Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The ...pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.
Objective The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing ...treatment. Study Design This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. Results Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. Conclusion Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.
STUDY QUESTION
Is there an association between high levels of sperm DNA damage and miscarriage?
SUMMARY ANSWER
Miscarriage rates are positively correlated with sperm DNA damage levels.
WHAT IS KNOWN ...ALREADY
Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We used the terms ‘DNA damage’ or ‘DNA fragmentation’ combined with ‘miscarriage’, ‘abortion’ or ‘pregnancy’ to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle–Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001). A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR = 3.94 (2.45, 6.32), P < 0.00001).
LIMITATIONS, REASONS FOR CAUTION
There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss.
WIDER IMPLICATIONS OF THE FINDINGS
The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy.
STUDY FUNDING/COMPETING INTEREST(S)
None.
Abstract
Background
Cervical cancer is the most common indication for ovarian transposition in reproductive-age women. Ovarian transposition should be performed in premenopausal women undergoing ...pelvic irradiation to preserve ovarian function, and prevent early menopause. As women become more knowledgeable about their fertility options, it is still unclear who will benefit from the intervention. We updated our previous meta-analysis of ovarian function preservation, symptomatic ovarian cysts, and metastases to the transposed ovaries following ovarian transposition in cervical cancer patients to further guide current clinical practice.
Methods
A systematic search of Medline, Embase, Web of Science, and The Cochrane Library databases, dating from January 1980 to July 2021, was conducted. We computed the summary proportions of women who had ovarian function preservation, non-ovarian cyst formation and metastases to the transposed ovaries following ovarian transposition by random-effects meta-analysis and we explored study heterogeneity by type of radiotherapy.
Results
There were 29 publications reporting on 1160 women with cervical cancer who underwent ovarian transposition. In the group that underwent surgery alone, 91% of the women had preserved ovarian function (95% CI 83–100), 89% (95% CI 80–99) of women who did not develop ovarian cysts, and 99% (95% CI 1–5) of women who did not suffer metastases to the transposed ovaries. In the surgery ± brachytherapy (BR) group, the proportion of women with the preserved ovarian function was 93% (95% CI 76–113), 84% (95% CI 69–103) of women who did not develop ovarian cysts, and 99% (95% CI 82–120) of women who did not suffer metastases to the transposed ovaries. In the external beam pelvic radiotherapy (EBRT) ± BR ± surgery group, the proportion of women with the preserved ovarian function was 61% (95% CI 55–69), and 95% (95% CI 85–107) of women who developed ovarian cysts. There were no metastases to the transposed ovaries in that group.
Conclusions
In women with cervical cancer, ovarian transposition offers a significant preservation of the ovarian function. Despite an expected incidence of ovarian cyst formation, it carries almost no risk for metastases to the transposed ovaries.
Objective To conduct a systematic review and metaanalysis of studies evaluating the regression rate of endometrial hyperplasia with oral progestogens and levonorgestrel-releasing intrauterine system. ...Study Design Searches were conducted on Medline, Embase, Cochrane Library, and Web of Science, and reference lists of relevant articles were examined. The methodologic index for nonrandomized studies was used for quality assessment. Metaanalysis was performed with random effects model. Results There were 24 observational studies (1001 women), of low methodologic quality, evaluating the outcome of regression of endometrial hyperplasia with oral progestogens or levonorgestrel-releasing intrauterine system. Metaanalysis showed that oral progestogens achieved a lower pooled regression rate compared with levonorgestrel-releasing intrauterine system for complex (pooled rate, 66% vs 92%; P < .01) and atypical hyperplasia (pooled rate, 69% vs 90%; P = .03). There was no statistical difference in simple hyperplasia (pooled rate, 89% vs 96%; P = .41). Conclusion Oral progestogens appear to induce a lower disease regression rate than Levonorgestrel-releasing intrauterine system in the treatment of endometrial hyperplasia.
What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome?
Data were analysed from 25,767 IVF ...cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses.
The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92).
Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.
Carbetocin: Worth the extra expense? Gallos, Ioannis D; Coomarasamy, Arri
Best practice & research. Clinical obstetrics & gynaecology
61
Journal Article
Recenzirano
Every six minutes, a mother dies from post-partum haemorrhage (PPH) in low- and middle-income countries, often in the prime of her life and often leaving behind a young family. To prevent PPH, the ...routine administration of a uterus-contracting ('uterotonic') agent is a standard practice across the world. Oxytocin is the standard uterotonic agent recommended for this purpose, and is recommended for all women giving birth. Oxytocin is problematic as it requires cold storage and transport, and in low-resource settings, the cold chain is not commonly available. Hence, using heat-stable carbetocin in these settings can be advantageous. Heat-stable carbetocin is a promising alternative to oxytocin. Because of its heat stability, it can overcome the persistent problems with oxytocin quality as it does not require cold chain for storage and transport. Considering the totality of the evidence, it appears to have some additional desirable effects compared with oxytocin and a very favourable side effect profile similar to oxytocin. However, because carbetocin costs 20 times more than oxytocin and is not widely available yet, oxytocin remains the mainstay for prevention of PPH. However, this may change as WHO has signed a memorandum of understanding with the manufacturer to provide carbetocin for the public sector of LMIC at a similar price level to that of oxytocin. Currently, carbetocin is being registered in 90 low- and middle-income countries to be made available and improve access to this life-saving uterotonic agent.
Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime, and 15% to 20% of ...pregnancies ending in a miscarriage. Progesterone has an important role in maintaining a pregnancy, and supplementation with different progestogens in early pregnancy has been attempted to rescue a pregnancy in women with early pregnancy bleeding (threatened miscarriage), and to prevent miscarriages in asymptomatic women who have a history of three or more previous miscarriages (recurrent miscarriage).
To estimate the relative effectiveness and safety profiles for the different progestogen treatments for threatened and recurrent miscarriage, and provide rankings of the available treatments according to their effectiveness, safety, and side-effect profile.
We searched the following databases up to 15 December 2020: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies.
We included all randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage. Cluster-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded quasi- and non-randomised trials.
At least two review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We performed pairwise meta-analyses and indirect comparisons, where possible, to determine the relative effects of all available treatments, but due to the limited number of included studies only direct or indirect comparisons were possible. We estimated the relative effects for the primary outcome of live birth and the secondary outcomes including miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy, congenital abnormalities, and adverse drug events. Relative effects for all outcomes are reported separately by the type of miscarriage (threatened and recurrent miscarriage). We used the GRADE approach to assess the certainty of evidence.
Our meta-analysis included seven randomised trials involving 5,682 women, and all provided data for meta-analysis. All trials were conducted in hospital settings. Across seven trials (14 treatment arms), the following treatments were used: three arms (21%) used vaginal micronized progesterone; three arms (21%) used dydrogesterone; one arm (7%) used oral micronized progesterone; one arm (7%) used 17-α-hydroxyprogesterone, and six arms (43%) used placebo. Women with threatened miscarriage Based on the relative effects from the pairwise meta-analysis, vaginal micronized progesterone (two trials, 4090 women, risk ratio (RR) 1.03, 95% confidence interval (CI) 1.00 to 1.07, high-certainty evidence), and dydrogesterone (one trial, 406 women, RR 0.98, 95% CI 0.89 to 1.07, moderate-certainty evidence) probably make little or no difference to the live birth rate when compared with placebo for women with threatened miscarriage. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with threatened miscarriage. The pre-specified subgroup analysis by number of previous miscarriages is only possible for vaginal micronized progesterone in women with threatened miscarriage. In women with no previous miscarriages and early pregnancy bleeding, there is probably little or no improvement in the live birth rate (RR 0.99, 95% CI 0.95 to 1.04, high-certainty evidence) when treated with vaginal micronized progesterone compared to placebo. However, for women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). Women with recurrent miscarriage Based on the results from one trial (826 women) vaginal micronized progesterone (RR 1.04, 95% CI 0.95 to 1.15, high-certainty evidence) probably makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. The evidence for dydrogesterone compared with placebo for women with recurrent miscarriage is of very low-certainty evidence, therefore the effects remain unclear. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with recurrent miscarriage. Additional outcomes All progestogen treatments have a wide range of effects on the other pre-specified outcomes (miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy) in comparison to placebo for both threatened and recurrent miscarriage. Moderate- and low-certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened (congenital abnormalities RR 1.00, 95% CI 0.68 to 1.46, moderate-certainty evidence; adverse drug events RR 1.07 95% CI 0.81 to 1.39, moderate-certainty evidence) or recurrent miscarriage (congenital abnormalities 0.75, 95% CI 0.31 to 1.85, low-certainty evidence; adverse drug events RR 1.46, 95% CI 0.93 to 2.29, moderate-certainty evidence) compared with placebo. There are limited data and very low-certainty evidence on congenital abnormalities and adverse drug events for the other progestogens.
The overall available evidence suggests that progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage. However, vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early pregnancy bleeding, with likely no difference in adverse events. There is still uncertainty over the effectiveness and safety of alternative progestogen treatments for threatened and recurrent miscarriage.
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or ...threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE PROgesterone in recurrent MIScarriagE trial) and the other targeting women with early pregnancy bleeding (the PRISM PRogesterone In Spontaneous Miscarriage trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03–1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08–1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy ...makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.
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