwati.Jha1@nhs.net0044 (0)114 2268568Fax : 0114 2268165

Title Page: Minicommentary