Karl-Gösta Nygren

The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009

BACKGROUND Many definitions used in medically assisted reproduction (MAR) vary in different settings, making it difficult to standardize and compare procedures in different countries and regions. With the expansion of infertility interventions worldwide, including lower resource settings, the importance and value of a common nomenclature is critical. The objective is to develop an internationally accepted and continually updated set of definitions, which would be utilized to standardize and harmonize international data collection, and to assist in monitoring the availability, efficacy, and safety of assisted reproductive technology (ART) being practiced worldwide. METHOD Seventy-two clinicians, basic scientists, epidemiologists and social scientists gathered together at the WHO headquarters in Geneva, Switzerland in December, 2008. Several months in advance, three working groups were established which were responsible for terminology in three specific areas: clinical conditions and procedures, laboratory procedures and outcome measures. Each group reviewed the existing ICMART glossary, made recommendations for revisions and introduced new terms to be considered for glossary expansion. RESULTS A consensus was reached on 87 terms, expanding the original glossary by 34 terms, which included definitions for numerous clinical and laboratory procedures. Special emphasis was placed in describing outcome measures such as cumulative delivery rates and other markers of safety and efficacy in ART. CONCLUSIONS Standardized terminology should assist in analysis of worldwide trends in MAR interventions and in the comparison of ART outcomes across countries and regions. This glossary will contribute to a more standardized communication among professionals responsible for ART practice, as well as those responsible for national, regional and international registries.

International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009∗

OBJECTIVE Many definitions used in medically assisted reproduction (MAR) vary in different settings, making it difficult to standardize and compare procedures in different countries and regions. With the expansion of infertility interventions worldwide, including lower resource settings, the importance and value of a common nomenclature is critical. The objective is to develop an internationally accepted and continually updated set of definitions, which would be utilized to standardize and harmonize international data collection, and to assist in monitoring the availability, efficacy, and safety of assisted reproductive technology (ART) being practiced worldwide. METHOD Seventy-two clinicians, basic scientists, epidemiologists and social scientists gathered together at the World Health Organization headquarters in Geneva, Switzerland, in December 2008. Several months before, three working groups were established as responsible for terminology in three specific areas: clinical conditions and procedures, laboratory procedures, and outcome measures. Each group reviewed the existing International Committee for Monitoring Assisted Reproductive Technology glossary, made recommendations for revisions and introduced new terms to be considered for glossary expansion. RESULT(S) A consensus was reached on 87 terms, expanding the original glossary by 34 terms, which included definitions for numerous clinical and laboratory procedures. Special emphasis was placed in describing outcome measures, such as cumulative delivery rates and other markers of safety and efficacy in ART. CONCLUSION(S) Standardized terminology should assist in analysis of worldwide trends in MAR interventions and in the comparison of ART outcomes across countries and regions. This glossary will contribute to a more standardized communication among professionals responsible for ART practice, as well as those responsible for national, regional, and international registries.

Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome?

OBJECTIVE To compare neonatal outcome of blastocyst and cleavage stage embryo transfers after IVF. DESIGN Register study. SETTING Births recorded in the Swedish Medical Birth Register after IVF performed, 2002-2006. PATIENT(S) Treatments reported from all Swedish IVF clinics. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Some neonatal characteristics were compared in 1,311 infants born after blastocyst-stage transfer and 12,562 infants born after cleavage-stage transfer. Comparisons were also made with all births, 2002-2007 (n = 598,687). RESULT(S) After adjusting for year of birth, maternal age, parity, smoking habits, and body mass index, the risk of preterm birth among singletons was significantly greater after blastocyst-stage transfer than after cleavage-stage transfer. The risk of congenital malformations was also significantly higher. When the analysis was restricted to clinics where blastocyst transfers were made, the risk estimates increased for preterm birth, low birth weight, low APGAR score, and respiratory diagnoses, but did not change for congenital malformations. CONCLUSION(S) The results indicate a small increase in risk associated with blastocyst transfer, perhaps owing to the longer period of in vitro culture. There is a possibility that this effect is due, at least in part, to a selection of women for blastocyst transfers. Further studies are needed either to verify or to refute the found associations.

Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study

The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levonorgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized, comparative multicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1 per hundred women) was significantly lower than that with the Nova T (0.9 per hundred). Removal rates for menstrual problems and/or pain were similar for the two methods (net rates 7.5 and 8.7, respectively). The 12-month continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was a highly effective contraceptive method which reduced menstrual bleeding. It is a promising alternative for women desiring a highly effective method for long-term use.

Congenital malformations in infants born after in vitro fertilization in Sweden

BACKGROUND The risk for congenital malformations is increased in infants born after in vitro fertilization (IVF). Some specific malformations appear to be more affected than others. METHODS The presence of congenital malformations in 15,570 infants born after IVF with an embryo transfer between April 1, 2001, and the end of 2006 were compared with all infants born in Sweden during 2001 to 2007 (n = 689,157). Risk estimates were made after adjusting for year of birth, maternal age, parity, smoking, and body mass index. The risks of specific malformations were compared with data from a previous study (1982 to March 31, 2001) of 16,280 infants born after IVF. Different IVF methods were compared to respect to malformation risk. RESULTS Increased risks of a similar magnitude were found for most cardiovascular malformations and limb reduction defects for both study periods. For neural tube defects, cardiac septal defects, and esophageal atresia, there was still an increased risk, but it was lower during the second than during the first period. For small bowel atresia, anal atresia, and hypospadias, the risk increase observed during the first study period had disappeared during the second period. An increased risk was seen for some syndromes that have been associated with imprinting errors. No difference in malformation risk according to IVF method was apparent. CONCLUSIONS A slightly increased risk for congenital malformations after IVF persists. A decreasing risk is seen for some specific malformations, either true or the result of multiple testing.

Cancer Risk in Children and Young Adults Conceived by In Vitro Fertilization

OBJECTIVES: Studies conducted so far have found no statistically significant increased risk for cancer among children who are born after in vitro fertilization (IVF). METHODS: We followed 26 692 children who were born after IVF during the years 1982–2005 by using the Swedish Cancer Register and compared the number of children who had cancer and were born after IVF with children who were not conceived by IVF. Adjustment was made for year of birth. RESULTS: Maternal age, parity, smoking, subfertility, previous miscarriages, BMI, and multiple births did not significantly affect cancer risk in offspring. High birth weight, premature delivery, and the presence of respiratory diagnoses and low Apgar score were risk factors for cancer. We identified 53 cases of cancer in children who were born after IVF against 38 expected cases: 18 of them with hematologic cancer (15 of them acute lymphoblastic leukemia), 17 with eye or central nervous system tumors, and 12 with other solid cancers. There were 6 cases of Langerhans histiocytosis against 1.0 expected. The total cancer risk estimate was 1.42 (95% confidence interval: 1.09–1.87). CONCLUSIONS: We found a moderately increased risk for cancer in children who were conceived by IVF. Putative intermediary factors could be preterm birth and neonatal asphyxia.

Maternal and child outcome after in vitro fertilization – a review of 25 years of population-based data from Sweden

Objective. To summarize data on deliveries after in vitro fertilization (IVF) performed in Sweden up to 2006. Design. Cohort study of women and children, conceived after IVF, with comparisons of deliveries after IVF before and after 1 April 2001. Setting. Study based on Swedish health registers. Population. Births registered in the Swedish Medical Birth Register with information on IVF from all IVF clinics in Sweden. Methods. Results from the second study period are summarized, and outcomes between the two periods are compared. Long‐term follow‐up is based on data from both periods. Main outcome measures. Maternal and perinatal outcomes, long‐term sequels. Results. Some maternal pregnancy complications decreased in rate, notably pre‐eclampsia and premature rupture of membranes. The rate of multiple births and preterm births decreased dramatically, with a better neonatal outcome, including reduced neonatal mortality. No difference in outcome existed between IVF and intracytoplasmic sperm injection or between the use of fresh and cryopreserved embryos, but children born after blastocyst transfer had a slightly higher risk for preterm birth and congenital malformations than children born after cleavage stage transfer. An increased risk for cerebral palsy, possibly for attention deficit and hyperactivity disorder, for impaired visual acuity and for childhood cancer was noted, but these outcomes were rare also after IVF. An increased risk for asthma was demonstrated. No effect on maternal cancer risk was seen. Conclusion. A marked decrease in multiple births was the main reason for better pregnancy and neonatal outcome and may also have a beneficial effect on long‐term results, notably cerebral palsy.

Ethinyl estradiol in human milk and plasma after oral administration

Abstract In order to estimate the concentration of ethinyl estradiol in milk, four fully lactating women were given an oral contraceptive containing 50 μg ethinyl estradiol + 4 mg megestrol acetate, starting two months after delivery, and four women who wanted to stop nursing after a lactation period of 6–18 months were given one tablet of 500 μg ethinyl estradiol. Milk and blood samples were taken simultaneously after 3, 7, 11 and 23 hours. The concentration of ethinyl estradiol in plasma and milk were estimated by radioimmunoassay. The method for the assay of ethinyl estradiol in milk is evaluated in this paper. The concentration of ethinyl estradiol in milk from the women taking the oral contraceptive was below the detection limit of the assay. In the women taking 500 μg of ethinyl estradiol, the plasma:milk ratio of ethinyl estradiol was found to be about 100:25. The relative dose of ethinyl estradiol ingested by a fully nursed baby, when its mother takes an oral contraceptive containing 50 μg of ethinyl estradiol, has been calculated to be about 10 ng per day, which is 0.02 per cent of the dose given to the mother.

Obstetric and neonatal outcome after oocyte donation in 106 women with Turner syndrome: a Nordic cohort study

STUDY QUESTION What are the obstetric and neonatal outcomes of deliveries after oocyte donation (OD) in women with Turner syndrome (TS)? SUMMARY ANSWER Pregnancies among women with TS carry a substantial risk, particularly for hypertensive disorders. Potentially life-threatening complications occurred in 3.3% of pregnancies. The neonatal outcomes were generally reassuring, with similar rates of preterm birth and low birthweight (LBW) as after conventional IVF and better than previously reported in deliveries after OD in women with TS. WHAT IS KNOWN ALREADY OD pregnancies in women with TS are known to be high-risk pregnancies. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 106 women with TS who delivered after OD (n = 122 deliveries, n = 131 newborns) in three Nordic countries (Finland, Denmark, Sweden) between 1992 and 2011. PARTICIPANTS, SETTING AND METHODS Women with TS who delivered after OD in three Nordic countries were identified (n = 110). Four women declined to participate or were lost to follow-up, thus 106 women were included in the study. The medical data from fertility clinics, antenatal clinics and the hospitals where the women had been treated and/or delivered were scrutinized. MAIN RESULTS AND THE ROLE OF CHANCE In this cohort, the karyotype was 45,X in 44% of the women with TS. Ten women (9.4%) had a known cardiac defect before pregnancy. Single embryo transfer was performed in 70.3% of the cases and the multiple birth rate was 7.4%. In total, 35.0% of the pregnancies were associated with a hypertensive disorder including pre-eclampsia in 20.5%. Potentially life-threatening complications occurred in four pregnancies (3.3%), including one woman with aortic dissection, one with mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and one who underwent a post-partum hysterectomy due to severe haemorrhaging. Neonatal outcomes were reassuring, with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. Major birth defects were found in 3.8% of the children. The perinatal mortality was 2.3% (3/131), including a set of extremely preterm twins. LIMITATIONS, REASONS FOR CAUTION Although this study was performed over a period of almost 20 years in three different countries, with a low drop-out rate and little missing data, much larger series are needed to assess rare events. This study also lacks an appropriate control group. WIDER IMPLICATIONS OF THE FINDINGS This study suggests that cardiovascular evaluation before and during pregnancy may contribute to favourable obstetric outcomes in many cases. Maternal outcomes were in agreement with the literature while neonatal outcomes were generally better than previously reported. The outcomes were consistent across the three countries, supporting generalizability to similar populations.

Maternal drug use during pregnancy and asthma risk among children

Maternal use of some drugs, notably paracetamol and drugs for gastroesophageal reflux, has been associated with an increased risk of childhood asthma in the child. We wanted to analyze these associations with consideration to the confounding of maternal asthma.