Obstetric care for women that use antidepressants in pregnancyLine Kolding, MD, PhDVera Ehrenstein, MPH, DSc, ProfessorLars Pedersen, MSc, PhD, ProfessorPuk Sandager, MD, PhD, Associate ProfessorOlav B. Petersen, MD, PhD, ProfessorNiels Uldbjerg, MD, DMSc, ProfessorLars H. Pedersen, MD, PhD, ProfessorCorresponding:Lars Henning PedersenAarhus University Hospital / Aarhus UniversityPalle Juul-Jensens Blvd. 99, 8200 Aarhus N, DenmarkEmail: email@example.comPhone: +45 50526512We are grateful to Drs. Braillon and Bewley for their interest in our recent paper in the BJOG 1 and would like to elaborate on some of the important points they raise.We agree with Braillon and Bewley on the urgent need for improved pharmacovigilance of medication in pregnancy in general, and for antidepressants in particular. There are excellent international collaborations (e.g., the EuroCat) and local initiatives (e.g., the Swedish JanusInfo), but clinically we’re often forced to rely on very limited information indeed. Systematic international recording as suggested by Braillon and Bewley would represent an important step forward.On a smaller scale, we are establishing an automated surveillance system based on curated data that include information on both pre- and postnatally diagnosed malformations. We have, however, faced substantial legal and bureaucratic challenges, and have been forced to use data from the Central Denmark Region only, instead of national data. The surveillance system is consequently based on information on approx. 75,000 pregnancies, and even though it has the potential to aide clinical management, it is a drop in the ocean of the huge potential of for instance a comparable European collaboration.In our study, we used ≥2 redeemed prescriptions to define exposure with a prevalence 1.1%.1 The prevalence of pregnant women that redeemed ≥1 prescription was 3.2% (p. 3/ Table S1), and even though this is likely an overestimation due to non-adherence, the estimates are in line with previously reported prevalences in Scandinavia.2Braillon and Bewley emphasise the need to also consider non-pharmacological treatment of some pregnant women with depression and, further, to provide evidence-based and individualised treatment of women in the reproductive ages. Optimal individualised care will definitely result in non-pharmacological treatment of some pregnant women but, reversely, will cause yet other women to continue or initiate pharmacological treatment. This is in line with what is almost a truism in this field, that the potential harmful foetal effects must be balanced against the potential benefits of a pharmacological treatment, but it is no easy task. Pregnant women might overestimate the foetal risks associated with use of medication3 and discontinue important treatment, on the other hand some may use medication when there may be a better alternative for them. Regardless, we need to provide optimal obstetric care for the pregnant women that choose treatment with antidepressants. If our results are correct, prenatal follow-up of pregnant women treated with venlafaxine may include targeted foetal heart scans, even though the underlying causal explanation for the observed association with cardiac malformations is undetermined.1. Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen OB, Uldbjerg N, et al. Antidepressant use in pregnancy and severe cardiac malformations: Danish register-based study. BJOG. 2021 May 25.2. Zoega H, Kieler H, Norgaard M, Furu K, Valdimarsdottir U, Brandt L, et al. Use of SSRI and SNRI Antidepressants during Pregnancy: A Population-Based Study from Denmark, Iceland, Norway and Sweden. PLoS One. 2015;10(12):e0144474.3. Wolgast E, Lindh-Åstrand L, Lilliecreutz C. Women’s perceptions of medication use during pregnancy and breastfeeding—A Swedish cross-sectional questionnaire study. Acta Obstetricia et Gynecologica Scandinavica. 2019;98(7):856-64.
BJOG-21-0722 Statistical associations versus causal inference.Øjvind Lidegaard, professor 11Department of Gynaecology, Rigshospitalet, University of Copenhagen, DenmarkMany clinicians are of the opinion that observational studies may provide only “statistical associations”, but not “causal inference”. And further, that only randomized designs ensure causal interpretation. For the same reason, many medical journals have made rules for all observational studies finding significant statistical associations to be presented as just “associations” often emphasizing that a causal inference is not possible.I hereby sign up to the growing group of epidemiologists, who are of the opinion that just well confounder controlled observational studies are the very design most often providing convincing evidence of a causal interference. Prospective cohort studies better than retrospective case-control studies, but even the latter design has given us important knowledge of risk factors of rare clinical outcomes such as thrombotic diseases, a long list of cancers, obstetrical complications, including latest stillbirths.In a new original Swedish study, Heiddis Valgeirsdottir et al. demonstrate in a nationwide historical follow-up study, that women with polycystic ovary syndrome (PCOS) once pregnant have a 50% increased risk of experiencing stillbirth, as compared to women without PCOS (1). Further, that the rate ratio of stillbirth between women with and without PCOS increased by increasing gestational age, peaking at 42 weeks with 4.3 deaths per 1000 ongoing pregnancies in women with PCOS versus 1.0 deaths per 1000 ongoing pregnancies in women without PCOS.Any such association should certainly be controlled for a long list of potential confounders, the most important being maternal age, calendar year, parity, hypertensive disorders, diabetes, and educational length. Adiposity (BMI) was undertaken in an additional adjustment, because this covariate correctly could be considered as both a confounder (adiposity being a risk factor for stillbirth, and PCOS women more often being adipose), but also as a mediator; women with PCOS are more likely to develop adiposity due to their PCOS. The authors chose carefully to present the BMI adjusted results as the main results, thereby if anything underestimating the risk of stillbirths in women with PCOS.This is far from the first contribution from Scandinavian National Health Registers, identifying and quantifying risk factors for different diseases. We should always be aware that some unknown or unmeasured potential confounders not being controlled for, could reduce (or enhance) the results, and that other research groups should confirm the Swedish findings. A causal inference was made more likely with a suggested biomedical mechanism by which PCOS could confer such a risk. But already with this new carefully provided observational evidence, we should reasonably consider pregnant women with PCOS not to go too far beyond term, to prevent stillbirths in this group, which according to the study results accounts about 5% of all stillbirths. A pragmatic first recommendation could be induction of women with PCOS at 41 gestational weeks.Valgeirsdottir H et al. BJOG 2021; 128: xxx-xxx.
Letter to the Editor RE: Modification of oxytocin use through a coaching-based intervention based on the WHO Safe Childbirth Checklist in Uttar Pradesh, India: a secondary analysis of a cluster randomized controlled trialAvir Sarkar, MD1; Shalini Venkatappa, MD1; Isha Wadhawan, MD, Diplomate to ABOG21 – Department of Obstetrics and Gynecology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India2 – Department of Obstetrics and Gynecology, Fortis Escorts Hospital, Faridabad, Haryana, IndiaCorresponding author: Avir SarkarAddress: House number 12, Block F, NIT-3, Faridabad, Haryana-121001, IndiaE mail: firstname.lastname@example.orgType of article: Letter to the EditorWord count: 464Number of references: 2Conflict of interest between authors: None declared
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 email@example.com
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:firstname.lastname@example.org; 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.
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: email@example.comTel: 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.
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. 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.  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% reduction; a 2.6% reduction for low risk women; and a 2.1% reduction in the various observational studies  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 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: firstname.lastname@example.orgDear 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