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Crisis in assisted conception: the British approach to an American dilemma.

Although British and American couples who are infertile have similar treatment options in their home countries, the British system for ensuring quality of care has striking advantages over the American status quo in reproductive medicine. The British system effectively addresses what continue to be serious problems on the American scene, such as the lack of any clear license or certification of infertility treatment centers to reassure consumers, the absence of a complete consumer-friendly account of success rates at various sites and by technique, and the continuing proportional increase in multiple births because of high numbers of embryos transferred in in vitro fertilization (IVF) and numbers of oocytes produced as a result of ovulation-stimulating drugs. In addition, the British system has clear compulsory guidelines in place that regulate what kinds of human embryo research can be performed, by whom, and where. In infertility practice, the British also have strict controls on the introduction of innovations, such as intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD). The British prohibition, for example, against cloning by nuclear replacement is already a matter of record, and there is no necessity (as is the case in the United States with cloning via nuclear transplantation) to invoke a public ban and hope that a private moratorium will be observed. Regardless of what one thinks about the clinical and research issues, the clarity and order that permeate practice and research in reproductive medicine in Great Britain have advantages that could serve as guideposts for necessary reforms in the United States.

Community Participation↗

Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia.

We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.

Abnormalities, Multiple↗

A survey of the effectiveness of the assessment of the welfare of the child in UK in-vitro fertilization units.

Seventy-one clinics in the UK offering in-vitro fertilization (IVF) treatment were surveyed for their protocols on the assessment of the welfare of the children produced. A total of 44 (62%) responded. Of these, five (12%) did not have operational protocols, seven (16%) declined to provide their protocols, and 32 (73%) provided information used in the survey. The information was in the form of a protocol for only 16 (50%) of these clinics. The remaining clinics submitted as their 'protocols' letters to general practitioners, patient information, patient questionnaires and/or a copy of their policy on the assessment of child welfare. From the submitted material, it was possible to determine that 94% of clinics seek information on aspects of child welfare assessment, 78% have a procedure for making further enquiries where there is any cause for concern, 44 % include counselling opportunities explicitly in protocols, 30-38% of clinics see a full medical and social history from each prospective parent as part of the child welfare assessment, 16% include explicit consideration of the impact of multiple births on the welfare of the child, and 3% include consideration of the issue of disclosure of the mode of conception of the child on its welfare. Most clinics did not have clearly defined procedures on how to reach a decision on whether or not to treat. Eight clinics (25%) made explicit in their protocols any exclusion criteria. It is concluded that clinics are not currently producing completely effective protocols. Two possible reasons for this are considered: lack of technical knowledge about what constitutes an effective protocol, and lack of clear policy development and propagation underlying protocols within clinics. Possible approaches to improving the situation are considered.

Adult↗

A Danish national cohort of 730 infants born after intracytoplasmic sperm injection (ICSI) 1994-1997.

This national cohort study included all clinical pregnancies obtained after intracytoplasmic sperm injection (ICSI) registered in Denmark between January 1994 and July 1997 at five public and eight private fertility clinics. Laboratory and clinical data were obtained from the fertility clinics. The couples answered a questionnaire regarding the pregnancy and the health of the child (response rate 94%). Data validation was carried out through discharge charts. The mean age of the women was 32.1 years. In 84.2% of couples, male factor was the main reason for performing ICSI, and in 4.8% epididymal spermatozoa were used. The mean number of embryos replaced was 2.3 (range 1-3) and in 95% of cases fresh embryos were transferred. Only 183 women (28.5%) underwent prenatal diagnosis, resulting in 209 karyotypes with seven (3.3%) chromosome aberrations. Six major chromosomal abnormalities (2.9%) and one inherited structural chromosome aberration (0.5%) were found, but no sex chromosome aberrations. The frequency of multiple birth, Caesarean section rate, gestational age, preterm birth, and birth weight were comparable with previous studies. The perinatal mortality rate was 13.7 per 1000 children born with a gestational age of 24 weeks or more. In 2.2% (n = 16) of the liveborn infants, and in 2.7% (n = 20) of all infants, major birth defects were reported by the parents. Minor birth defects were found in nine liveborn infants (1.2%). In conclusion, the results of this study on outcome of ICSI pregnancies are in line with earlier reports, except that no sex chromosome abnormalities were found.

Adult↗

Early embryo cleavage is a strong indicator of embryo quality in human IVF.

BACKGROUND: In order to decrease multiple birth rates without decreasing birth rates overall, it is important to increase the capability of selecting the most optimal embryos for transfer. It has been shown that human embryos which cleave early, i.e. complete the first mitotic division within 25-27 h post insemination, provide higher pregnancy and implantation rates. METHODS AND RESULTS: In this prospective study, an evaluation of 10 798 scored embryos showed that early cleavage resulted in a significantly higher proportion of good quality embryos compared with late cleavage (62.5 versus 33.4%, P < 0.0001). When examining both day 2 and day 3 transfers together, early-cleaving embryos (306 transfers) gave rise to significantly higher rates of pregnancy/transfer (40.5 versus 31.3%, P = 0.0049), implantation (28.0 versus 19.5%, P = 0.0001) and birth/ongoing pregnancy (34.3 versus 24.0%, P = 0.0009) than did late-cleaving embryos (521 transfers). A stepwise logistic regression of all data showed that the total number of good quality embryos and female age were independent predictors of both pregnancies and birth. For intracytoplasmic sperm injection (ICSI) embryos, early cleavage was found to be an independent predictor of birth. CONCLUSIONS: Early embryo cleavage is a strong biological indicator of embryo potential, and may be used as an additional embryo selection factor for ICSI embryos.

Adult↗

Pregnancy outcome and neonatal data of children born after ICSI using testicular sperm in obstructive and non-obstructive azoospermia.

BACKGROUND: Registries on outcome of ICSI pregnancies obtained with testicular sperm do not differentiate between obstructive (OA) and non-obstructive azoospermia (NOA). We evaluated the pregnancy outcome and neonatal data on children born after ICSI using testicular sperm of men with histologically proven OA or NOA. METHODS: Pregnancies obtained after ICSI using testicular sperm of men with defined NOA (n = 70) were compared with those of men with OA (n = 204). RESULTS: Multiple birth rates in NOA and OA couples, respectively, were 21 versus 27% (P = NS), overall preterm delivery rates were 38 versus 26% (NS), and prematurity rates were 24 versus 13% for singletons (NS) and 86 versus 54% for twins (relative risk 1.59, 95% confidence interval 1.04-2.42). Median gestational age for singletons was 38.3 versus 39.3 weeks, respectively (P < 0.05). The low birth weight rates were 34 versus 31%, respectively (NS). The early perinatal mortality rate was 66 versus 15 per 1000 births, respectively, (NS). Major congenital malformations were observed in 4 versus 3%, respectively, of the live born babies (NS). Prenatal karyotypes showed 7% de-novo abnormalities in the NOA group versus 1% in the OA group (NS). CONCLUSIONS: Our data do not show differences between NOA and OA pregnancies except for a strong tendency towards a lower gestational age in singletons and a higher percentage of premature twins in the NOA group. Although our data are based on a limited sample, the differences observed call for further analysis. Given the low pregnancy rates after ICSI with NOA, a multicentre study, differentiating NOA and OA patients, would be recommended.

Adult↗

Growth, psychomotor development and morbidity up to 3 years of age in children born after IVF.

BACKGROUND: To examine the long-term child outcome after IVF until the age of 3 years in Northern Finland, we conducted a population-based cohort study. METHODS: First, a cohort of 299 IVF children born in 1990-1995 was compared with a cohort of 558 controls representing the general population in terms of a multiple birth rate of 1.2%, randomly chosen from the Finnish Medical Birth Register (FMBR) and matched for sex, year of birth, area of residence, parity, maternal age and social class (full sample analyses). Second, IVF singletons (n = 150) were compared with singleton controls (n = 280). Third, a plurality matched control cohort (n = 100) for IVF twins (n = 100) was randomly chosen, matched as above, from the FMBR and analysed separately. Infant mortality rate was compared with the national rate from the FMBR. RESULTS: Infant mortality in the IVF group was >2-fold higher compared to the national rate in the general population. The risk (OR, 95% CI) of low weight and height, below the lowest quartile, at 1 year of age (1.6, 1.1-2.2; 1.6, 1.1-2.4) and 2 years of age (1.5, 1.1-2.4; 1.7, 1.2-2.5) was significantly higher in the IVF group when compared with the general population control group. No statistically significant differences were found in the psychomotor development between the cohorts. Cumulative incidence of different diseases up to 3 years of age was significantly higher among IVF children in the full sample and singleton analyses (OR, 95% CI: 2.3, 1.7-3.2; 2.1, 1.3-3.3 respectively) especially regarding respiratory diseases (3.5, 1.9-6.5; 3.1, 1.0-9.4) and diarrhoea (3.7, 2.2-6.2; 5.7, 2.6-12.7), but not in twin comparisons. CONCLUSIONS: The growth of IVF children was behind that of control children during the first 3 years of life, but their psychomotor development was similar. Their postnatal health was worse, probably reflecting the problems in the neonatal period.

Body Height↗

Cigarette smoking in pregnancy and fetal growth. Does the type of tobacco play a role?

The effect of nicotine content of cigarettes on fetal growth was studied. From April 1985 to April 1987, 86% of all pregnant women in two well-defined geographical areas responded to a questionnaire on social conditions and lifestyle factors in pregnancy. After excluding multiple births and women who gave birth after elective caesarean section, 10,485 pregnant women were available for the study. Results showed that not only smoking, but also nicotine content in cigarettes was related to reduced fetal growth as measured by birthweight, birth length, and head circumference. The timing of smoking during pregnancy played a role. Smoking before pregnancy or smoking early in pregnancy was not related to fetal growth, nor were the partners' smoking habits. The study corroborates the hypothesis that smoking reduces fetal growth and points to nicotine as one of the potential causal factors.

Adolescent↗

Prevalence of cerebral palsy in twins, triplets and quadruplets.

BACKGROUND: Twins and triplets are at higher risk of cerebral palsy than singletons. This study investigated the degree of risk for cerebral palsy in twins, triplets and quadruplets, and identified factors associated with the increased risk. METHODS: The subjects were recruited from the Kinki University Twin and Higher Order Multiple Births Registry. RESULTS: The subjects were 705 twins pairs (1410 twins), 96 sets of triplets (287 triplets excluding one infant death), and 7 sets of quadruplets (27 quadruplets excluding one infant death), who were born after 1977. The prevalence of cerebral palsy was 0.9% among 1410 twins, 3.1% among 287 triplets, and 11.1% among 27 quadruplets. Furthermore, the risks of producing at least one child with cerebral palsy were 1.5%, 8.0%, 42.9% in twin, triplet, quadruplet pregnancies, respectively. After adjusting for each associated factor using logistic regression, the risk of cerebral palsy was significantly associated with decrease in gestational age and asphyxia. The odds ratio indicated that infants whose gestational age was < 32 weeks were 20 times more likely to develop cerebral palsy than infants whose gestational age was > or = 36 weeks. CONCLUSIONS: The prevalence of cerebral palsy in triplets and quadruplets was higher than that in twins. Lower gestational age was associated with a greater risk of cerebral palsy.

Asphyxia Neonatorum↗

Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group.

BACKGROUND: Family history of breast cancer is an established risk factor for this disease and is used to identify women at higher risk, although the impact of risk factors for breast cancer among women with a family history is not well defined. PURPOSE: Using a modified extended log-incidence Pike model, we prospectively examined the impact of risk factors for breast cancer among women with and without a family history of the disease. METHODS: Data analyzed were obtained prospectively from the Nurses' Health Study. Two thousand two hundred forty-nine incident cases of invasive breast cancer were identified in a cohort of 89,132 women aged 30-55 years in 1976 followed biennially through 1990 (1.1 million person years of follow-up). With the use of proportional hazards models, we evaluated the association between risk factors for breast cancer and risk among women with and those without a family history of the disease. We then fit a modified extended log-incidence Pike model to these data. RESULTS: Among women with a family history of breast cancer, reproductive risk factors has associations that were different from those observed among women without a family history of the disease. In particular, we observed little protection from later age at menarche, no protection from multiple births when compared with nulliparity, nor from early, as compared with later, age at first birth. Fitting these data to a model of breast cancer incidence on the basis of reproductive risk factors, we observed an adverse effect of first pregnancy on risk of breast cancer among women with a family history of breast cancer that was approximately 50% greater in magnitude than among women without a family history. Additional births after the first birth conveyed little protection for women with a family history. History of benign breast disease, past use of oral contraceptives, and use of postmenopausal hormones showed relative risks that did not differ between women with a family history and those without a family history of the disease. CONCLUSIONS: We observed a consistent increase in risk of breast cancer among women with a mother or sister history of the disease that was exacerbated by first pregnancy. Among women with a family history of breast cancer, the adverse effect of pregnancy persisted so that to age 70 years, parous women were at higher risk of breast cancer than nulliparous women. Among women without a family history of the disease, first pregnancy was associated with a smaller increase in risk, and early pregnancy and higher number of births were each associated with reduced breast cancer incidence.

Adult↗

A stochastic simulation model of U.S. breast cancer mortality trends from 1975 to 2000.

BACKGROUND: We present a simulation model that predicts U.S. breast cancer mortality trends from 1975 to 2000 and quantifies the impact of screening mammography and adjuvant therapy on these trends. This model was developed within the Cancer Intervention and Surveillance Network (CISNET) consortium. METHOD: A Monte Carlo simulation is developed to generate the life history of individual breast cancer patients by using CISNET base case inputs that describe the secular trend in breast cancer risk, dissemination patterns for screening mammography and adjuvant treatment, and death from causes other than breast cancer. The model generates the patient's age, tumor size and stage at detection, mode of detection, age at death, and cause of death (breast cancer versus other) based in part on assumptions on the natural history of breast cancer. Outcomes from multiple birth cohorts are summarized in terms of breast cancer mortality rates by calendar year. RESULT: Predicted breast cancer mortality rates follow the general shape of U.S. breast cancer mortality rates from 1975 to 1995 but level off after 1995 as opposed to following an observed decline. Sensitivity analysis revealed that the impact adjuvant treatment may be underestimated given the lack of data on temporal variation in treatment efficacy. CONCLUSION: We developed a simulation model that uses CISNET base case inputs and closely, but not exactly, reproduces U.S. breast cancer mortality rates. Screening mammography and adjuvant therapy are shown to have both contributed to a decline in U.S. breast cancer mortality.

Age Factors↗

How to find a wombmate: validation of an algorithm to identify twin pairs in Linked Birth/Infant Death Files.

Linked Birth/Infant Death Files available from the National Center for Health Statistics identify an infant as a twin, but do not identify twin pairs. An algorithm based on maternal, paternal, and infant characteristics has been used to identify twin pairs, but the validity of this algorithm has never been tested. The Missouri linked birth/infant death file from 1980 to 1990 identifies twin pairs by a sequence number. The authors tested the rate and accuracy with which the algorithm identified true pairs in the Missouri file and whether estimates of risk and possible risk factors calculated from pairs of twins identified by the algorithm agreed with these characteristics as calculated from known twin pairs. The algorithm identified 96% (8,273 of 8,620) of true pairs and one false pair. Despite incomplete pair identification, and even identification of a false pair, estimates from the subset identified by the algorithm generally agreed well with characteristics measured from all twin pairs. Nonetheless, incorporation of a multiple birth sequence number into Linked Birth/Infant Death Files would enhance their utility.

Algorithms↗

Cryopreservation.

Embryo cryopreservation is now firmly established as a routine component of in vitro fertilization (IVF) and other assisted conception techniques for the resolution of human infertility. Excess fertilized oocytes and embryos can be preserved for infertile couples avoiding the necessity to replace large numbers of embryos which reduces the incidence of multiple births and their sequelae. The additional pregnancies obtained from replacement of cryopreserved embryos has effectively increased the success rate of a cycle of IVF treatment for a couple by 1 to 10%. There is an increasing preference to cryopreserve fertilized pronuclear oocytes by slow cooling in 1,2-propanediol (PROH) although many clinics also cryopreserve early cleavage stage embryos by slow cooling in PROH or dimethyl sulphoxide (DMSO) with similar success rates to those for pronuclear oocytes. Numerous problems have appeared with the attempted cryopreservation of mature unfertilized oocytes, including nonreversible disassembly of the meiotic spindle during cooling, reduced fertilization rates due to the effects of cryoprotectants and cooling on the zona pellucida, parthenogenetic activation of oocytes by PROH, substantially increased polyploidy and aneuploidy when frozen-thawed oocytes are fertilized and increased cryoinjury to unfertilized oocytes when compared to fertilized oocytes. It is also necessary to address problems which have arisen through the disagreement of separated couples about the disposition of embryos in cryostorage.

Cryopreservation↗

The GIFT experience: an evaluation of the outcome of 115 cases.

The outcome of a series of 115 patients undergoing GIFT by minilaparotomy is described, their duration of infertility ranging between 3 and 19 years. Ovarian stimulation was carried out using clomiphene from day 3 and HMG from day 6, and HCG was used to induce follicular maturation. A maximum of four oocytes, two per oviduct with 100,000 spermatozoa, were replaced. Thirty-six pregnancies were established. The highest incidence of pregnancy was obtained in cases of unexplained infertility (42%) and endometriosis (28%), and the lowest with male factors (13%). The most mature oocytes gave the best results. There were eleven miscarriages (30.5%) and two ectopic pregnancies (5.5%). Eleven of the 23 deliveries involved multiple births.

Adult↗

A program of oocyte donation and gamete intra-fallopian transfer.

The outcome of a series of 19 patients with premature ovarian failure (POF) undergoing gamete intra-Fallopian transfer (GIFT), utilizing donated oocytes, is described. The steroid replacement protocol consisted of the administration of increasing dosages of 17 beta-oestradiol (E2) and progesterone (P4). Hormonal replacement was maintained until day 100 of gestation. All patients underwent an evaluation cycle in which serum levels of E2 and P4 were monitored and an endometrial biopsy was performed either 7 or 11 days after initiation of progesterone administration. All cases of GIFT were performed between days 12 and 15 of the induced menstrual cycle. Of the 19 patients treated, 11 became pregnant, giving a clinical pregnancy rate of 58% (visualization of gestational sac by ultrasound). Two patients aborted between the 4th and 5th weeks of gestation. No ectopic pregnancies occurred. Three of the seven deliveries involved multiple births. Details of the circulating hormone levels and endometrial response are discussed.

Adult↗

IVF in the Nordic countries 1981-1987: a collaborative survey.

This report concerns the development of in-vitro fertilization (IVF) in the Nordic countries from the start of 1981 to January 1, 1988. All the 24 clinics in the Nordic countries which treat infertile couples with IVF participated in the study. The number of IVF clinics in the Nordic countries has increased from four in 1981 to 24 in 1987. In the same period, the number of people who spent some of their professional time as a part of an IVF team increased from 17 to 150. The majority of the clinics (19) based their activity mainly on governmental funding, while five of the clinics were private. During the period from 1981 to 1987, the Nordic clinic changed their methods of oocyte retrieval. In 1981, all oocyte retrievals were done using laparoscopy. Transvesical, ultrasound-guided follicular punctures domainated in 1985 and transvaginal ultrasound-guided punctures were used in 81.5% of the retrievals in 1987. A total of 852 pregnancies were reported. Of these, 313 (36.8%) were miscarriages, including 66 (7.7%) ectopic pregnancies. At January 1, 1988, 433 babies had been born, including 48 sets of twins, 14 sets of triplets and two sets of quadruplets. This gave a multiple birth rate of 18.2%. Premature births (less than 36 weeks of gestation) were reported in 14.6% of the births. Five babies (1.1%) died in the neonatal period and five (1.1%) were born with various types of malformation. One hundred and eight-eight pregnancies were in progress at January 1, 1988.

Adult↗

Effect of prenatal exposure to ethanol on intestinal development of rat fetuses.

BACKGROUND: Chronic alcoholism in pregnant animals and humans lead to general growth impairment in their offspring, which show multiple birth defects and delayed grown (fetal alcohol syndrome). Here we study the maturation of the intestine under the effect of chronic exposure to ethanol in utero together with associated malnutrition. METHODS: Lactase, acid beta-galactosidase, maltase, and alkaline phosphatase activity profiles were monitored in 18-, 19-, 20-, and 21-day-old fetuses from rats kept under three nutritional treatments before and during gestation: alcohol-treated (25% ethanol in drinking water), fiber-treated (50% cellulose-diluted diet) as a control of the malnutrition associated with chronic alcoholism, and control or normal diet. Serum corticosterone determination and lactase immunolocalization were carried out. To detect possible direct effects of ethanol during the period of mucosa development, intestinal explants from 18-, 19-, and 20-day-old control fetuses were cultured either in the basal medium alone or in a medium containing 25 mM ethanol for 72, 48, and 24 h of incubation, respectively. RESULTS: Following chronic ethanol exposure in utero, intestinal weight and brush-border protein content and the specific activities of lactase, acid beta-galactosidase, maltase, and alkaline phosphatase were significantly lower than those of nutritional controls. Organ culture results, under the assay conditions stated, did not show a direct effect of ethanol 25 mM on prenatal mucosal functionality. CONCLUSIONS: All these results suggest that maternal malnutrition is not primarily responsible for the impaired intestinal maturation in rat fetuses from alcohol-treated mothers; indirect effects of ethanol and/or its derivatives throughout embryo-fetal development could be necessary to promote this intestinal delay.

Alcoholism↗

Kangaroo skin-to-skin care for premature twins and their adolescent parents.

Risk factors associated with prematurity and adolescent parenting greatly increase when combined with multiple birth. Kangaroo care (KC) for preterm infants is well documented, although KC with twins or with adolescent parents is mentioned only briefly. In this case study, adolescent parents experience KC with their 32-week twin sons beginning 19 hours postbirth. These young parents interacted with, responded to, and took responsibility for their newborn sons, behaviors that are sometimes difficult for adolescent parents. Thus, KC appeared to be an effective intervention for these adolescent parents. Additionally, three kinds of KC with twins were identified: separate, sequential, and shared.

Adolescent↗