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

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:[email protected]; 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.

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

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.

Title Page: Minicommentary

Objective: To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. Design: Prospective cohort study. Setting: 13 NHS Trusts in England, Wales and Northern Ireland. Population: 202,506 postmenopausal women recruited between 2001-2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. Methods: Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow-up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. Main outcome measures: Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. Results: Hysterectomy with conservation of one or both adnexa was reported in 41,912 (20.7%; 41,912/202,506) women. Median follow up was 11.1years (IQR 9.96-12.04), totalling >2.17million women-years. Among women who had undergone hysterectomy, 0.55% (231/41912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (RR=0.98, 95%CI 0.85-1.13, p=0.765). Conclusions: This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. This data is important both for clinical counselling and for refining risk prediction models.

Objective: To estimate the effect of oestrogen-only and combined hormone replacement therapy (HRT) on the hazards of overall and age-specific all-cause mortality in healthy women aged 46 to 65 at first prescription. Design: Matched cohort study.  Setting: Electronic primary care records from The Health Improvement Network (THIN) database, UK (1984−2017). Population: 105,199 HRT users (cases) and 224,643 non-users (controls) matched on age and general practice. Methods: Weibull-Double-Cox regression models adjusted for age at first treatment, birth cohort, type 2 diabetes, hypertension and hypertension treatment, coronary heart disease, oophorectomy/hysterectomy, body mass index, smoking, and deprivation status. Main outcome measures: All-cause mortality. Results: A total of 21,751 women died over an average of 13.5 years follow-up per participant, of whom 6,329 were users and 15,422 non-users. The adjusted hazard ratio (HR) of overall all-cause mortality in combined HRT users was 0.91 (95%CI 0.88−0.94), and in oestrogen-only users was 0.99 (0.93−1.07), compared to non-users. Age-specific adjusted HRs for participants aged 46-50, 51-55, 56-60, and 61-65 years at first treatment were 0.98 (0.92−1.04), 0.87 (0.82−0.92), 0.88 (0.82−0.93), and 0.92 (0.85−0.98), for combined HRT users compared to non-users, and 1.01 (0.84−1.21), 1.03 (0.89−1.18), 0.98 (0.86−1.12), and 0.93 (0.81−1.07) for oestrogen-only users, respectively. Conclusions: Combined HRT was associated with a 9% lower risk of all-cause mortality and oestrogen-only formulation was not associated with any significant changes.  Funding: IFoA. Keywords: Hormone replacement therapy, menopause, mortality, primary care records, THIN. Tweetable abstract: Oestrogen-only HRT is not associated with all-cause mortality and combined HRT reduces the risks.

Objective To determine the prevalence of genital mycoplasma infection and the risk of spontaneous preterm birth (sPTB) in asymptomatic pregnant women. Design Prospective cohort. Setting Public and private health services in Ribeirão Preto-SP, Brazil. Population 1.349 asymptomatic women with a singleton pregnancy at 20-25 weeks of gestation (WG) recruited between 2010 and 2011. Methods Baseline data was assessed using a questionnaire, in addition to cervicovaginal fluid and blood samples, to analyze lower reproductive tract infections (RTIs) and immune mediators, respectively. The association between variables and the risk of sPTB was evaluated using logistic regression analysis to estimate the odds ratios (ORs). Main outcome measures Genital mycoplasma infection and prematurity. Results The prevalence of the sPTB and genital mycoplasma was 6.8% and 18%, respectively. The infection was not a risk factor for sPTB (aOR 0.66; 95% CI 0.32-1.35), even when associated with bacterial vaginosis (BV). However, it was associated with a low socioeconomic status (p=0.0470), cigarette use (p=0.0009), number of sexual partners (p=0.0019), and BV (p<.0001). Regarding the risk factors associated with sPTB, previous history of PTB (aOR 12.06; 95% CI 6.21-23.43) and a cervical length ≤ 2.5 cm (aOR 3.97; 95% CI 1.67-9.47) were significant. Conclusions The risk of sPTB was independently associated with the history of PTB and the cervical length but not with the genital mycoplasma infection. Funding: This work was founded by CNPq, FAPESP and CAPES. Keywords: Preterm birth, pregnancy, genital mycoplasma, bacterial vaginosis, risk factor

Objective: To compare the host and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold to the response to PP mesh in an animal model of vaginal POP surgery. Design: A study employing a sheep model Setting: KU Leuven Center for Surgical Technologies Population: 14 parous female Mule sheep Methods: P4HB scaffolds were surgically implanted in the posterior vaginal wall of sheep. The comparative PP mesh data were obtained from an identical protocol. Main outcome measures: Gross necropsy, histological and biomechanical evaluation of explants, and the in vivo P4HB scaffold degradation were evaluated at 60- and 180-days post-implantation. Results: Gross necropsy revealed no implant related adverse events using P4HB scaffolds. The tensile stiffness of the P4HB explants increased at 180-days (12.498 ± 2.66 N/mm (P=0.019)) as compared to 60-days (4.585 ± 1.57 N/mm) post-implantation, while P4HB degraded gradually. P4HB scaffolds exhibited excellent tissue integration with dense connective tissue and a moderate initial host response. P4HB scaffolds induced a significantly higher M2/M1 ratio (1.70 ± 0.67 SD, score 0-4), as compared to PP mesh (0.99 ± 0.78 SEM, score 0-4) at 180-days. Conclusions: P4HB scaffold facilitated a gradual load transfer to vaginal tissue over time. The fully absorbable P4HB scaffold, in comparison to PP mesh, has a favorable host response with comparable load bearing capacity. If these results are also observed at longer follow-up, a clinical study for vaginal POP surgery may be warranted to demonstrate efficacy. Key words: Pelvic organ prolapse, vaginal surgery, Poly-4-hydroxybutyrate, degradable scaffold, host response, biomechanics.

Objective To describe the characteristics and outcomes of women with inherited bleeding disorder during pregnancy and birth. Design Retrospective cohort study. Setting Tertiary care hospitals, NSW and Victoria Australia. Population 100 women with inherited bleeding disorders, who birthed 134 live infants from 132 pregnancies. Methods Data was retrospectively obtained from the patient and neonatal medical records. Descriptive analysis was used to report maternal and pregnancy characteristics, birth and neonatal outcomes. Main outcome measures Factor replacement, neuraxial analgesia use and complications, post-partum haemorrhage and neonatal complications. Results PPH occurred in 22% of deliveries with primary PPH occurring in 20% and secondary PPH in 4% of births. 48% of PPHs were classified as major. PPHs occurred across the spectrum of IBD and was evenly distributed between women who had “normalised” their factor levels in pregnancy compared to those requiring factor at the time of birth. An obstetric cause was identified in more than half of PPHs. Conclusions Women with inherited bleeding disorders can deliver safely and receive neuraxial analgesia without complication when best practices are adhered to. PPH appears to occur at higher rates than the general population despite adequate factor levels or planned replacement. Whilst an obstetric cause was demonstrable in the many cases, these findings raise concern over the current definition of “adequate” factor levels at the time of birth.

BJOG commentary for BJOG-21-0466 A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study

Objective: to evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: multicentre retrospective cohort study between 2008-2021 Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population.

Background Guidelines standardise high-quality evidence-based management strategies for clinicians. Uterine fibroids are a highly prevalent condition and may exert significant morbidity. Objectives The purpose of this study was to appraise national and international uterine fibroid guidelines using the validated AGREE-II instrument. Selection Strategy An electronic database search of PubMed and EMBASE from inception to October 2020 for all published English-language uterine fibroid clinical practice guidelines was undertaken. Data Collection and Analysis 939 abstracts were screened for eligibility by two reviewers independently. Three reviewers used the AGREE-II instrument to assess guideline quality in six domains (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence). Recommendations were mapped to allow a narrative synthesis regarding areas of consensus and disagreement. Main Results Eight national (AAGL, SOGC 2014, ACOG, ACR, SOGC 2019, CNGOF, ASRM, and SOGC 2015) and one international guideline (RANZOG) were appraised. The highest scoring guideline was RANZOG 2001(score 56.5%). None of the guidelines met the a priori criteria for being high-quality overall (score >= 66%). There were 166 recommendations across guidelines. There were several areas of disagreement and uncertainty. Conclusions There is a need for high-quality fibroid guidelines given heterogeneity across individuals and a large range of treatment modalities available. There are also areas of controversy in the management of fibroids (e.g. Ulipristal acetate, power morcellation) which also should be addressed in any guidelines. Future guidelines should be methodologically robust to allow high-quality decision-making regarding fibroid treatments.