Cost-effectiveness of embryo transfer strategies: a decision analytic model using long-term costs and consequences of singletons and multiples born as a consequence of IVF.

STUDY QUESTION: What is the cost-effectiveness of elective single embryo transfer (eSET) versus double embryo transfer (DET) strategies from a societal perspective, when applying a time horizon of 1, 5 and 18 years? SUMMARY ANSWER: From a short-term perspective (1 year) it is cost-effective to replace DET with single embryo transfer; however when intermediate- (5 years) and long-term (18 years) costs and consequences are incorporated, DET becomes the most cost-effective strategy, given a ceiling ratio of €20 000 per quality-adjusted life years (QALY) gained. WHAT IS ALREADY KNOWN: According to previous cost-effectiveness research into embryo transfer strategies, DET is considered cost-effective if society is willing to pay around €20 000 for an extra live birth. However, interpretation of those studies is complicated, as those studies fail to incorporate long-term costs and outcomes and used live birth as a measure of effectiveness instead of QALYs. With this outcome, both multiple and singletons were valued as one live birth, whereas costs of all children of a multiple were incorporated. STUDY DESIGN, SIZE, DURATION: A Markov model (cycle length: 1 year; time horizon: 1, 5 and 18 years) was developed comparing a maximum of: (i) three cycles of eSET in all patients; (ii) four cycles of eSET in all patients; (iii) five cycles of eSET in all patients; (iv) three cycles of standard treatment policy (STP), i.e. eSET in women <38 years with a good quality embryo, and DET in all other women; and (v) three cycles of DET in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Expected life years (LYs), child QALYs and costs were estimated for all comparators. Input parameters were derived from a retrospective cohort study, in which hospital resource data were collected (n=580) and a parental questionnaire was sent out (431 respondents). Probabilistic sensitivity analysis (5000 iterations) was performed. MAIN RESULTS AND THE ROLE OF CHANCE: With a time horizon of 18 years, DETx3 is most effective (0.54 live births, 10.2 LYs and 9.8 QALYs) and expensive (€37 871) per couple starting IVF. Three cycles of eSET are least effective (0.43 live births, 7.1 LYs and 6.8 QALYs) and expensive (€25 563). We assumed that society is willing to pay €20 000 per QALY gained. With a time horizon of 1 year, eSETx3 was the most cost-effective embryo transfer strategy with a probability of being cost-effective of 99.9%. With a time horizon of 5 or 18 years, DETx3 was most cost-effective, with probabilities of being cost-effective of 77.3 and 93.2%, respectively. LIMITATIONS, REASONS FOR CAUTION: This is the first study to use QALYs generated by the children in the economic evaluation of embryo transfer strategies. There remains some disagreement on whether QALYs generated by new life should be used in economic evaluations of fertility treatment. A further limitation is that treatment ends when it results in live birth and that only child QALYs were considered as measure of effectiveness. The results for the time horizon of 18 years might be less solid, as the data beyond the age of 8 years are based on extrapolation. WIDER IMPLICATIONS OF THE FINDINGS: The current Markov model indicates that when child QALYs are used as measure of outcome it is not cost-effective on the long term to replace DET with single embryo transfer strategies. However, for a balanced approach, a family-planning perspective would be preferable, including additional treatment cycles for couples who wish to have another child. Furthermore, the analysis should be extended to include QALYs of family members. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: A retrospective cohort study.

OBJECTIVE: To compare intrapartum- and neonatal mortality and intervention rates in term women starting labour in primary midwife-led versus secondary obstetrician-led care. DESIGN: Retrospective cohort study. SETTING: Amsterdam region of the Netherlands. PARTICIPANTS: Women with singleton pregnancies who gave birth beyond 37+0 weeks gestation in the years 2005 up to 2008 and lived in the catchment area of the neonatal intensive care units of both academic hospitals in Amsterdam. Women with a primary caesarean section or a pregnancy complicated by antepartum death or major congenital anomalies were excluded. For women in the midwife-led care group, a home or hospital birth could be planned. MEASUREMENTS: Analysis of linked data from the national perinatal register, and hospital- and midwifery record data. We assessed (unadjusted) relative risks with confidence intervals. Main outcome measures were incidences of intrapartum and neonatal (<28 days) mortality. Secondary outcomes included incidences of caesarean section and vaginal instrumental delivery. FINDINGS: 53,123 women started labour in primary care and 30,166 women in secondary care. Intrapartum and neonatal mortality rates were 37/53,123 (0.70‰) in the primary care group and 24/30,166 (0.80‰) in the secondary care group (relative risk 0.88; 95% CI 0.52-1.46). Women in the primary care group were less likely to deliver by secondary caesarean section (5% versus 16%; RR 0.31; 95% CI 0.30-0.32) or by instrumental delivery (10% versus 13%; RR 0.76; 95% CI 0.73-0.79). KEY CONCLUSIONS: We found a low absolute risk of intrapartum and neonatal mortality, with a comparable risk for women who started labour in primary versus secondary care. The intervention rate was significantly lower in women who started labour in primary care. IMPLICATIONS FOR PRACTICE: These findings suggest that it is possible to identify a group of women at low risk of complications that can start labour in primary care and have low rates of medical interventions whereas perinatal mortality is low.

Hospital costs during the first 5 years of life for multiples compared with singletons born after IVF or ICSI.

STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3-7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to €10 018 and €2093 during the birth admission period (P < 0.001), €1131 and €696 after the birth admission period to the first birthday (not significant (n.s.)) and €1084 and €938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Decreasing perinatal mortality in The Netherlands, 2000-2006: a record linkage study.

BACKGROUND: The European PERISTAT-1 study showed that, in 1999, perinatal mortality, especially fetal mortality, was substantially higher in The Netherlands than in other European countries. The aim of this study was to analyse the recent trend in Dutch perinatal mortality and the influence of risk factors. METHODS: A nationwide retrospective cohort study of 1,246,440 singleton births in 2000-2006 in The Netherlands. The source data were available from three linked registries: the midwifery registry, the obstetrics registry and the neonatology/paediatrics registry. The outcome measure was perinatal mortality (fetal and early neonatal mortality). The trend was studied with and without risk adjustment. Five clinical distinct groups with different perinatal mortality risks were used to gain further insight. RESULTS: Perinatal mortality among singletons declined from 10.5 to 9.1 per 1000 total births in the period 2000-2006. This trend remained significant after full adjustment (odds ratio 0.97; 95% CI 0.96 to 0.98) and was present in both fetal and neonatal mortality. The decline was most prominent among births complicated by congenital anomalies, among premature births (32.0-36.6 weeks) and among term births. Home births showed the lowest mortality risk. CONCLUSIONS: Dutch perinatal mortality declined steadily over this period, which could not be explained by changes in known risk factors including high maternal age and non-western ethnicity. The decline was present in all risk groups except in very premature births. The mortality level is still high compared with European standards.

[Higher perinatal mortality in The Netherlands than in other European countries: the Peristat-II study]. / Hoge perinatale sterfte in Nederland vergeleken met andere Europese landen: de Peristat-II-studie.

OBJECTIVE: Comparison of perinatal mortality in The Netherlands with that in other European countries (Peristat-II), and with data collected 5 years previously (Peristat-I). DESIGN: Descriptive study. METHOD: Indicators ofperinatal mortality which were developed for Peristat-I were used again in Peristat-II. Data on perinatal mortality in 2004 were delivered by 26 European countries. The Dutch data originated from national registers of midwives and gynaecologists and the National Neonatology Register. RESULTS: In Peristat-I, from 22 weeks gestation, The Netherlands had the highest fetal mortality rate (7.4 per 1,000 total number of births). Furthermore, after Greece, The Netherlands had the highest early neonatal mortality rate (3.5 per 1,000 live births). In Peristat-II from 22 weeks gestation, after France, The Netherlands had the highest fetal mortality rate (7.0 per 1,000 total number of births). Of all western European countries, The Netherlands had the highest early neonatal mortality rate (3.0 per 1,000 live births). Over the past 5 years the perinatal mortality rate in The Netherlands has dropped from 10.9 to 10.0 per 1,000 total births but this drop has been faster in other countries. CONCLUSION: The Netherlands has a relatively high number of older mothers and multiple pregnancies, but this only partly explains the high Dutch perinatal mortality rate which still ranks unfavourably in the European tables. More research is necessary to gain insight into the prevalence of risk factors for perinatal mortality compared with other European countries. In addition, perinatal health and the quality ofperinatal healthcare deserve a more prominent position in Dutch research programmes.

[Perinatal mortality in The Netherlands 2000-2006; risk factors and risk selection]. / Perinatale sterfte in Nederland gedurende 2000-2006; risicofactoren en risicoselectie.

OBJECTIVE: To gain insight in recent perinatal mortality figures in The Netherlands and their relation with important risk factors, risk groups and risk selection among pregnant women. DESIGN: Retrospective cohort study. METHOD: The National Obstetrical Registrations and the National Neonatal Registration were linked into The Netherlands Perinatal Registry to prevent double counting. From this database, data on 1.3 million births in the years 2000-2006 were analysed with perinatal mortality as outcome measure. RESULTS: In 2006, perinatal mortality was 9.8 per 1000 total births (foetal mortality 6.8 per 1000 births and early neonatal mortality 3.1 per 1000 live births). Maternal age (< 20 and > or = 40 years) and high multiparity (> or = 4) were risk factors for perinatal mortality but showed low prevalence (< 3%). Non-Western ethnicity and nulliparity were important risk factors (relative risk of both 1.4) with a prevalence of 16% and 46%, respectively. The very preterm births (22.0-25.6 weeks of gestation) provided 29% ofall perinatal mortality with a mortality risk of 935 per 1000 births. Full-term births (> or = 37.0 weeks) accounted for 26% of all perinatal mortality with a mortality risk of 2.8 per 1000 births. In the full-term born group, perinatal mortality was 0.4 per 1000 births in home births, 2.7 per 1000 births in outpatient clinics and 4.5 per 1000 births when the women were referred to the gynaecologist before start of labour. CONCLUSION: At a population level, low or high maternal age and high parity are less important risk factors than expected. More detailed research is indicated into the mortality ofvery preterm births but also offull-term born children.

Development of macronutrient composition of very preterm human milk.

The effects of gestational age at delivery (GA), postnatal age (PNA) and post-menstrual age (PMA = PNA + GA, an indicator of autonomous developmental processes not affected by the moment of birth) on macronutrient composition of very preterm milk were studied. Total N, fat, lactose and carbohydrate concentrations, energy density and 24 h volume were determined in 282 24 h milk samples collected at weekly intervals (days 7-55 of lactation) from seventy-nine women delivering their babies between 25 and 29 weeks of gestation. GA related differences were found for carbohydrate concentration only: carbohydrate concentration was lower with increasing GA. PNA was related to a decrease in total N and an increase in lactose concentration. PMA was not related to milk composition. Our data indicate that PNA strongly influences the development of the composition of very preterm human milk, while GA affects carbohydrate content with a negligible effect on the nutritional value of the milk. We conclude that in accordance with current opinion in paediatrics, human milk is the best source of nutrients even for very preterm (< 30 weeks GA) infants.

Restrictive dermopathy. Report of 12 cases. Dutch Task Force on Genodermatology.

BACKGROUND: This study describes 12 cases of restrictive dermopathy seen during a period of 8 years by the Dutch Task Force on Genodermatology. We present these unique consecutive cases to provide more insight into the clinical picture and pathogenesis of the disease. OBSERVATIONS: Clinical features in more than 85% of these children were prematurity, fixed facial expression, micrognathia, mouth in O position, rigid and tense skin with erosions and denudations, and multiple joint contractures. Ten patients underwent histopathologic skin biopsy. The biopsy results showed flattening of rete ridges in all 10 patients, a thin dermis with collagen aligned parallel to the epidermis in 9 patients, and poorly developed dermal appendages in 9 patients. Additional findings in individual patients included blepharophimosis, inguinal skin tear, skin tear in the frontal neck area that developed during delivery, absent eyelashes, a wide ascendent aorta, and dextrocardia. Fibroblast cultures taken from 5 patients did not show abnormal alpha 2 beta 1 and alpha 1 beta 1 integrin expressions. CONCLUSIONS: The alleged rarity of restrictive dermopathy may be partially caused by medical unfamiliarity with this entity, despite its characteristic clinical and histopathologic picture. The pathogenesis of the disease still needs to be elucidated.

Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation.

BACKGROUND: Premature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known. METHODS: We carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks' gestation. Thyroxine (8 microg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity). RESULTS: Mortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed significantly between the study groups at any time, nor was the frequency of abnormal neurologic outcome significantly different. In thyroxine-treated infants born at gestational ages of less than 27 weeks, the score on the Bayley Mental Development Index at 24 months of age was 18 points higher than the score for the infants with similar gestational ages at birth in the placebo group (P=0.01); for thyroxine-treated infants born at 27 weeks or later, the mental-development score was 10 points lower than that of their counterparts in the placebo group (P=0.03). There was no relation between the initial plasma free thyroxine concentration and the effect of treatment. CONCLUSIONS: In infants born before 30 weeks' gestation, thyroxine supplementation does not improve the developmental outcome at 24 months.

Cerebellar hypoplasia in respiratory chain dysfunction.

Disruption of early or late fetal brain development resulting in structural abnormalities may be associated with inborn errors of mitochondrial metabolism. It is common in patients with deficiency of pyruvate dehydrogenase activity and it has sporadically been described in patients with dysfunction of the tricarboxylic acid cycle. Mitochondrial respiratory chain disorders are not commonly known to interfere with early brain development. We describe here a girl with an encephalomyopathy likely to be due to a novel type of deficiency of cytochrome c oxidase (complex IV) activity that presented with severe hypotonia, myoclonic seizures, optic atrophy and elevated lactate concentration in cerebrospinal fluid shortly after birth. Cranial magnetic resonance imaging revealed hypoplasia of the cerebellum with rudimentary cerebellar hemispheres and relative sparing of the vermis. This case suggests that deficiency of cytochrome c oxidase and possibly respiratory chain disorders in general have to be considered in the differential diagnosis of cerebellar hypoplasia.

Molybdenum-cofactor deficiency: an easily missed cause of neonatal convulsions.

Intractable seizures in the neonatal period may be caused by molybdenum-cofactor deficiency, an inborn error which combines the deficiencies of sulphite oxidase and xanthine dehydrogenase. The neurological symptoms of molybdenum cofactor and isolated sulphite oxidase deficiencies are identical. Two new cases are reported, and the literature on neonatal convulsions due to molybdenum-cofactor and sulphite deficiencies is reviewed. Because of the high incidence of neonatal convulsions a search for this deficiency is advocated in each case of unexplained refractory neonatal convulsions. Diagnosis may be missed or delayed on standard metabolic screening for several reasons discussed. By simply using a sulphite strip test in a fresh urine sample an indication for the defect can be obtained. Antenatal diagnosis can be performed by assay of sulphite oxidase activity in a chorionic villus sample.

An infant with Marfanoid phenotype and congenital contractures associated with ocular and cardiovascular anomalies, cerebral white matter hypoplasia and spinal axonopathy.

An infant is presented with a Marfanoid phenotype and congenital contractures. In addition to this she showed severe neurological and ocular abnormalities. Cardiac insufficiency due to mitral and tricuspidal valve prolapse caused her death at the age of 6 months. Postmortem examination showed axonal pathology of the anterior horns and roots of the spinal cord, and white matter hypoplasia of the brain.