Obstetrics and Gynaecology

Perioperative management of women on oral anticoagulants and antiplatelet agents undergoing gynaecological procedures (2020)

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Type of publication:
Journal article

Author(s):
*Goh E.; Barker V.; Lee P.L.; *Eden D.; *Davies O.; *Sahu B.

Citation:
Obstetrician and Gynaecologist; 2020; Vol 22(2) p. 131-136

Abstract:
Key content: The number of women attending gynaecological services who are taking oral anticoagulants and antiplatelet agents is increasing. Direct oral anticoagulants are becoming increasingly popular and offer an alternative to warfarin. Knowledge of the use of anticoagulants in the perioperative period is imperative to provide optimal care and ensure patient safety. It is essential that health professionals practising gynaecology, at all levels, keep up to date to reduce unnecessary cancellations, delays in treatment and risks of thrombosis and bleeding. Learning objectives: To understand the management of women on oral anticoagulant and antiplatelet agents undergoing elective and emergency gynaecological procedures. To appreciate the importance of assessing patient- and procedural-related risks of thrombosis and bleeding. To review commonly used anticoagulant and antiplatelet agents.

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Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT (2019)

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Type of publication:
Journal article

Author(s):
Dhillon-Smith R K, Middleton L J, Sunner K K, Cheed V, Baker K, Farrell-Carver S, Bender-Atik R, Agrawal R, Bhatia K, Edi-Osagie E, Ghobara T, Gupta P, Jurkovic D, Khalaf Y, MacLean M, McCabe C, Mulbagal K, Nunes N, Overton C, Quenby S, Rai R, Raine-Fenning N, Robinson L, Ross J, Sizer A, Small R, Tan A, *Underwood M , Kilby M D, Boelaert K, Daniels J, Thangaratinam S, Chan S,  Coomarasamy A.

Citation:
Efficacy and Mechanism Evaluation; Volume: 6, Issue: 11, October 2019

Abstract:
Background: Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy.
Objectives: The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses.
Design: This was a randomised, double-blind, placebo-controlled, multicentre study.
Setting: The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016.
Participants: Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible.
Intervention: Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation.
Main outcome measures: The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at < 24 weeks; clinical pregnancy at 7 weeks; ongoing pregnancy at 12 weeks; gestation at delivery; birthweight; appearance, pulse, grimace, activity and respiration (Apgar) scores; congenital abnormalities; and neonatal survival at 28 days of life.
Methods: Participants were randomised in a 1 : 1 ratio. Minimisation was implemented for age (< 35 or ≥ 35 years), number of previous miscarriages (0, 1 or 2, ≥ 3), infertility treatment (yes/no) and baseline thyroid-stimulating hormone concentration (≤ 2.5 or > 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time.
Results: Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome.
Conclusions: Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies.
Limitations: Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored.
Future work: Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism.
Trial registration: Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19.
Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM Trial (2020)

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Type of publication:
Journal article

Author(s):
CB Okeke Ogwulu, I Goranitis, AJ Devall, V Cheed, ID Gallos, LJ Middleton, HM Harb, HM Williams, A Eapen, JP Daniels, A Ahmed, R Bender‐Atik, K Bhatia, C Bottomley, J Brewin, M Choudhary, S Deb, WC Duncan, AK Ewer, K Hinshaw, T Holland, F Izzat, J Johns, M Lumsden, P Manda, JE Norman, N Nunes, CE Overton, K Kriedt, S Quenby, S Rao, J Ross, A Shahid, *M Underwood , N Vaithilingham, L Watkins, C Wykes, AW Horne, D Jurkovic, A Coomarasamy, TE Roberts

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; May 2020; Vol 127 (no. 6); p. 757-767

Abstract:
Objectives: To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding.
Design: Economic evaluation alongside a large multi‐centre randomised placebo‐controlled trial.
Setting: Forty‐eight UK NHS early pregnancy units.
Population: Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac.
Methods: An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages.
Main outcome measures: Cost per additional live birth at ≥34 weeks of gestation.
Results: Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673).
Conclusions: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s).

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A method to improve the accuracy between the presumed depth of excision and the actual depth of excision in women (2018)

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Type of publication:
Journal article

Author(s):
*Papoutsis D.; *Kandanearachchi P.; *Sahu B.; Antonakou A.; Tzavara C.

Citation:
Hippokratia; 2018; vol. 22 (no. 3); p. 113-121

Abstract:
Background: We aimed to determine whether continuous auditing of the presumed depth of excision and
comparing with the actual depth of excision in women having large loop excision of the transformation zone (LLETZ) improves the ability to acquire the desired depth of excision.
Method(s): This was a prospective study of women submitted to a single LLETZ treatment between 2017-2018. Two senior colposcopists recorded what they presumed was the depth of excision at the time of treatment and the subsequent histopathology report provided the actual excised depth. Multiple linear regression identified independently associated parameters with the difference between presumed and actual excision depth. Nonlinear regression determined the learning plateau defined as the theoretical minimal score of difference one could achieve with infinite practice.
Result(s): There were significant differences in practices with the first colposcopist using an 18-mm loop and the second colposcopist a 15-mm loop in the majority of cases. The median absolute and percentage difference between the presumed and actual excised depth was 2 mm and 16.6% and 3.5 mm and 35.4% for the two colposcopists, respectively. A learning plateau was identified only for the first colposcopist. We found that auditing consecutive excisions decreased significantly the difference between the presumed and actual depth of excision with a learning plateau at 2.2 mm of absolute difference and 22.6% of percentage difference and with a learning rate of 13 cervical excisions.
Conclusion(s): There might be a benefit in auditing our treatment practice as there seems to be a learning
plateau through this method

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A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy (2019)

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Type of publication:
Randomised controlled trial

Author(s):
A. Coomarasamy, A.J. Devall, V. Cheed, H. Harb, L.J. Middleton, I.D. Gallos, H. Williams, A.K. Eapen, T. Roberts, C.C. Ogwulu, I. Goranitis, J.P. Daniels, A. Ahmed, R. Bender‑Atik, K. Bhatia, C. Bottomley, J. Brewin, M. Choudhary, F. Crosfill, S. Deb, W.C. Duncan, A. Ewer, K. Hinshaw, T. Holland, F. Izzat, J. Johns, K. Kriedt, M.-A. Lumsden, P. Manda, J.E. Norman, N. Nunes, C.E. Overton, S. Quenby, S. Rao, J. Ross, A. Shahid, *M. Underwood , N. Vaithilingam, L. Watkins, C. Wykes, A. Horne, and D. Jurkovic

Citation:
New England Journal of Medicine 2019;380:p.1815-24.

Abstract:
BACKGROUND
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy.
METHODS
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data.
RESULTS
A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups.
CONCLUSIONS
Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.)

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Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception (2019)

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Type of publication:
Randomised controlled trial

Author(s):
Dhillon-Smith, Rima K; Middleton, Lee J; Sunner, Kirandeep K; Cheed, Versha; Baker, Krys; Farrell-Carver, Samantha; Bender-Atik, Ruth; Agrawal, Rina; Bhatia, Kalsang; Edi-Osagie, Edmond; Ghobara, Tarek; Gupta, Pratima; Jurkovic, Davor; Khalaf, Yacoub; MacLean, Marjory; McCabe, Christopher; Mulbagal, Khashia; Nunes, Natalie; Overton, Caroline; Quenby, Siobhan; Rai, Raj; Raine-Fenning, Nick; Robinson, Lynne; Ross, Jackie; *Sizer, Andrew; Small, Rachel; Tan, Alex; *Underwood, Martyn ; Kilby, Mark D; Boelaert, Kristien; Daniels, Jane; Thangaratinam, Shakila; Chan, Shiao Y; Coomarasamy, Arri

Citation:
The New England Journal of Medicine Apr 2019; 380 (no. 14); p. 1316-1325

Abstract:
BACKGROUND Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

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Cited by 94 other articles

Evaluating the value of intrapartum fetal scalp blood sampling to predict adverse neonatal outcomes: A UK multicentre observational study (2019)

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Type of publication:
Journal article

Author(s):
Al Wattar, Bassel H; Lakhiani, Aarti; Sacco, Adalina; Siddharth, Aditi; Bain, Alexandra; Calvia, Alexandra; Kamran, Atiyah; Tiong, Bing; Warwick, Bethan; MacMahon, Caroline; Marcus, Diana; Long, Emma; Coyle, Gillian; Lever, Gillian Elizabeth; Michel, Gina; Gopal, Gomathy; Baig, Hana; Price, Hannah Louise; Badri, Hawra; Stevenson, Helen; Hoyte, Helene; Malik, Humaira; Edwards, Jade; Hartley, Jennifer; Hemers, Jennifer; Tamblyn, Jennifer; Dalton, John Alexander William; Frost, Jonathan; Subba, Kamana; Baxter, Kathryn; Sivakumar, Kavitha; Murphy, Kelly; Papadakis, Konstantinos; Bladon, Laura Rachel; Kasaven, Lorraine; Manning, Louisa; Prior, Mathew; Ghosh, Mausumi; Couch, Melanie; Altunel, Melis; Pearce, Melissa; Cocker, Michael; Stephanou, Michael; Jie, Michelle; Mistry, Minesh; Wahby, Mohammed Osama; Saidi, Nabila Shahid; Ramshaw, Nicola Louise; Tempest, Nicola; Parker, Nina; Tan, Phoebe L; Johnson, Racheal Louise; Harris, Rachel; Tildesley, Rachel; Ram, Ramya; Painuly, Ritu; Cuffolo, Romana; Bugeja, Roberta; Ngadze, Rose; Grainger, Rosie; Gurung, Sabitra; Mak, Sammy; Farrell, Sara; Cowey, Sarah; Neary, Sarah; Quinn, Sarah; Nijjar, Simrit Kaur; Kenyon, Sophie; Lamb, Stephanie; Tracey, Susan; Lee, Tara; Kinsella, Therese; Davidson, Trecia; Corr, Trent; Sampson, Uzo; McQueen, Victoria; *Parry-Smith, William; Castling, Zora; AB-FAB study group

Citation:
European Journal of Obstetrics, Gynecology, and Reproductive Biology; Sep 2019; vol. 240 ; p. 62-67

Abstract:
OBJECTIVE To evaluate the value of fetal scalp blood sampling (FBS) as an adjunct test to cardiotocography, to predict adverse neonatal outcomes. STUDY DESIGN A multicentre service evaluation observational study in forty-four maternity units in the UK. We collected data retrospectively on pregnant women with singleton pregnancy who received FBS in labour using a standardised data collection tool. The primary outcome was prediction of neonatal acidaemia diagnosed as umbilical cord arterial pH < 7.05, the secondary outcomes were the prediction of Apgar scores<7 at 1st and 5th minutes and admission to the neonatal intensive care unit (NICU). We evaluated the correlation between the last FBS blood gas before birth and the umbilical cord blood and adjusted for time intervals. We constructed 2 × 2 tables to calculate the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) and generated receiver operating curves to report on the Area Under the Curve (AUC). RESULTS In total, 1422 samples were included in the analysis; pH values showed no correlation (r = 0.001, p = 0.9) in samples obtained within an hour (n = 314), or within half an hour from birth (n = 115) (r=-0.003, p = 0.9). A suboptimal FBS pH value (<7.25) had a poor sensitivity (22%) and PPV (4.9%) to predict neonatal acidaemia with high specificity (87.3%) and NPV (97.4%). Similar performance was noted to predict Apgar scores <7 at 1st (sensitivity 14.5%, specificity 87.5%, PPV 23.4%, NPV 79.6%) and 5th minute (sensitivity 20.3%, specificity 87.4%, PPV 7.6%, NPV 95.6%), and admission to NICU (sensitivity 20.3%, specificity 87.5%, PPV 13.3%, NPV 92.1%). The AUC for FBS pH to predict neonatal acidaemia was 0.59 (95%CI 0.59-0.68, p = 0.3) with similar performance to predict Apgar scores<7 at 1st minute (AUC 0.55, 95%CI 0.51-0.59, p = 0.004), 5th minute (AUC 0.55, 95%CI 0.48-0.62, p = 0.13), and admission to NICU (AUC 0.58, 95%CI 0.52-0.64, p = 0.002). Forty-one neonates had acidaemia (2.8%, 41/1422) at birth. There was no significant correlation in pH values between the FBS and the umbilical cord blood in this subgroup adjusted for sampling time intervals (r = 0.03, p = 0.83). CONCLUSIONS As an adjunct tool to cardiotocography, FBS offered limited value to predict neonatal acidaemia, low Apgar Scores and admission to NICU.

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Perivascular epitheloid cell tumor and mesonephric adenocarcinoma of the uterine cervix: an unknown co-existence (2019)

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Type of publication:
Journal article

Author(s):
*Dimitrios Papoutsis, *Banchhita Sahu, *Joanna Kelly, Angeliki Antonakou

Citation:
Oxford Medical Case Reports, Volume 2019, Issue 1, January 2019

Abstract:
A 67-year-old woman with post-menopausal bleeding and a suspicious endocervical mass was referred to gynaecology outpatients’ for diagnosis and management. Cervical punch biopsies taken showed a benign cervical perivascular epithelioid cell tumour (PEComa), with MRI imaging and PET-CT scan indicating a 3–4 cm endocervical tumour with malignant features. The patient underwent radical hysterectomy with lymph node dissection and the surgical specimen histopathology demonstrated a residual benign PEComa and a stage IIB mesonephric adenocarcinoma (MNA) of the cervix. There is no disease recurrence 12 months after surgery. Cervical PEComas are extremely rare tumours of mesenchymal origin deriving from the perivascular epithelioid cells with only 14 cases described so far. Cervical MNAs are rare tumours originating from the remnants of the mesonephric duct of Wolff with only 40 cases reported. Our case adds to the existing literature and highlights the challenges with regard to preoperative diagnosis, treatment and prognosis.

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