Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer?

BACKGROUND: Initial observational studies and a systematic review published 5 years ago have suggested that obstetric and perinatal outcomes are better in offspring conceived following frozen rather than fresh embryo transfers, with reduced risks of preterm birth, small for gestational age, low birth weight and pre-eclampsia. More recent primary studies are beginning to challenge some of these findings. We therefore conducted an updated systematic review and cumulative meta-analysis to examine if these results have remained consistent over time. OBJECTIVE AND RATIONALE: The aim of this study was to perform a systematic review and cumulative meta-analysis (trend with time) of obstetric and perinatal complications in singleton pregnancies following the transfer of frozen thawed and fresh embryos generated through in-vitro fertilisation. SEARCH METHODS: Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984-2016) were searched using appropriate key words. Observational and randomised studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived through IVF using either fresh or frozen thawed embryos. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using CASP scoring. Both aggregated as well as cumulative meta-analysis was done using STATA. OUTCOMES: Twenty-six studies met the inclusion criteria. Singleton babies conceived from frozen thawed embryos were at lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84-0.97) low birth weight (0.72; 95% CI 0.67-0.77) and small for gestational age (0.61; 95% CI 0.56-0.67) compared to those conceived from fresh embryo transfers, but faced an increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07-1.56) large for gestational age (1.54; 95% CI 1.48-1.61) and high birth weight (1.85; 95% CI 1.46-2.33). There was no difference in the risk of congenital anomalies and perinatal mortality between the two groups. The direction and magnitude of effect for these outcomes have remained virtually unchanged over time while the degree of precision has improved with the addition of data from newer studies. WIDER IMPLICATIONS: The results of this cumulative meta-analysis confirm that the decreased risks of small for gestational age, low birth weight and preterm delivery and increased risks of large for gestational age and high birth weight associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with increasing precision around the point estimates. Replication in a number of different populations has provided external validity for the results, for outcomes of birth weight and preterm delivery. Meanwhile, caution should be exercised about embarking on a policy of electively freezing all embryos in IVF as there are increased risks for large for gestational age babies and hypertensive disorders of pregnancy. Therefore, elective freezing should ideally be undertaken in specific cases such as ovarian hyperstimulation syndrome, fertility preservation or in the context of randomised trials.

Is initial excision of cutaneous melanoma by General Practitioners (GPs) dangerous? Comparing patient outcomes following excision of melanoma by GPs or in hospital using national datasets and meta-analysis.

BACKGROUND: Melanomas are initially excised in primary care, and rates vary internationally. Until now, there has been no strong evidence one way or the other that excising melanomas in primary care is safe or unsafe. European guidelines make no recommendations, and the United Kingdom (UK) melanoma guidelines require all suspicious skin lesions to be initially treated in secondary care based on an expert consensus, which lacks supporting evidence, that primary care excision represents substandard care. Despite this, studies have found that up to 20% of melanomas in the UK are excised by general practitioners (GPs). Patients receiving primary care melanoma excision may fear that their care is substandard and their long-term survival threatened, neither of which may be justified. METHODS: Scottish cancer registry data from 9367 people diagnosed with melanoma in Scotland between 2005 and 2013 were linked to pathology records, hospital data and death records. A Cox proportional hazards regression analysis, adjusting for key confounders, explored the association between morbidity and mortality and setting of primary melanoma excision (primary versus secondary care). A pooled estimate of the relative hazard of death of having a melanoma excised in primary versus secondary care including 7116 patients from a similar Irish study was also performed. RESULTS: The adjusted hazard ratio (95% CI) of death from melanoma for those having primary care excision was 0.82 (0.61-1.10). Those receiving primary care excision had a median (IQR) of 8 (3-14) out-patient attendances compared to 10 (4-17) for the secondary care group with an adjusted relative risk (RR) (95% CI) of 0.98 (0.96-1.01). Both groups had a median of 1 (0-2) hospital admissions with an adjusted rate ratio of 1.05 (0.98-1.13). In the meta-analysis, with primary care as the reference, the pooled adjusted hazard ratio (HR, 95% CI) was 1.26 (1.07-1.50) indicating a significantly higher all-cause mortality among those with excision in secondary care. CONCLUSIONS: The results of the Scottish and pooled analyses suggest that those receiving an initial excision for melanoma in primary care do not have poorer survival or increased morbidity compared to those being initially treated in secondary care. A randomised controlled trial to inform a greater role for GPs in the initial excision of melanoma is justified in the light of these results.

Inherited predisposition to spontaneous preterm delivery.

OBJECTIVE: To assess inherited predisposition to spontaneous preterm delivery. METHODS: In this retrospective cohort study, intergenerational data on deliveries in mother-daughter pairs were analyzed from the Aberdeen Maternity Neonatal Databank using multilevel logistic regression. The study included an exposed cohort of all women born spontaneously preterm or whose mothers had experienced at least one spontaneous preterm delivery (at 24-37 weeks of gestation). The unexposed cohort included women who were born at term (after 37 weeks of gestation) or those whose mothers had never experienced any spontaneous preterm deliveries (24-37 weeks of gestation). The primary outcome was spontaneous preterm delivery in the daughters' pregnancies. Results are shown as adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We identified 22,343 pregnancies occurring in 13,845 daughters born to 11,576 mothers. Women who were born spontaneously preterm had significantly higher odds of delivering preterm babies (OR 1.49, 95% CI 1.12-1.99). A stronger association was seen when the analysis was restricted to nulliparous women who had been born spontaneously preterm (OR 1.60, 95% CI 1.16-2.21). Other predictors of a woman having a spontaneous preterm delivery were age at delivery younger than 20 years (OR 1.67, 95% CI 1.43-1.94), lower socioeconomic status (OR 1.22, 95% CI 1.04-1.44), smoking more than 10 cigarettes per day (OR 1.47, 95% CI 1.27-1.71), body mass index 19 kg/m or less (OR 1.48, 95% CI 1.24-1.77), previous preterm delivery (OR 2.51, 95% CI 1.71-3.66). The risk of a woman delivering spontaneously preterm was increased even if her mother had a history of spontaneous preterm delivery in any other pregnancy (OR 1.35, 95% CI 1.12-1.63). The absolute risk of spontaneously delivering preterm in women who were born preterm was 9% as opposed to 6.2% in those who were born full-term. This gives an increase in risk of spontaneous preterm birth of 2.8% in women who were born spontaneously preterm. CONCLUSION: Women born spontaneously preterm or with siblings delivered in a similar manner have an increased risk of spontaneous preterm delivery in their own pregnancies. LEVEL OF EVIDENCE: II.