Risk of ectopic pregnancy is linked to endometrial thickness in a retrospective cohort study of 8120 assisted reproduction technology cycles.

STUDY QUESTION: Is endometrial combined thickness (ECT) measured prior to embryo transfer (ET) associated with ectopic pregnancy (EP)? SUMMARY ANSWER: Following IVF, the risk of EP is 4-fold increased in women with an ECT of <9 mm compared with women with an ECT of >12 mm. WHAT IS KNOWN ALREADY: Known risk factors for EP include tubal damage, maternal cigarette smoking and endometriosis. EP is also more common following IVF but the underlying causes for this remain unclear. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study restricted to all IVF cycles leading to a pregnancy (ßhCG > 50 IU/l) between January 2006 and December 2014. A total of 6465 patients achieved a pregnancy in 8120 cycles. Cycles using preimplantation genetic screening or donor oocytes were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: This cohort consists of 6465 patients achieving a pregnancy in 6920 stimulated cycles with fresh embryo transfers (STIM ET) and 1200 hormone replacement therapy frozen embryo transfers (HRT-FET) cycles at a private IVF unit (Monash IVF, Melbourne, Australia). ECT was the primary independent variable of interest; the primary outcome was a diagnosis of EP. The dataset was analysed using binary logistic general estimating equations (SPSS v22.0) to calculate odds ratio (OR) for EP adjusted for known confounders (aOR). There was no loss to follow-up in the dataset. MAIN RESULTS AND THE ROLE OF CHANCE: The study groups did not differ significantly prior to IVF treatment. After adjusting for confounders, ECT remained statistically significant as an independent risk factor for EP. Compared with women with an ECT of <9 mm, women with an ECT of 9-12 mm had an aOR of 0.44 (95% CI 0.29-0.69, P < 0.01) and women with an ECT > 12 mm had an aOR of 0.27 (95% CI 0.10-0.77, P = 0.01). These differences remained statistically significant after performing a sensitivity analysis excluding HRT-FET, smokers and patients with tubal infertility. LIMITATIONS, REASONS FOR CAUTION: The study design is retrospective, and it is possible that not all confounders have been accounted for. Measurement of ECT was performed by highly trained sonographers, but some inconsistency between individuals may be present. WIDER IMPLICATIONS OF THE FINDINGS: Our group has previously demonstrated an increased risk of placenta praevia with increased ECT. These new findings suggest that the directionality of the uterine peristalsis waves matters more than their frequency or amplitude. Combining the data from both studies we now hypothesize that increased ECT is a marker for increased fundus-to-cervix uterine peristalsis, explaining both the increased placenta praevia risk and the lower EP risk. Further prospective studies are required to confirm these observations.

Live birth rates after combined adjuvant therapy in IVF-ICSI cycles: a matched case-control study.

The effectiveness of combined co-treatment with aspirin, doxycycline, prednisolone, with or without oestradiol patches, was investigated on live birth (LBR) rates after fresh and frozen embryo transfers (FET) in IVF and intracytoplasmic sperm injection cycles. Cases (n = 485) and controls (n = 485) were extensively matched in a one-to-one ratio on nine physical and clinical parameters: maternal age, body mass index, smoking status, stimulation cycle number, cumulative dose of FSH, stimulation protocol, insemination method, day of embryo transfer and number of embryos transferred. No significant differences were found in fresh cycles between cases and controls for the pregnancy outcomes analysed, but fewer surplus embryos were available for freezing in the combined adjuvant group. In FET cycles, LBR was lower in the treatment group (OR: 0.49, 95% CI 0.25 to 0.95). The lower LBR in FET cycles seemed to be clustered in patients receiving combined adjuvant treatment without luteal oestradiol (OR 0.37, 95% CI 0.17 to 0.80). No difference was found in LBR between cases and controls when stratified according to the number of previous cycles (<3 or ≥3). There is no benefit of this combined adjuvant strategy in fresh IVF cycles, and possible harm when used in frozen cycles.

Risk of placenta praevia is linked to endometrial thickness in a retrospective cohort study of 4537 singleton assisted reproduction technology births.

STUDY QUESTION: Is endometrial thickness measured prior to embryo transfer associated with placenta praevia? SUMMARY ANSWER: Following IVF, the risk of placenta praevia is increased 4-fold in women with an endometrial thickness of >12 mm compared with women with an endometrial thickness of <9 mm. WHAT IS KNOWN ALREADY: Placenta praevia is a serious complication of pregnancy with adverse maternal and neonatal outcomes. Placenta praevia is 2- to 6-fold more likely to occur following IVF treatment but it remains unknown what factors contribute to that increased risk. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study involving 4007 women who had 4537 singleton assisted reproduction technology (ART) births occurring between January 2006 and June 2012 with no loss to follow-up. The primary outcome measure was the diagnosis of placenta praevia, made by the treating obstetrician on a transvaginal ultrasound in the third trimester. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had singleton births following single embryo transfer performed at Monash IVF in Melbourne, Australia were included. Of the 4537 cycles leading to a singleton ART birth, 2951 were stimulated cycles with fresh embryo transfers; 355 were hormone replacement therapy frozen embryo transfers and 1231 were natural cycles with frozen embryo transfers. The dataset was analysed using binary logistic general estimating equations to calculate odds ratios for placenta praevia adjusted (aOR) for known confounders. MAIN RESULTS AND THE ROLE OF CHANCE: The study groups did not differ significantly in age, BMI and aetiologies of infertility prior to IVF treatment. When compared with stimulated cycles, placenta praevia was less common in women undergoing natural cycles with frozen embryo transfers (OR 0.44, 95% confidence interval (CI) 0.27-0.70, P < 0.01) but hormone replacement therapy frozen embryo transfer cycles were not associated with a lower risk (OR 0.89, 95% CI 0.48-1.63). After adjusting for confounders, smoking (aOR 2.58, 95% CI 1.07-6.24, P = 0.04, endometriosis (aOR 2.01, 95% CI 1.21-3.33, P < 0.01) and endometrial thickness remained statistically significant as independent risk factors for placenta praevia. Compared with women with an endometrial thickness of <9 mm, women with an endometrial thickness of 9-12 mm had an aOR of 2.02 (95% CI 1.12-3.65, P = 0.02) and women with an endometrial thickness >12 mm had an aOR of 3.74 (95% CI 1.90-7.34, P < 0.01). These differences remained statistically significant after performing a sensitivity analysis limited to women with no previous births. LIMITATIONS, REASONS FOR CAUTION: The study is retrospective in nature, not all confounders may have been accounted for and details on previous intrauterine surgery, a known risk factor, were not available. In addition, ultrasound assessments were carried out by several highly trained operators measuring the endometrial thickness, the main independent variable, in a two-dimensional plane and some inter-observer variability may therefore be present. WIDER IMPLICATIONS OF THE FINDINGS: The findings of a higher risk of placenta praevia in patients with endometriosis and in those that smoke are in agreement with the current literature on natural conception. There have so far been no reports of an association between endometrial thickness and placenta praevia after ART. This novel finding warrants further study to elucidate the underlying cause of the association and to assess how to minimize harm to IVF patients and their offspring. The fact that the observed increased risk is not linked to the type of embryo transfer (fresh/frozen) but to the type of endometrial preparation, suggests that the risk of placenta praevia in ART can be reduced by considering an elective frozen embryo transfer in a natural cycle, especially given the growing evidence that this strategy also provides a number of other maternal and neonatal benefits. STUDY FUNDING/COMPETING INTERESTS: No funding was required for this study. L.R. has a minority shareholding in Monash IVF and has received unconditional research and educational grants from MSD, Merck-Serono and Ferring. L.R. serves on an advisory board for MSD and Ferring.

Incidence and zygosity of twin births following transfers using a single fresh or frozen embryo.

STUDY QUESTION: Are all twin births following single embryo transfer (SET) monozygotic? SUMMARY ANSWER: Between 1 in 10 and in 1 in 5 twins born after SET are the result of a concurrent natural conception. WHAT IS KNOWN ALREADY: The twinning rate after SET is higher than following natural conception. Most studies of twins following SET have incorrectly assumed monozygosity or have not been able to assess the zygosity. STUDY DESIGN, SIZE, DURATION: This study is a retrospective cohort study assessing the gender discordance of all live born twins following fresh or frozen SET. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 4701 patients in a large private IVF unit who gave birth following SET with a fresh or frozen embryo with complete follow-up. Of 137 viable twins at the 7-week ultrasound, 109 were delivered as twins. Gender discordance and Weinberg's differential rule were used to estimate dizygosity. Twin rates were compared for fresh and frozen transfers by insemination method and transfer day. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live twin birth rate was 2.3% (109/4701). Based on the 7-week scan, 2 of the twins were monochorionic monoamniotic, 62 were monochorionic diamniotic and 45 were dichorionic diamniotic. There were a total of 12 gender discordant twins (11%), 7 from the Day 2/3 transfers and 5 from Day 5 transfers. Nine of the 12 discordant twins were from natural cycle frozen embryo transfers, the remaining 3 were from fresh cycles. LIMITATIONS, REASONS FOR CAUTION; To assess gender discordance only live born twins were studied. DNA fingerprinting of twins is a more accurate way to assess zygosity than measuring gender discordance. Same sex twins in this study are not necessarily monozygotic and the dizygotic rate in this study may therefore be higher. This rate was estimated using Weinberg's differential rule. WIDER IMPLICATIONS OF THE FINDINGS: As many as 1 in 5 twins born after SET may be the result of a concurrent natural conception. Couples therefore need to be counselled regarding the relative benefits and risks of intercourse in assisted reproduction technology cycles where spontaneous conception is possible. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable.