Economic evaluations of assisted reproductive technologies in high-income countries: a systematic review.

STUDY QUESTION: Which assited reproductive technology (ART) interventions in high-income countries are cost-effective and which are not? SUMMARY ANSWER: Among all ART interventions assessed in economic evaluations, most high-cost interventions, including preimplantation genetic testing for aneuploidy (PGT-A) for a general population and ICSI for unexplained infertility, are unlikely to be cost-effective owing to minimal or no increase in effectiveness. WHAT IS KNOWN ALREADY: Approaches to reduce costs in order to increase access have been identified as a research priority for future infertility research. There has been an increasing number of ART interventions implemented in routine clinical practice globally, before robust assessments of evidence on economic evaluations. The extent of clinical effectiveness of some studied comparisons has been evaluated in high-quality research, allowing more informative decision making around cost-effectiveness. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and searched seven databases (MEDLINE, PUBMED, EMBASE, COCHRANE, ECONLIT, SCOPUS, and CINAHL) for studies examining ART interventions for infertility together with an economic evaluation component (cost-effectiveness, cost-benefit, cost-utility, or cost-minimization assessment), in high-income countries, published since January 2011. The last search was 22 June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two independent reviewers assessed publications and included those fulfilling the eligibility criteria. Studies were examined to assess the cost-effectiveness of the studied intervention, as well as the reporting quality of the study. The chosen outcome measure and payer perspective were also noted. Completeness of reporting was assessed against the Consolidated Health Economic Evaluation Reporting Standard. Results are presented and summarized based on the intervention studied. MAIN RESULTS AND THE ROLE OF CHANCE: The review included 40 studies which were conducted in 11 high-income countries. Most studies (n = 34) included a cost-effectiveness analysis. ART interventions included medication or strategies for controlled ovarian stimulation (n = 15), IVF (n = 9), PGT-A (n = 7), single embryo transfer (n = 5), ICSI (n = 3), and freeze-all embryo transfer (n = 1). Live birth was the mostly commonly reported primary outcome (n = 27), and quality-adjusted life years was reported in three studies. The health funder perspective was used in 85% (n = 34) of studies. None of the included studies measured patient preference for treatment. It remains uncertain whether PGT-A improves pregnancy rates compared to IVF cycles managed without PGT-A, and therefore cost-effectiveness could not be demonstrated for this intervention. Similarly, ICSI in non-male factor infertility appears not to be clinically effective compared to standard fertilization in an IVF cycle and is therefore not cost-effective. Interventions such as use of biosimilars or HMG for ovarian stimulation are cheaper but compromise clinical effectiveness. LIMITATIONS, REASONS FOR CAUTION: Lack of both preference-based and standardized outcomes limits the comparability of results across studies. The selection of efficacy evidence offered for some interventions for economic evaluations is not always based on high-quality randomized trials and systematic reviews. In addition, there is insufficient knowledge of the willingness to pay thresholds of individuals and state funders for treatment of infertility. There is variable quality of reporting scores, which might increase uncertainty around the cost-effectiveness results. WIDER IMPLICATIONS OF THE FINDINGS: Investment in strategies to help infertile people who utilize ART is justifiable at both personal and population levels. This systematic review may assist ART funders decide how to best invest to maximize the likelihood of delivery of a healthy child. STUDY FUNDING/COMPETING INTEREST(S): There was no funding for this study. E.C. and R.W. receive salary support from the National Health and Medical Research Council (NHMRC) through their fellowship scheme (EC GNT1159536, RW 2021/GNT2009767). M.D.-T. reports consulting fees from King Fahad Medical School. All other authors have no competing interests to declare. REGISTRATION NUMBER: Prospero CRD42021261537.

An unusual presentation of a primary lung adenocarcinoma: A case report.

INTRODUCTION AND IMPORTANCE: Lung cancer is one of the most common malignancies worldwide and common sites of metastasis are to brain, liver, adrenal glands, and bones [1]. Metastasis to the gastrointestinal (GI) tract is extremely rare (<1%) and the most common site is the small intestine [5]. CASE PRESENTATION: A 60-year-old female referred for intermittent colicky abdominal pain and diarrhoea, with cross-sectional imaging showing a distal small bowel mass with lymphadenopathy. Malignancy workup revealed an additional mediastinal mass and raised tumour marker carcinoembryonic antigen (CEA). Bronchoscopy confirmed primary lung adenocarcinoma of the mediastinal mass. Given the raised CEA, evolving obstructive symptoms, and concerns for synchronous lung and gastrointestinal primaries, the patient proceeded to have a small bowel resection leading to the diagnosis of a GI lung metastasis. CLINICAL DISCUSSION: If Symptomatic, suggested treatment of lung metastasis to the GI tract is surgical resection. Current evidence suggests that in isolated GI metastases, resection may have a therapeutic benefit and an association with overall survival rate. CONCLUSION: In patients with symptomatic or isolated GI lung metastasis, surgical resection should be considered for treatment and management of metastatic disease. The role of tumour marker CEA in primary lung adenocarcinoma is unclear.

Adipocyte Atrophy Mimicking Signet Ring Cell Carcinoma of the Gallbladder.

Signet ring cell morphology may result from a variety of causes and ranges from a benign reactive phenomenon to being indicative of highly aggressive malignancy. Benign epithelial signet ring cell change is well described in a variety of tissues, but nonepithelial signet ring cell change is a rare morphologic adaptation of adipose tissue principally described in the setting of cachexia. The location of these atrophic adipocytes outside the plane of normal epithelial layers may raise concern for invasive or metastatic malignancy, and consideration of a benign reactive process is critical to avoid catastrophic overdiagnosis and overtreatment. Further, this change is itself associated with significant mortality related to the underlying cachexia and may be important to highlight to treating clinicians. Compared to malignant signet ring cell carcinoma, benign signet ring cell change is more likely to retain normal lobulated architecture without mass formation, lack significant atypia, have myxoid stroma with a prominent capillary network, and show positive staining S100 protein with negative staining for cytokeratins and mucin. To our knowledge, we present the first described case of nonepithelial signet ring cell change involving the gallbladder, detected as an incidental finding following routine cholecystectomy in an elderly cachectic man.

Trends and recurrence of placenta praevia: a population-based study.

We determined recent trends and recurrence rates of placenta praevia in 790,366 deliveries in NSW. From 2001 to 2009, the rate of placenta praevia increased by 26%, from 0. 69% to 0. 87% (trend P < 0.001). The placenta praevia recurrence rate in a second birth was 4.8%. Two-thirds of the increase in placenta praevia was accounted for by trends in known risk factors, and the unexplained portion may reflect changes in unidentified risk factors or in the threshold for placenta praevia diagnosis.

Birth at hospitals with co-located paediatric units for infants with correctable birth defects.

OBJECTIVES: To determine the percentage of liveborn infants with selected antenatally identifiable and correctable birth defects who were delivered at hospitals with co-located paediatric surgical units (co-located hospitals). Additionally, to determine the survival rates for these infants. PATIENTS AND METHODS: Data were from linked New South Wales hospital discharge records from 2001 to 2004. Livebirths with one of the selected defects were included if they underwent an appropriate surgical repair, or died during the first year of life. Infants with multiple lethal birth defects were excluded. Deliveries at co-located hospitals were identified, but no data on antenatal diagnosis were available. RESULTS: The study identified 287 eligible livebirths with the selected defects. The highest rates of delivery at co-located hospitals were for gastroschisis (88%), exomphalos (71%), spina bifida (63%) and diaphragmatic hernia (61%), and the lowest for transposition of the great arteries (43%) and oesophageal atresia (40%). Mothers resident outside of metropolitan areas, where the co-located hospitals are located, had a similar rate of delivery at co-located hospitals as metropolitan women. For the non-metropolitan mothers of infants with a birth defect, this represented a 30-fold increase over the baseline delivery rate of 1.8%. Post-surgery survival rates were 87% or higher. Overall survival rates were > or = 86% except for infants with a diaphragmatic hernia. CONCLUSIONS: Delivery rates at co-located hospitals were high for mothers of infants with these correctable birth defects. Regionalised health care appears to work well for these pregnancies, as women living outside metropolitan areas had a similar rate of delivery at co-located hospitals to that of urban women.

Diagnostic accuracy of clinical examination for detection of non-cephalic presentation in late pregnancy: cross sectional analytic study.

OBJECTIVE: To examine the diagnostic accuracy of clinical examination to determine fetal presentation in late pregnancy. DESIGN: Cross sectional analytic study with index test of clinical examination and reference standard of ultrasonography. SETTING: Antenatal clinic in tertiary obstetric hospital in Sydney, Australia. PARTICIPANTS: 1633 women with a singleton pregnancy between 35 and 37 weeks' gestation attending antenatal clinics. INTERVENTION: Fetal presentation assessed by clinical examination during routine antenatal care, followed by ultrasonography to confirm the diagnosis. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of clinical examination compared with ultrasonography. Diagnostic rates by maternal characteristics. RESULTS: Ultrasonography identified non-cephalic presentation in 130 (8%) women, comprising 103 (6.3%) with breech and 27 (1.7%) with transverse or oblique lie. Sensitivity of clinical examination for detecting non-cephalic presentation was 70% (95% confidence interval 62% to 78%) and specificity was 95% (94% to 96%). The positive predictive value and negative predictive value were 55% and 97%, respectively. CONCLUSIONS: Clinical examination is not sensitive enough for detection and timely management of non-cephalic presentation.

Trends in postpartum haemorrhage.

OBJECTIVE: To assess trends and outcomes of postpartum haemorrhage (PPH) in New South Wales (NSW). METHODS: A population-based descriptive study of all 52,151 women who had a PPH either during the hospital stay for the birth of their baby or requiring a re-admission to hospital between 1994 and 2002. Data were obtained from the de-identified computerised census of NSW hospital in-patients and analysed to examine trends over time. The outcome measures included maternal death, hysterectomy, admission to intensive care unit (ICU), transfusion and major maternal morbidity, including procedures to reduce blood supply to the uterus, acute renal failure and postpartum coagulation defects. RESULTS: From 1994 to 2002 both the number and adjusted (for under-reporting) rate of PPH during the birth admission increased from 8.3% of deliveries to 10.7%. The rate of PPH adjusted for maternal age and mode of delivery was similar to the unadjusted rate. There was a sixfold increase in the rate of transfusions from 1.9% of women who haemorrhaged to 11.7%. Hospital readmissions for PPH declined from 1.2% of deliveries to 0.9%. These were statistically significant changes. There were no significant changes in the rate of hysterectomies, procedures to reduce blood supply to the uterus, admissions to ICU, acute renal failure or coagulation defects. CONCLUSION: The increased rate of PPH during the birth admission is concerning. The increase in PPH could not be explained by increasing maternal age or caesarean sections. Linked birth and hospital discharge data could determine whether the increase in PPH is caused by other changes in obstetric practices or

Systematic review of adverse outcomes of external cephalic version and persisting breech presentation at term.

The aim of this study was to determine the frequency of adverse maternal and fetal outcomes of both external cephalic version (ECV) and persisting breech presentation at term. We conducted a systematic review of the literature using Medline, Embase and All Evidence Based Medicine (EBM) Reviews databases. Data were extracted from studies that compared women who had an ECV from 36 weeks' gestation with a similar control group of women enrolled at the same gestational age, eligible for, but who did not have an ECV. Eleven studies with a total of 2503 women were included. Adverse outcomes related to ECV were rarely reported and in most studies there was no evidence that relevant outcomes were ascertained among similar women who did not have an ECV. There was no increased risk of antepartum fetal death associated with ECV, but numbers were small. There were no reported cases of uterine rupture, placental abruption, prelabour rupture of membranes or cord prolapse, but these outcomes were not examined among controls. Onset of labour within 24 h and nuchal cord was non-significantly higher among women who had an ECV compared with those with a persisting breech. Despite limited reporting and small numbers, the results of our review suggest that adverse maternal and fetal outcomes of both ECV and persisting breech presentation are rare. Only with improved reporting and collection of safety data on ECV and persisting breech presentation can we provide high-quality information to assist informed decision making by pregnant women with a breech presentation at term.

Risk of complications in a second pregnancy following caesarean section in the first pregnancy: a population-based study.

OBJECTIVE: To estimate the risks of maternal and perinatal morbidity and mortality in a second pregnancy, attributable to caesarean section in a first pregnancy. DESIGN AND SETTING: Cross-sectional analytic study of hospital births in New South Wales, based on linked population databases. PARTICIPANTS: 136 101 women with one previous birth who gave birth to a singleton infant in NSW in 1998-2002. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for maternal and perinatal morbidity and mortality. RESULTS: 19% of mothers had a caesarean section in their first pregnancy. Compared with mothers who had had primary vaginal births, mothers who had had primary caesarean section and underwent labour in the second birth were at increased risk of uterine rupture (aOR, 12.3; 95% CI, 5.0-30.1; P < 0.0001), hysterectomy (3.5; 1.5-8.4; P < 0.01), postpartum haemorrhage (PPH) following vaginal delivery (1.6; 1.4-1.7; P < 0.0001), manual removal of placenta (1.3; 1.1-1.6; P < 0.01), infection (6.2; 4.7-8.2; P < 0.0001) and intensive care unit (ICU) admission (3.1; 2.1-4.7; P < 0.0001); among mothers who did not undergo labour (ie, had an elective caesarean section), there was a lower risk of PPH (0.6; 0.5-0.7; P < 0.0001) and ICU admission (0.4; 0.3-0.5; P < 0.0001). For infants there was increased risk of preterm delivery (1.2; 1.1-1.3; P < 0.0001) and neonatal intensive care unit admission following labour (1.6; 1.4-1.9; P < 0.0001) in the birth after primary caesarean section. The occurrence of stillbirth was not modified by labour. CONCLUSIONS: Caesarean section in a first pregnancy confers additional risks on the second pregnancy, primarily associated with labour. These should be considered at the time caesarean section in the first pregnancy is being considered, particularly for elective caesarean section for non-medical reasons.

How useful are hospital morbidity data for monitoring conditions occurring in the perinatal period?

BACKGROUND: There is currently no published information on the full range of morbid conditions affecting mothers and newborns in Australia. Hospital morbidity data collections are a possible source of this information, but have not been widely utilised due to concerns about data quality. AIMS: To assess the accuracy and reliability of perinatal morbidity reporting to the New South Wales Inpatient Statistics Collection (NSW ISC). METHODS: A sample of 1000 records relating to 500 mothers and 500 newborns were randomly selected from the NSW ISC for the financial year 1999-2000 and compared with information obtained from medical records. Sensitivities and specificities were calculated for conditions of clinical relevance. RESULTS: There was a wide range of sensitivities among the 41 conditions selected, indicating a variable level of under-enumeration. Only 17 (41%) had a sensitivity of 80% or more. Sensitivities were more than 95% for gestational diabetes, prolonged pregnancy, perineal laceration, single live birth, low birth weight, and intracranial haemorrhage. However, numbers are small and confidence intervals wide for some of these conditions. Specificities were generally high. Neonatal conditions tended to be more accurately reported than maternal conditions. The pattern of results was similar to that reported for state perinatal data collections. CONCLUSIONS: While hospital administrative data are readily available, data quality is a valid concern. However, if the data are viewed critically and information on accuracy is available, they can be a useful resource for monitoring the health of mothers and babies.

Interleukin-10 regulates arterial pressure in early primate pregnancy.

OBJECTIVES: In pregnancy, the placental contribution of cytokines to maternal immunosuppression has been established, however their role in normal maternal blood pressure regulation has not been identified. We investigate the contribution of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) to the vasodilation of early pregnancy in non-human primates. We also sequenced the IL-10 baboon gene and compared it with humans. METHODS: The effect of four different treatments, administered sequentially (semi-random-design) on resting 18h, night time, or hourly mean arterial pressure (MAP) and heart rate (HR) were measured using telemetry. An anti-human IL-10 monoclonal antibody (MAb, 1mg, n=7), anti-TNF-alpha antibody (n=3), a combination of anti-IL-10 and anti-TNF-alpha antibodies (n=5) or saline (n=3) control were administered intravenously to baboons in early pregnancy. Plasma and placental IL-10 concentration was measured before and after injection in all animals. RESULTS: Anti-human IL-10 MAb caused a significant increase in MAP of 2.6+/-0.5mmHg over the 18-h period (p<0.05). Administration of TNF-alpha alone or in combination with IL-10 did not alter MAP. There was 97% sequence homology of IL-10 cDNA between humans and baboons. CONCLUSIONS: IL-10 was shown to regulate the vasodilation of early pregnancy in Papio hamadryas. This partial role of IL-10 in the early BP response of primate pregnancy may be relevant to pathophysiological states of human pregnancy such as preeclampsia.

Placenta praevia: maternal morbidity and place of birth.

BACKGROUND: International guidelines recommend that women with placenta praevia should be delivered by an experienced operator at a hospital with an on-site blood bank. AIM: To determine the risk factors, level of care at the birth hospital and incidence of maternal morbidity for women with placenta praevia. METHODS: Data were obtained from linked hospital separation and perinatal databases for 375,790 women giving birth in a NSW hospital, 1998-2002. We defined clinically significant placenta praevia as those women who were delivered by Caesarean section at or after 26 weeks gestation. Outcomes for women with and without placenta praevia were compared. Among women with placenta praevia, antenatal predictors of maternal morbidity were assessed. RESULTS: A total of 1612 (4.3/1000) women had significant placenta praevia. Women with placenta praevia were more likely to be older, have a prior Caesarean section, require general anaesthetic for delivery and deliver preterm. Among women with placenta praevia, 61% delivered in hospitals with 24-h on site blood banks, 33% in hospitals with on-call blood bank services after hours and 6% in hospitals with no blood bank. Two hundred and twenty three (14%) women with placenta praevia suffered a major morbidity (OR = 15.0, 95%CI 12.9-17.4). The proportion of this morbidity that occurred among women delivered electively at term was 40% in hospitals with 24 h blood banks and 55% in other hospitals (P = 0.06). CONCLUSIONS: For women with placenta praevia, the risk of major morbidity is high, yet 39% deliver in hospitals without immediate access to a 24-h blood bank. Australian guidelines on the appropriate level of care for women with placenta praevia are needed.

Impact of first-stage ambulation on mode of delivery among women with epidural analgesia.

BACKGROUND: New techniques for administering epidural analgesia allow increased mobility for labouring women with epidurals. AIM: To determine the effect of ambulation or upright positions in the first stage of labour among women with epidural analgesia on mode of delivery and other maternal and infant outcomes. METHODS: We undertook a systematic review and meta-analysis of randomised controlled trials (RCT) of ambulation or upright positions versus recumbency in the first stage of labour among women with effective first-stage epidural analgesia in an uncomplicated pregnancy. Trials were identified by searching Medline, Embase and CINAHL databases and the Cochrane Trials Register to March 2004. Trial eligibility and outcomes were prespecified. Group tabular data were obtained for each trial and analysed using meta-analytic techniques. RESULTS: There were five eligible RCT, with a total of 1161 women. There was no statistically significant difference in the mode of delivery when women with an epidural ambulated in the first stage of labour compared with those who remained recumbent: instrumental delivery (relative risk (RR) = 1.16, 95% confidence interval (CI) 0.93-1.44) and Caesarean section (RR = 0.91, 95% CI 0.70-1.19). There were no significant differences between the groups in use of oxytocin augmentation, the duration of labour, satisfaction with analgesia or Apgar scores. There were no apparent adverse effects of ambulation, but data were reported by only a few trials. CONCLUSIONS: Although ambulation in the first stage of labour for women with epidural analgesia provided no clear benefit to delivery outcomes or satisfaction with analgesia, neither were there are any obvious harms.