Orvar Finnström

Neurological sequelae in children born after in-vitro fertilisation: a population-based study

BACKGROUND There is an absence of population-based long-term studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls. METHODS We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres. FINDINGS Children born after IVF are more likely to need habilitation services than controls (odds ratio 1.7, 95% CI 1.3-2.2). For singletons, the risk was 1.4 (1.0-2.1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3.7(2.0-6.6), and IVF singletons of 2.8 (1.3-5.8). Suspected developmental delay was increased four-fold (1.9-8.3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low-birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk. INTERPRETATION Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.

The Swedish national prospective study on extremely low birthweight (ELBW) infants. Incidence, mortality, morbidity and survival in relation to level of care.

In a 2‐year (1990‐92) prospective national investigation, comprising all stillborn and live‐born ELBW infants with a birthweight of ≤1000 g born at 23 completed weeks of gestation or more, we examined the incidence, neonatal mortality, major morbidity and infant survival in relation to level of care and place of residence. A total of 633 ELBW infants were live‐born, i.e. 0.26% of all live‐born infants, and 298 were stillborn. The average neonatal mortality was 37% and 91% at 23 weeks, 70% at 24 weeks, and 40% at 25 weeks of gestation. Of neonatal survivors, 8% had intraventricular haemorrhage grade 3,10% retinopathy of prematurity of stage ≥3, 2% necrotizing enterocolitis, and 28% were oxygen‐dependent at a time corresponding to 36 weeks of gestation. In all, 77% were treated with mechanical ventilation, whereas 19% survived without, almost all of them being CPAP treated. Infant mortality among infants born at level III (tertiary centres) was 30%, at level Ha (with full perinatal service) 46% and at level IIb (with basic neonatal service) 55 %. Only 1 % was born at hospital level I. Regarding the relation to place of residence, the mortality rates among infants residing in the areas served by levels III, IIa and lib hospitals were 36%, 45% and 41%, respectively. The referral system thus functioned well, but can be improved, and increased perinatal referral, at borderline perinatal viability, might provide a better quality of care and a better chance of survival.

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.

In vitro fertilisation in Sweden: obstetric characteristics, maternal morbidity and mortality

Objective  To investigate obstetric characteristics, maternal morbidity and mortality among Swedish women giving birth after in vitro fertilisation (IVF) treatment.

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.

Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years.

BACKGROUND Marked changes have occurred in in vitro fertilization (IVF) methodology during the past 25 years but also in characteristics of couples undergoing treatment. METHODS This study was based on 27 386 women undergoing IVF treatment from 1982 to 2006 and giving birth to 31 850 infants. Outcomes of deliveries were studied using Swedish health registers. Comparisons were made with all deliveries in the population (n = 2 603 601). Adjusted odds ratios were calculated when important changes in background rates had occurred. RESULTS There was a substantial increase in the use of intracytoplasmatic sperm injection (ICSI) and the transfer of cryopreserved embryos. Among all ICSI cases, the proportion using epididymal or testicular sperm varied between 5 and 10%. Maternal characteristics changed during the observation period but the median age remained relatively constant in spite of the increasing maternal age in the population. There was a decline in the rate of some maternal pregnancy diagnoses (notably pre-eclampsia, premature rupture of membranes) and some neonatal diagnoses (notably preterm births, low birthweight, cerebral hemorrhage, respiratory diagnoses, use of continuous positive airway pressure and mechanical ventilation, sepsis/pneumonia). Up till 1992, the twinning rate increased to a maximum of about 30% and then declined to 5% towards the end of the period whereas higher order multiples nearly disappeared. The total rate of infants with congenital malformations changed only little. CONCLUSIONS The decrease in unwanted outcomes can, to a large extent, be explained by the reduced rate of multiple births but was seen also among singletons. Other explanations can be sought in changes in the characteristics of patients undergoing IVF.

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.

STUDIES ON MATURITY IN NEWBORN INFANTS IX. Further Observations on the Use of External Characteristics in Estimating Gestational Age

Abstract. A simple method for assessing maturity based on 8 external characteristics has previously been described. Some new results with the use of this method are now presented. The precision in estimating gestational age is sufficiently good, more than 95% of the infants were correctly estimated within ±3 weeks. Reducing the criteria to seven and thereby excluding the ophthalmoscopic examination did not significantly change the precision of the estimation. The examination based on external characteristics is a very simple and useful method for maturity assessment, even in sick newborn infants. Tables for transforming maturity score into gestational age are presented.

Neurosensory outcome and growth at three years in extremely low birthweight infants : follow-up results from the Swedish national prospective study

A prospective national investigation comprising 633 extremely low birthweight (ELBW) infants born alive in the 2‐y period 1990‐1992 with a birthweight of ≤ 1000 g and gestational age of ≥ 23 completed weeks was conducted regarding neurosensory outcome and growth. Three‐hundred and sixty‐two (98%) surviving ELBW infants were assessed at a median age of 36 months, using a specially designed protocol. At follow‐up, mean height, weight and head circumference in both boys and girls were significantly lower than the reference values. The incidence of cerebral palsy was 7% among all children and 14%, 10% and 3% in children born at 23‐24,25‐26 and ≥ 27 gestational weeks, respectively. At least one obvious handicap was present in 14%, 9% and 3% of these three groups of children, respectively. After adjustment for gestational age, a significantly increased risk of handicap was found in children with intraventricular haemorrhage grade ≥ 3 and/or periventricular leucomalacia and in children with retinopathy of prematurity stage ≥ 3. The results show that more than 90% of ELBW children born at ≥ 25 completed gestational weeks were without neurosensory handicap at 36 months of corrected age. In infants born at 23–24 weeks of gestation, both survival and long‐term outcome were less favourable.

Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study.

We assessed the relationship between very low birth weight (VLBW) (≤1500 g) and the development of asthma, lung function and atopy. The study groups comprised 74 of all 86 (86%) VLBW and 64 of all 86 (74%) matched term children who were prospectively followed for 12 years. A questionnaire on asthmatic and allergic symptoms was completed and skin prick tests, spirometry and hypertonic saline provocation tests were performed at 12 years of age. Cytokine secretion was analysed in stimulated blood leukocyte cultures in 28 VLBW and 23 term children. A history of asthma was more frequent among the VLBW children, as compared with the term children at age 12 (22% vs. 9%, p = 0.046). Among the VLBW children, very preterm birth (gestational age: week 25 to 29) (RR 2.5, 95%CI 1.1–5.8), neonatal mechanical ventilation (RR 2.8, 95%CI 1.2–6.4) and neonatal oxygen supplementation (RR 4.3, 95%CI 1.3–14.0) were significantly associated with a history of asthma by the age of 12 years in univariate analyses. In multivariate logistic regression, neonatal oxygen supplementation ≥ 9 days was the only remaining significant risk factor for a history of asthma (adjusted OR 6.7, 95%CI 1.0–44). The VLBW children who required mechanical ventilation during the neonatal period were more likely to have bronchial hyperresponsiveness than those not requiring mechanical ventilation (60% vs. 28%, p = 0.050). The spirometric values were similar among the VLBW and the term children at 12 years. Very low birth weight was not significantly related to allergic rhinoconjunctivitis, eczema or positive skin prick tests. Furthermore, the levels of IL‐4, IL‐5 and IFN‐γ in stimulated cell cultures were similar in the VLBW and the term children. A history of asthma by 12 years of age was twice as common among the VLBW as the term children, and neonatal oxygen supplementation seemed to be associated with the increased risk. Furthermore, mechanical ventilation during the neonatal period was associated with bronchial hyperresponsiveness at age 12. Very low birth weight per se was not, however, related to atopy.