Abha Maheshwari

Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis

BACKGROUND Earlier reviews have suggested that IVF/ICSI pregnancies are associated with higher risks. However, there have been recent advances in the way IVF/ICSI is done, leading to some controversy as to whether IVF/ICSI singletons are associated with higher perinatal risks. The objective of this systematic review was to provide an up-to-date comparison of obstetric and perinatal outcomes of the singletons born after IVF/ICSI and compare them with those of spontaneous conceptions. METHODS Extensive searches were done by two authors. The protocol was agreed a priori. PRISMA guidance was followed. The data were extracted in 2 × 2 tables. Risk ratio and risk difference were calculated on pooled data using Rev Man 5.1. Quality assessment of studies was performed using Critical Appraisal Skills programme. Sensitivity analysis was performed when the heterogeneity was high (I(2) > 50%). RESULTS There were 20 matched cohort studies and 10 unmatched cohort studies included in this review. IVF/ICSI singleton pregnancies were associated with a higher risk (95% confidence interval) of ante-partum haemorrhage (2.49, 2.30-2.69), congenital anomalies (1.67, 1.33-2.09), hypertensive disorders of pregnancy (1.49, 1.39-1.59), preterm rupture of membranes (1.16, 1.07-1.26), Caesarean section (1.56, 1.51-1.60), low birthweight (1.65, 1.56-1.75), perinatal mortality (1.87, 1.48-2.37), preterm delivery (1.54, 1.47-1.62), gestational diabetes (1.48, 1.33-1.66), induction of labour (1.18, 1.10-1.28) and small for gestational age (1.39, 1.27-1.53). CONCLUSIONS Singletons pregnancies after IVF/ICSI are associated with higher risks of obstetric and perinatal complications when compared with spontaneous conception. Further research is needed to determine which aspect of assisted reproduction technology poses most risk and how this risk can be minimized.

Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis

OBJECTIVE To perform a systematic review and meta-analysis of obstetric and perinatal complications in singleton pregnancies after the transfer of frozen thawed and fresh embryos generated through IVF. DESIGN Systematic review. SETTING Observational studies, comparing obstetric and perinatal outcomes in singleton pregnancies subsequent to frozen thawed ET versus fresh embryo transfer, were included from Medline, EMBASE, Cochrane Central Register of Clinical Trials, DARE, and CINAHL (1984-2012). PATIENT(S) Women undergoing IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S) Two independent reviewers extracted data and assessed the methodological quality of the relevant studies using critical appraisal skills program scoring. Risk ratios and risk differences were calculated in Rev Man 5.1. Subgroup analysis was performed on matched cohort studies. MAIN OUTCOME MEASURE(S) Antepartum hemorrhage, very preterm birth, preterm birth, small for gestational age, low birth weight, very low birth weight, cesarean section, congenital anomalies, perinatal mortality, and admission to neonatal intensive care unit. RESULT(S) Eleven studies met the inclusion criteria. Singleton pregnancies after the transfer of frozen thawed embryos were associated with better perinatal outcomes compared with those after fresh IVF embryos. The relative risks (RR) and 95% confidence intervals (CI) of antepartum hemorrhage (RR = 0.67, 95% CI 0.55-0.81), preterm birth (RR = 0.84, 95% CI 0.78-0.90), small for gestational age (RR = 0.45, 95% CI 0.30-0.66), low birth weight (RR = 0.69, 95% CI 0.62-0.76), and perinatal mortality (RR = 0.68, 95% CI 0.48-0.96) were lower in women who received frozen embryos. CONCLUSION(S) Although fresh ET is the norm in IVF, results of this systematic review of observational studies suggest that pregnancies arising from the transfer of frozen thawed IVF embryos seem to have better obstetric and perinatal outcomes.

Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review

The objective of this study was to perform a systematic review of the literature to determine whether there is an association between polycystic ovary syndrome (PCOS) and gynaecological malignancy. Medline and Embase databases (1968-2008) were searched to identify publications on the association between PCOS and gynaecological cancers including breast cancer. Studies were selected that examined the association between PCOS and all types of gynaecological malignancies. A total of 19 studies exploring the association between PCOS and breast, endometrial and ovarian cancer were identified. Of these, only eight could be included after review. The data showed variability in the definition of PCOS. A meta-analysis of the data suggests that women with PCOS are more likely to develop cancer of the endometrium (OR 2.70, 95% CI 1.00-7.29) and ovarian cancer (OR 2.52, 95% CI 1.08-5.89) but not breast cancer (OR 0.88, 95% CI 0.44-1.77). Women with PCOS appear to be three times more likely to develop endometrial cancer but are not at increased risk of breast cancer. There is insufficient evidence to implicate PCOS in the development of vaginal, vulval, cervical or ovarian cancers. The paucity of studies investigating the association between PCOS and gynaecological cancers is likely to affect the reliability of the conclusions.

Effect of female age on the diagnostic categories of infertility

BACKGROUND As more women choose to delay childbearing, increasing numbers of them face age-related fertility problems. We aimed to explore the association between age and diagnosed causes of female infertility. METHODS Anonymized data (age of male and female partner, year of first visit, diagnosis, duration and type of infertility) were obtained on all couples attending Aberdeen Fertility Centre from 1993-2006. The prevalence of different causes of infertility was determined for women <35 and >or=35 years of age at the time of their first clinic visit. Binary logistic regression and multinomial regression were used to determine the association between age and diagnostic categories of infertility. RESULTS Of a total of 7172 women, 26.9% were over the age of 35 years and 51.4% of the total had primary infertility. The mean female age was 31.2 (5.2 SD) years. There was an association between female age and the cause of female infertility (likelihood ratio, P < 0.001). More women over 35 had unexplained infertility (26.6 versus 21.0%, P < 0.001). Compared with women under 30 years, the adjusted odds ratio (95% confidence intervals, CI) of the following diagnoses in women over 35 were: unexplained infertility = 1.8 (1.4-2.2), ovulatory dysfunction = 0.3 (0.3-0.4) and tubal factor = 2.2 (1.7-2.7). CONCLUSIONS The causes of infertility in older women are different from those in younger women. Women over 35 years of age are nearly twice as likely to present with unexplained infertility.

Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes

BACKGROUND Uterine adenomyosis was initially thought to be found only in parous women, and final diagnosis was made at histology after hysterectomy. With better imaging techniques and with women attending clinics at older ages, adenomyosis is diagnosed with increasing frequency in women attending infertility clinics. A dozen conservative interventions have been advocated, with variable reports of their impact on fertility. This presents a dilemma for clinicians managing such patients. Hence, this systematic review of adenomyosis was performed to determine (i) the prevalence in a subfertile population, (ii) the accuracy of diagnostic tests, (iii) the efficacy of fertility sparing treatment options and (iv) the reproductive and obstetric/perinatal outcomes in women with adenomyosis. METHODS Systematic searches of various databases were performed independently by two reviewers, and data were extracted according to predefined criteria by two reviewers. RESULTS There is little data on the epidemiology of adenomyosis associated with subfertility. Both magnetic resonance imaging and ultrasound are non-invasive tests with equivalent accuracy in diagnosing adenomyosis (area under curve 0.91 and 0.88, respectively). Most studies on treatments have been uncontrolled and outcomes are usually reported in the form of case series. Hence, the true impact of various treatments on fertility is not known. There are variable reports of the impact of adenomyosis on the success of IVF. Increased incidence of preterm labour and premature rupture of membranes has been reported in women with adenomyosis. CONCLUSIONS Further studies are needed to determine the natural history of adenomyosis and implications for fertility and reproductive outcomes, with and without treatment. Currently, there is no evidence that we should find and treat adenomyosis in patients who wish to conceive.

Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?

BACKGROUND Klinefelter syndrome is a common genetic condition. Affected non-mosaic men are azoospermic and have been labelled as infertile. Despite reports that these men can have children using assisted reproduction techniques, it is not common practice in the UK to offer sperm retrieval to these men. METHODS Medline and EMBASE (1980-2009) were searched independently by two authors and all studies involving surgical sperm retrieval in non-mosaic Klinefelter syndrome were included. The primary outcome was success of surgical sperm retrieval and the secondary outcome was live birth rate. RESULTS The overall success rate for sperm retrieval was 44%, with a higher rate of success using micro-dissection testicular sperm aspiration (micro-TESE) (55%). This, along with ICSI, has led to the birth of 101 children. However, there are no known predictors for successful sperm retrieval. Although there are concerns about genetic risk to the offspring of non-mosaic Klinefelter patients, this risk has not been found to be greater than that of patients with non-obstructive azoospermia with normal karyotype. CONCLUSIONS It is possible for a man with non-mosaic Klinefelter to father a child. However, before these techniques are offered, some ethical issues need to be explored.

Global variations in the uptake of single embryo transfer

BACKGROUND Single embryo transfer (SET) is the most effective way of reducing multiple pregnancy rates associated with assisted reproductive technology (ART). Despite published evidence suggesting that the judicious use of elective SET can lead to near-elimination of multiples without compromising cumulative live birth rates, the uptake of this strategy has been variable. METHODS Medline, EMBASE and the Cochrane Database of Systematic Reviews (1978-2010) were searched using appropriate MeSH headings. Leading fertility journals along with appropriate cross references were hand searched and information retrieved from national ART registers and websites of national fertility societies in order to determine current rates of SET. We explored social, economic and clinical factors determining the uptake of SET. RESULTS It was not possible to distinguish elective from non-elective SET from national ART reports. Data from 31 countries suggest that there has been a gradual increase in SET rates over a 3 year period (2003-2005) but major geographical differences were noted. SET rates are highest in Sweden (69.4%) but are as low as 2.8% in the USA. Access to public funding for ART, availability of good cryopreservation facilities and legislation appear to be the most important reasons favouring the uptake of SET. Personal choice plays a significant role as many subfertile couples have a strong preference for twins. Awareness that double embryo transfer (DET) increases live birth per fresh treatment cycle, inability to accurately identify women at high risk for twins and limitations of existing embryos selection criteria are barriers to a wider acceptance of SET. CONCLUSIONS The current variation in the uptake of elective SET is likely to persist until there are major changes in the way ART is viewed, funded and legislated.

Elective frozen replacement cycles for all: ready for prime time?

Conventionally, most in vitro fertilization (IVF) embryos are transferred in fresh treatment cycles with freezing reserved for spare ones. Improvement in cryopreservation facilities over time has encouraged the greater use of this technology with the success rate of frozen replacement cycles approaching that associated with fresh embryo transfer. Data from observational studies suggest that obstetric and perinatal outcomes are better in pregnancies resulting from frozen replacement cycles. In the interests of promoting feto-maternal safety is it therefore time to avoid fresh embryo transfers in IVF, freeze all available embryos and replace them in subsequent cycles? In this article we explore the biological plausibility of this concept, appraise the evidence underpinning it and consider the implications of adopting such a strategy in routine clinical practice. The outcomes of existing randomized trials appear to favour a strategy of frozen embryo transfer, but larger trials are needed before a major change in clinical practice can be considered.

Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of blastocyst-stage versus cleavage-stage embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis

OBJECTIVE To perform a systematic review and meta-analysis of obstetric and perinatal complications in singleton pregnancies after the transfer of blastocyst-stage and cleavage-stage embryos generated through IVF. DESIGN Systematic review. SETTING University hospital. PATIENT(S) Singleton pregnancies resulting from ET at the blastocyst stage versus those at the cleavage stage. INTERVENTION(S) Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE, and CINAHL (1980-2013) were searched. Two independent reviewers extracted data and assessed the methodological quality of the relevant studies using CASP scoring. Risk ratios and risk differences were calculated in Rev Man 5.1. MAIN OUTCOME MEASURE(S) Very preterm birth, preterm birth, small for gestational age, low birth weight, very low birth weight, congenital anomalies, perinatal mortality, preeclampsia, and placenta previa. RESULT(S) In vitro fertilization pregnancies occurring as a result of ET at the blastocyst stage were associated with a higher relative risk (RR; 95% confidence interval [CI]) of preterm (RR 1.27; 95% CI 1.22-1.31) and very preterm delivery (RR 1.22; 95% CI 1.10-1.35) in comparison with those resulting from the transfer of cleavage-stage embryos. The risk of growth restriction was lower in babies conceived through blastocyst transfer (RR 0.82; 95% CI 0.77-0.88). CONCLUSION(S) Data from observational studies show that ET at the blastocyst stage is associated with a higher risk of very preterm delivery. However, we were not able to adjust for confounders. Perinatal outcome data from existing randomized trials are needed to determine the safety of ET at the blastocyst stage compared with the cleavage stage.

Anti-Müllerian hormone—is it a crystal ball for predicting ovarian ageing?

Several studies have demonstrated that anti-Müllerian hormone (AMH) is a better marker of ovarian reserve than age, basal FSH, estradiol and inhibin. AMH is very good in (i) predicting both over- and poor-response in the controlled ovarian stimulation environment, (ii) determining the most appropriate stimulation regimen and (iii) pre-treatment counselling for couples to make an appropriate and informed choice. Recent reports are exploring the use of AMH in various other indications, including (i) predicting long-term fertility and guiding how long a woman can delay childbearing without facing the risk of reduced ovarian reserve, (ii) predicting the age of menopause, (iii) prediction of ovarian ageing in women prior to or following chemotherapy, (iv) prediction of long-term fertility following ovarian surgery and (v) screening for polycystic ovaries. However, widespread use of AMH for indications not proved by evidence-based medicine can lead to either false reassurance or distress, leading to unnecessary medical interventions . It also has huge implications for costs. We evaluated the evidence basis for using AMH for various indications to decide how justified it is to promote AMH as a crystal ball, until more evidence is available.