Comparing very low birth weight versus very low gestation cohort methods for outcome analysis of high risk preterm infants.

BACKGROUND: Compared to very low gestational age (<32 weeks, VLGA) cohorts, very low birth weight (<1500 g; VLBW) cohorts are more prone to selection bias toward small-for-gestational age (SGA) infants, which may impact upon the validity of data for benchmarking purposes. METHOD: Data from all VLGA or VLBW infants admitted in the 3 Networks between 2008 and 2011 were used. Two-thirds of each network cohort was randomly selected to develop prediction models for mortality and composite adverse outcome (CAO: mortality or cerebral injuries, chronic lung disease, severe retinopathy or necrotizing enterocolitis) and the remaining for internal validation. Areas under the ROC curves (AUC) of the models were compared. RESULTS: VLBW cohort (24,335 infants) had twice more SGA infants (20.4% vs. 9.3%) than the VLGA cohort (29,180 infants) and had a higher rate of CAO (36.5% vs. 32.6%). The two models had equal prediction power for mortality and CAO (AUC 0.83), and similarly for all other cross-cohort validations (AUC 0.81-0.85). Neither model performed well for the extremes of birth weight for gestation (<1500 g and ≥32 weeks, AUC 0.50-0.65; ≥1500 g and <32 weeks, AUC 0.60-0.62). CONCLUSION: There was no difference in prediction power for adverse outcome between cohorting VLGA or VLBW despite substantial bias in SGA population. Either cohorting practises are suitable for international benchmarking.

Increased incidence of gestational hypertension and preeclampsia after assisted reproductive technology treatment.

OBJECTIVE: To determine the association between assisted reproductive technology (ART) treatment and the rate of combined gestational hypertension (GH), preeclampsia (PE). DESIGN: Retrospective population study. SETTING: Not applicable. PATIENT(S): A total of 596,520 mothers (3.6% ART mothers) who gave birth between 2007 and 2011. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Comparison of the rate of GH/PE for ART and non-ART mothers, with odds ratio (OR), adjusted odds ratio (AOR), and 95% confidence interval (CI) used to assess the association between ART and GH/PE. RESULT(S): The overall rate of GH/PE was 4.3%, with 6.4% for ART mothers and 4.3% for non-ART mothers. The rate of GH/PE was higher for mothers of twins than singletons (12.4% vs. 5.7% for ART mothers; 8.6% vs. 4.2% for non-ART mothers). The ART mothers had a 17% increased odds of GH/PE compared with the non-ART mothers (AOR 1.17; 95% CI, 1.10-1.24). After stratification by plurality, the difference in GH/PE rates between ART and non-ART mothers was not statistically significant, with AOR 1.05 (95% CI, 0.98-1.12) for mothers of singletons and AOR 1.10 (95% CI, 0.94-1.30) for mothers of twins. CONCLUSION(S): The changes in AOR after stratification indicated that multiple pregnancies after ART are the single most likely explanation for the increased rate of GH/PE among ART mothers. The lower rate of GH/PE among mothers of singletons compared with mothers of twins suggests that a policy to minimize multiple pregnancies after ART may reduce the excess risk of GH/PE due to ART treatment.

Risk of preterm birth after blastocyst embryo transfer: a large population study using contemporary registry data from Australia and New Zealand.

OBJECTIVE: To investigate whether there is an increased risk of preterm birth with blastocyst transfer compared with cleavage-stage embryo transfer (ET) after assisted reproductive technology (ART). DESIGN: A retrospective, population-based study. SETTING: Not applicable. PATIENT(S): A total of 50,788 infants conceived after ART treatment performed from 2009 to 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rates of preterm birth, low birth weight (LBW), and small for gestational age (SGA) for 43,952 singleton and 3,418 twin deliveries after transfers of blastocyst or cleavage-stage embryos. RESULT(S): Among singletons, there was no significant difference in the odds of preterm birth between blastocyst and cleavage-stage ET (9.1% compared with 9.3%, respectively, adjusted odds ratio 1.00, 95% confidence interval 0.94-1.08). Among twins, the crude rates of preterm birth were similar after blastocyst and cleavage-stage ETs (61.5% and 64.4%, respectively). However, after adjusting for potential confounders, blastocyst transfer was associated with a lower odds of preterm birth among twins (adjusted odds ratio 0.80, 95% confidence interval 0.70-0.93). There was no difference in risks of LBW and SGA between blastocyst and cleavage-stage ETs for both singletons and twins after adjusting for potential confounders. CONCLUSION(S): In contrast with the findings from a number of other studies, blastocyst culture in Australian and New Zealand is not associated with an increased risk of preterm, LBW, and SGA for singletons. Further studies are needed to assess longer-term outcomes of children born after ART treatment and possible biological or treatment factors related to adverse outcomes.

Risk factors associated with preterm birth among singletons following assisted reproductive technology in Australia 2007-2009--a population-based retrospective study.

BACKGROUND: Preterm birth, a leading cause of neonatal death, is more common in multiple births and thus there has being an increasing call for reducing multiple births in ART. However, few studies have compared risk factors for preterm births amongst ART and non-ART singleton birth mothers. METHODS: A population-based study of 393,450 mothers, including 12,105 (3.1%) ART mothers, with singleton gestations born between 2007 and 2009 in 5 of the 8 jurisdictions in Australia. Univariable and multivariable logistic regression models were conducted to evaluate socio-demographic, medical and pregnancy factors associated with preterm births in contrasting ART and non-ART mothers. RESULTS: Ten percent of singleton births to ART mothers were preterm compared to 6.8% for non-ART mothers (P < 0.01). Compared with non-ART mothers, ART mothers were older (mean 34.0 vs 29.7 yr respectively), less socio-economically disadvantaged (12.4% in the lowest quintile vs 20.7%), less likely to be smokers (3.8% vs 19.4%), more likely to be first time mothers (primiparous 62.4% vs 40.5%), had more preexisting hypertension and complications during pregnancy. Irrespective of the mode of conception, preexisting medical and pregnancy complications of hypertension, diabetes and antepartum hemorrhages were consistently associated with preterm birth. In contrast, socio-demographic variables, namely young and old maternal age (<25 and >34), socioeconomic disadvantage (most disadvantaged quintile Odds Ratio (OR) 0.95, 95% Confidence Interval (CI): 0.77-1.17), smoking (OR 1.12, 95%CI: 0.79-1.61) and priminarity (OR 1.19, 95% CI: 1.05-1.35, AOR not significant) shown to be associated with elevated risk of preterm birth for non-ART mothers were not demonstrated for ART mothers, even after adjusting for potential confounders. Nonetheless, in multivariable analysis, the association between ART and the elevated risk for singleton preterm birth persisted after controlling for all included confounding medical, pregnancy and socio-economic factors (AOR 1.51, 95% CI: 1.42-1.61). CONCLUSIONS: Preterm birth rate is approximately one-and-a-half-fold higher in ART mothers than non-ART mothers albeit for singleton births after controlling for confounding factors. However, ART mothers were less subject to the adverse influence from socio-demographic factors than non-ART mothers. This has implications for counselling prospective parents.

Birthweight percentiles by gestational age for births following assisted reproductive technology in Australia and New Zealand, 2002-2010.

STUDY QUESTION: What is the standard of birthweight for gestational age for babies following assisted reproductive technology (ART) treatment? SUMMARY ANSWER: Birthweight for gestational age percentile charts were developed for singleton births following ART treatment using population-based data. WHAT IS KNOWN ALREADY: Small for gestational age (SGA) and large for gestational age (LGA) births are at increased risks of perinatal morbidity and mortality. A birthweight percentile chart allows the detection of neonates at high risk, and can help inform the need for special care if required. STUDY DESIGN, SIZE, DURATION: This population study used data from the Australian and New Zealand Assisted Reproduction Database (ANZARD) for 72 694 live born singletons following ART treatment between January 2002 and December 2010 in Australia and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 69 315 births (35 580 males and 33 735 females) following ART treatment were analysed for the birthweight percentile. Exact percentiles of birthweight in grams were calculated for each gestational week between Week 25 and 42 for fresh and thaw cycles by infant sex. Univariate analysis was used to determine the exact birthweight percentile values. Student t-test was used to examine the mean birthweight difference between male and female infants, between single embryo transfer (SET) and double embryo transfer (DET) and between fresh and thaw cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Preterm births (birth before 37 completed weeks of gestation) and low birthweight (<2500 g) were reported for 9.7 and 7.0% of live born singletons following ART treatment. The mean birthweight was 3280 g for live born singletons following fresh cycles (3338 g for male infants and 3217 for female infants) and 3413 g for live born singletons following thaw cycles (3475 g for male infants and 3349 for female infants). The proportion of SGA for male ART births following thaw cycles at 35-41 weeks gestation was significantly lower than for the Australian general population, ranging from 3.8% (95% confidence interval (CI): 1.3%, 6.2%) at 35 weeks gestation to 7.9% (95% CI: 6.3%, 9.5%) at 41 weeks gestation. The proportion of LGA for male ART births following thaw cycles was significantly higher than for the Australian general population between 33 weeks (17.1%, 95% CI: 8.9%, 25.2%) and 41 weeks (14.4%, 95% CI: 12.3%, 16.5%). A similar trend was shown for female infants following thaw cycles. The live born singletons following SET were, on average, 45 g heavier than live born singletons following DET (P< 0.001). Overall, SGA was reported for 8.9% (95% CI: 8.6%, 9.1%) of live born singletons following SET and for 9.9% (95% CI: 9.5%, 10.3%) of live born singletons following DET. LIMITATIONS, REASONS FOR CAUTION: Birthweight percentile charts do not represent fetal growth standards but only the weight of live born infants at birth. WIDER IMPLICATIONS OF THE FINDINGS: The comparison of birthweight percentile charts for ART births and general population births provide evidence that the proportion of SGA births following ART treatment was comparable to the general population for SET fresh cycles and significantly lower for thaw cycles. Both fresh and thaw cycles showed better outcomes for singleton births following SET compared with DET. Policies to promote single embryo transfer should be considered in order to minimize the adverse perinatal outcomes associated with ART treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was obtained. The authors have no conflicts of interest to declare.

Perinatal mortality following assisted reproductive technology treatment in Australia and New Zealand, a public health approach for international reporting of perinatal mortality.

BACKGROUND: There is a need to have uniformed reporting of perinatal mortality for births following assisted reproductive technology (ART) treatment to enable international comparison and benchmarking of ART practice. METHODS: The Australian and New Zealand Assisted Reproduction Database was used in this study. Births of ≥ 20 weeks gestation and/or ≥ 400 grams of birth weight following embryos transfer cycles in Australia and New Zealand during the period 2004 to 2008 were included. Differences in the mortality rates by different perinatal periods from a gestational age cutoff of ≥ 20, ≥ 22, ≥ 24, or ≥ 28 weeks (wks) to a neonatal period cutoff of either < 7 or < 28 days after birth were assessed. Crude and specific (number of embryos transferred and plurality) rates of perinatal mortality were calculated for selected gestational and neonatal periods. RESULTS: When the perinatal period is defined as ≥ 20 wks gestation to < 28 days after birth, the perinatal mortality rate (PMR) was 16.1 per 1000 births (n = 630). A progressive contraction of the gestational age groups resulted in marked reductions in the PMR for deaths at < 28 days (22 wks 11.0; 24 wks 7.7; 28 wks 5.6); and similarly for deaths at < 7 days (20 wks 15.6, 22 wks 10.5; 24 wks 7.3; 28 wks 5.3). In contrast, a contraction of the perinatal period from < 28 to < 7 days after birth only marginally reduced the PMR from 16.2 to 15.6 per 1000 births which was consistent across all gestational ages.The PMR for single embryo transfer (SET) births (≥ 20 weeks gestation to < 7 days post-birth) was significantly lower (12.8 per 1000 SET births) compared to double embryo transfer (DET) births (PMR 18.3 per 1000 DET births; p < 0.001, Fisher's Exact Test). Similarly, the PMR for SET births (≥ 22 weeks gestation to < 7 days post-birth) was significantly lower (8.8 per 1000 SET births, p < 0.001, Fisher's Exact Test) when compared to DET births (12.2 per 1000 DET births). The highest PMR (50.5 per 1000 SET births, 95% CI 36.5-64.5) was for twins following SET births (≥ 20 weeks gestation to < 7 days post-birth) compared to twins following DET (23.9 per 1000 DET births, 95% CI 20.8-27.1). CONCLUSION: Reporting of perinatal mortality of ART births is an essential component of quality ART practice. This should include measures that monitor the impact on perinatal mortality of multiple embryo transfer. We recommend that reporting of perinatal deaths following ART treatment, should be stratified for three gestation-specific perinatal periods of ≥ 20, ≥ 22 and ≥ 28 completed weeks to < 7 days post-birth; and include plurality specific rates by SET and DET. This would provide a valuable international evidence-base of PMR for use in evaluating ART policy, practice and new research.

What can we learn from a decade of promoting safe embryo transfer practices? A comparative analysis of policies and outcomes in the UK and Australia, 2001-2010.

STUDY QUESTION: Given similar socio-demographic profiles and costs of healthcare, why has Australia been significantly more successful than the UK in reducing the assisted reproductive technology (ART) multiple birth rate? SUMMARY ANSWER: The Australian model of supportive public ART funding, permissive clinical guidelines and an absence of published clinic league tables has enabled Australian fertility specialists to act collectively to achieve rapid and widespread adoption of single embryo transfer (SET). WHAT IS KNOWN ALREADY: There are striking differences in ART utilization and clinical practice between Australia and the UK. The ART multiple birth rate in Australia is <8% compared with slightly <20% in the UK. The role played by public funding, clinical guidelines, league tables and educational campaigns deserves further evaluation. STUDY DESIGN, SIZE, DURATION: Parallel time-series analysis was performed on ART treatment and outcome data sourced from the Human Fertilisation and Embryology Authority (HFEA) ART Registry and the Australian and New Zealand Assisted Reproduction Database (ANZARD). Funding arrangements, clinical practice guidelines and key professional and public education campaigns were mapped to trends in clinical practice and ART treatment outcomes between 2001 and 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 425 360 and 422 003 autologous treatment cycles undertaken between 2001 and 2010 in the UK and Australia were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: From 2001 to 2010, the most striking difference in clinical practice was the increase in SET cycles in Australia from 21 to 70% of cycles, compared with an increase from 8.4 to 31% in the UK. In 2004-2005, both countries introduced clinical guidelines encouraging safe embryo practices, however, Australia has a history of supportive funding for ART, while the National Health Service has a more restrictive and fragmented approach. While clinical guidelines and education campaigns have an important role to play, funding remains a key element in the promotion of SET. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive population study and therefore quantifying the independent effect of differential levels of public funding was not possible. WIDER IMPLICATIONS OF THE FINDINGS: With demand for ART continuing to increase worldwide, it is imperative that we remove barriers that impede safe embryo transfer practices. This analysis highlights the importance of supportive public funding in achieving this goal.

Multiple deliveries: the reduced impact of in vitro fertilisation in Australia.

BACKGROUND: The number of twins born in Australia steadily increased from 2420 sets in 1983 to 4458 sets in 2010. At one stage, almost 25% of all twin deliveries in Australia were a consequence of assisted reproductive technologies. AIMS: To determine the influence of a policy of single embryo transfer (SET) on the rate of multiple deliveries in Australia. METHODS: We used population data to compare the prevalence of twin and higher order multiple births in women giving birth in Australia before and after the implementation of the RTAC COP 2001 and 2005 revisions for ART units. RESULTS: There was a steady fall in the twin delivery rate for assisted reproductive technologies from 210.4 per 1000 deliveries in 2001 to 84.3 per 1000 deliveries in 2009. In 2009, assisted reproductive technologies accounted for approximately 16% of all twin births from 3% of all conceptions, substantially less than the 24.5% in 2002. CONCLUSIONS: The decline in multiple births is multifactorial. However, the fall in the proportion of ART multiple births has paralleled adoption of a voluntary policy of SET within a setting of largely public funding of ART.

Single embryo transfer reduces the risk of perinatal mortality, a population study.

STUDY QUESTION: Do births following single embryo transfers (SET) have a reduced risk of perinatal mortality compared with those following double embryo transfers (DET)? SUMMARY ANSWER: SET is associated with reduced risk of perinatal mortality compared with DET. WHAT IS KNOWN ALREADY: Fetal, neonatal and perinatal mortality are important indicators for monitoring pregnancy and childbirth, particularly for births following assisted reproductive technology (ART) treatments. Following the introduction of SET, there has been a decline in the perinatal mortality rate (PMR) among babies born after ART in Australia and New Zealand. STUDY DESIGN, SIZE, DURATION: This population study (census) included 50,258 births of ≥ 20 weeks gestation and/or ≥ 400 g of birthweight following embryos transfer cycles in Australia and New Zealand during the period 2004-2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: The PMR was calculated according to the number of embryos transferred and other demographic and treatment-related factors. Perinatal deaths were defined as the number of fetal deaths (stillbirths) plus the number of neonatal deaths (deaths that occur before 28 days after birth). MAIN RESULTS AND THE ROLE OF CHANCE: The PMR was 16.2 per 1000 births (n= 813). Of the 813 perinatal deaths, 630 were fetal deaths and 183 neonatal deaths. Twins had a significantly higher PMR (27.8 per 1000 births) than singletons (12.4 per 1000 births). The risk of perinatal mortality for all births following DET was 53% higher than for all births following SET (adjusted risk ratio 1.53, 95% confidence interval (95% CI): 1.29-1.80). Births following fresh DET had a 58% increased risk of perinatal mortality compared with births following fresh SET (risk ratio 1.58, 95% CI: 1.32-1.90). LIMITATIONS, REASONS FOR CAUTION: Information on outcomes was missing from <1% of clinical pregnancies recorded in Australian and New Zealand Assisted Reproduction Database for the study period. There are no data on the timing of fetal death, the cause of perinatal death or on late termination of pregnancy at ≥ 20 weeks' gestation. WIDER IMPLICATIONS OF THE FINDINGS: Double and higher order embryo transfer is associated with a higher risk of perinatal mortality when compared with SET. The number of embryos transferred is determined by the clinician with consent of the patient and is a modifiable treatment factor. SET should be advocated as the first-line management in ART as it is the single most effective public health intervention for preventing excess perinatal mortality among ART pregnancies. STUDY FUNDING/COMPETING INTEREST(S): Nil.

Randomized controlled trial of cough test versus no cough test in the tension-free vaginal tape procedure: effect upon voiding dysfunction and 12-month efficacy.

INTRODUCTION AND HYPOTHESIS: This is a prospective randomized controlled trial of cough versus no cough test in the tension-free vaginal tape (TVT) procedure to determine its effect upon voiding dysfunction and 12-month efficacy. METHODS: The trial was conducted in a single tertiary urogynecology unit. Women ≥21 years old with primary urodynamic stress incontinence without voiding dysfunction were considered eligible. Participants were randomized to undergo the TVT procedure using either an intraoperative cough test or using no intraoperative cough test. Our hypothesis was that postoperative voiding dysfunction would be more common in the "no cough test" arm. The primary outcome was proportion of patients successfully completing a trial of void (TOV) within 24 h of catheter removal. Efficacy at 12 months comprised the secondary outcome. Participants were randomized using a computer-generated randomization sequence by an independent party who was not the operating surgeon. Due to the nature of the intervention to be tested, neither the patients nor the operating surgeons were blinded to the randomization process during the procedure. RESULTS: This trial is reported according to the recommendations of the 2010 CONSORT statement. In total, 94 women were recruited over a 4-year study period. Of these, 92 women were randomized (47 in the "cough" group and 45 in the "no cough" group). In one case, the TVT procedure was abandoned intraoperatively, leaving 91 women who underwent analysis. There was no significant difference in the proportion of women with a successful TOV within 24 h between the two arms (79% in the "cough" group versus 71% in the "no cough" group; p = 0.47). Efficacy data at 12 months were not significantly different between groups. CONCLUSION: Our data suggest that the performance of the intraoperative cough test during the TVT procedure does not reduce the incidence of postoperative voiding dysfunction (as determined by successful TOV within 24 h) nor affect efficacy. The removal of the cough test from the standard TVT technique may be appropriate.

Population-based study of cesarean section after in vitro fertilization in Australia.

BACKGROUND: Decisions about method of birth should be evidence based. In Australia, the rising rate of cesarean section has not been limited to births after spontaneous conception. This study aimed to investigate cesarean section among women giving birth after in vitro fertilization (IVF). METHODS: Retrospective population-based study was conducted using national registry data on IVF treatment. The study included 17,019 women who underwent IVF treatment during 2003 to 2005 and a national comparison population of women who gave birth in Australia. The outcome measure was cesarean section. RESULTS: Crude rate of cesarean section was 50.1 percent versus 28.9 percent for all other births. Single embryo transfer was associated with the lowest (40.7%) rate of cesarean section. Donor status and twin gestation were associated with significantly higher rates of cesarean section (autologous, 49.0% vs donor, 74.9%; AOR: 2.20, 95% CI: 1.80, 2.69) and (singleton, 45.0% vs twin gestations, 75.7%; AOR: 3.81, 95% CI: 3.46, 4.20). The gestation-specific rate (60.1%) of cesarean section peaked at 38 weeks for singleton term pregnancies. Compared with other women, cesarean section rates for assisted reproductive technology term singletons (27.8% vs 43.8%, OR: 2.02 [95% CI: 1.95-2.10]) and twins (62.0% vs 75.7%, OR: 1.92 [95% CI: 1.74-2.11]) were significantly higher. CONCLUSIONS: Rates for cesarean section appear to be disproportionately high in term singleton births after assisted reproductive technology. Vaginal birth should be supported and the indications for cesarean section evidence based.

Perinatal outcomes after assisted reproductive technology treatment in Australia and New Zealand: single versus double embryo transfer.

OBJECTIVE: To compare the perinatal outcomes of babies conceived by single embryo transfer (SET) with those conceived by double embryo transfer (DET). DESIGN, SETTING AND PARTICIPANTS: A retrospective population-based study of embryo transfer cycles in Australia and New Zealand between 2002 and 2006, using data from the Australia and New Zealand Assisted Reproduction Database. MAIN OUTCOME MEASURES: Proportion of SET procedures; comparison of SET and DET procedures with respect to multiple births, low birthweight (LBW), preterm birth and fetal death. RESULTS: The proportion of SET procedures has increased from 28.4% in 2002 to 32.0% in 2003, 40.5% in 2004, 48.2% in 2005 and 56.9% in 2006. The multiple birth rate for all babies conceived by SET (4.0%) was 10 times lower than for those conceived by DET (39.1%) (P < 0.01). The average birthweight for all liveborn babies conceived by SET (3290 g) was higher than for those conceived by DET (2934 g) (P < 0.01). The preterm birth rate of all DET-conceived babies (30.3%) was higher than for SET-conceived babies (12.3%) (adjusted odds ratio [AOR], 3.19 [95% CI, 3.01-3.38]). All babies conceived by DET were more likely to be stillborn than those conceived by SET (AOR, 1.49 [95% CI, 1.21-1.82]). Singletons conceived by DET were more likely to be born preterm than singletons conceived by SET (AOR, 1.13 [95% CI, 1.05-1.22]). Liveborn singletons conceived by DET were 15% more likely to have LBW than liveborn singletons conceived by SET (AOR, 1.15 [95% CI, 1.05-1.26]). There was no significant difference in fetal death rate between DET- and SET-conceived singletons. CONCLUSION: The increase in proportion of SET procedures has resulted in a lower rate of multiple births and in better perinatal outcomes in Australian and New Zealand assisted reproduction programs.