Ulla-Britt Wennerholm

Deliveries and children born after in-vitro fertilisation in Sweden 1982–95: a retrospective cohort study

BACKGROUND In-vitro fertilisation is an effective treatment for infertility, but there is concern about the health of children. We investigated, in a retrospective registry study, malformations, cancers, and deaths in the complete Swedish in-vitro-fertilisation birth cohort compared with the general population. METHODS We collected data from all in-vitro-fertilisation clinics in Sweden and compared the obstetric outcomes of babies (n=5856) born between 1982 and 1995 with all babies born in the general population (n=1,505,724) during the same period, according to data from the Swedish Medical Birth Registry and the Registry of Congenital Malformations. We investigated the incidence of childhood cancer through the Swedish Cancer Registry. Data were stratified for maternal age, parity, previous subfertility, year of birth, and multiple of pregnancies. FINDINGS Multiple births occurred in 27% of pregnancies compared with 1% in the control group. In the in-vitro-fertilisation group, more babies were born preterm (<37 weeks) than controls (30.3 vs 6.3%) and more had low birthweights (<2500 g, 27.4 vs 4.6%). The perinatal mortality was 1.9% in the in-vitro fertilisation group and 1.1% in the controls. For in-vitro-fertilisation singletons, the risk ratios, adjusted for year of birth, for very preterm birth (<32 weeks) and very low birthweight (<1500 g) were 3.54 (95% CI 2.90-4.32) and 4.39 (3.62-5.32), respectively. Malformations occurred in 5.4% of all babies in the in-vitro-fertilisation group (1.39 [1.25-1.54]), and the rates of neural-tube defects and oesophageal atresia were higher than those in the controls. There was no increase in childhood cancer in the in-vitro-fertilisation group. INTERPRETATION A high frequency of multiple births and maternal characteristics were the main factors that led to adverse outcomes, and not the in-vitro-fertilisation technique itself. The clinical practice of in-vitro-fertilisation needs to be changed to lower the rate of multiple pregnancy.

Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women with preterm prelabor rupture of membranes

Background.  Previous studies have shown an association between intra‐amniotic microbial invasion and/or inflammation and spontaneous preterm birth. The aim of this study was to investigate the occurrence of intra‐amniotic microorganisms and cytokines [interleukin (IL)‐6 and IL‐8] in a Swedish population, with low incidence of preterm birth, of women with preterm prelabor rupture of membranes and their correlation to preterm birth.

Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group

STUDY QUESTIONS What are the risks of adverse outcomes in singletons born after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER Singletons born after FET have a better perinatal outcome compared with singletons born after fresh IVF and ICSI as regards low birthweight (LBW) and preterm birth (PTB), but a worse perinatal outcome compared with singletons born after spontaneous conception. WHAT IS KNOWN ALREADY Previous studies have shown a worse perinatal outcome in children born after IVF in general compared with children born after spontaneous conception. In singletons born after FET, a lower rate of PTB and LBW and a higher rate of large for gestational age (LGA) compared with singletons born after fresh IVF have been shown. STUDY DESIGN A retrospective Nordic population-based cohort study of all singletons conceived after FET in Denmark, Norway and Sweden until December 2007 was performed. PARTICIPANTS/MATERIALS, SETTING AND METHODS Singletons born after FET (n = 6647) were compared with a control group of singletons born after fresh IVF and ICSI (n = 42 242) and singletons born after spontaneous conception (n = 288 542). Data on perinatal outcomes were obtained by linkage to the national Medical Birth Registries. Odds ratios were calculated for several perinatal outcomes and adjustments were made for maternal age, parity, year of birth, offspring sex and country of origin. MAIN RESULTS AND THE ROLE OF CHANCE Singletons born after FET had a lower risk of LBW (adjusted odds ratio (aOR) 0.81, 95% confidence interval (CI) 0.71-0.91), PTB (aOR 0.84, 95% CI 0.76-0.92), very PTB (VPTB; aOR 0.79, 95% CI 0.66-0.95) and small for gestational age (SGA; aOR 0.72, 95% CI 0.62-0.83), but a higher risk of post-term birth (aOR 1.40, 95% CI 1.27-1.55), LGA (aOR 1.45, 95% CI 1.27-1.64), macrosomia (aOR 1.58, 95% CI 1.39-1.80) and perinatal mortality (aOR 1.49, 95% CI 1.07-2.07) compared with singletons born after fresh IVF and ICSI. Compared with children conceived after spontaneous conception, singletons born after FET had a higher risk of LBW (aOR 1.27, 95% CI 1.13-1.43), very LBW (aOR 1.69, 95% CI 1.33-2.15), PTB (aOR 1.49, 95% CI 1.35-1.63), VPTB (aOR 2.68, 95% CI 2.24-3.22), SGA (aOR 1.18, 95% CI 1.03-1.35), LGA (aOR 1.29, 95% CI 1.15-1.45), macrosomia (aOR 1.29, 95% CI 1.15-1.45) and perinatal (aOR 1.39, 95% CI 1.03-1.87) neonatal (aOR 1.87, 95% CI 1.23-2.84) and infant mortality (aOR 1.92, 95% CI 1.36-2.72). When analyzing trends over time, the risk of being born LGA increased over time for singletons born after FET compared with singletons born after fresh IVF and ICSI (P = 0.04). LIMITATIONS, REASONS FOR CAUTION As in all observational studies, the possible role of residual confounding factors and bias should be considered. In this study, we were not able to control for confounding factors, such as BMI, smoking and reason for, or length of, infertility. WIDER IMPLICATIONS OF THE FINDINGS Perinatal outcomes in this large population-based cohort of children born after FET from three Nordic countries compared with fresh IVF and ICSI and spontaneous conception were in agreement with the literature.

International Collaborative Study of Intracytoplasmic Sperm Injection–Conceived, In Vitro Fertilization–Conceived, and Naturally Conceived 5-Year-Old Child Outcomes: Cognitive and Motor Assessments

Objective. To date, very few studies have been conducted on the neurodevelopmental well-being of children conceived through intracytoplasmic sperm injection (ICSI). The limitations of these studies often include a lack of comparison with a demographically matched, naturally conceived (NC) group and the investigation of only very young children, with relatively small samples sizes. One study showed that there were no differences in IQ scores among ICSI-conceived, in vitro fertilization (IVF)-conceived, and NC children at 5 years of age. Unfortunately, psychomotor development was not assessed in that study. Because findings regarding these childrens cognitive and motor development are inconclusive, the aim of this study was to shed more light on the cognitive and motor development of 5-year-old ICSI-conceived children. Methods. A total of 511 ICSI-conceived children were compared with 424 IVF-conceived children and 488 NC controls. Children were recruited in 5 European countries, ie, Belgium, Denmark, Greece, Sweden, and the United Kingdom. Participation rates ranged from 45% to 96% in the ICSI and IVF groups and from 34% to 78% in the NC group. Cognitive and motor development was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) and McCarthy Scales of Childrens Abilities (MSCA) Motor Scale, respectively. The WPPSI-R consists of 2 major scales, ie, Verbal and Performance, each including 6 subtests. The 6 Performance Scale subtests are object assembly, geometric design, block design, mazes, picture completion, and animal pegs. The 6 Verbal Scale subtests are information, comprehension, arithmetic, vocabulary, similarities, and sentences. Scores on the Performance and Verbal Scale subtests are summed to yield the performance IQ (PIQ) and verbal IQ (VIQ), respectively. Scores on both the Performance Scale and the Verbal Scale yield the full-scale IQ (FSIQ). IQ scales have a mean score of 100 and a SD of 15. Each subtest has a mean score of 10 and a SD of 3. The MSCA consists of 6 scales, ie, Verbal, Perceptual-Performance, Quantitative, General Cognitive, Memory, and Motor Scale. In this study, only the Motor Scale was administered. This scale assesses the childs coordination during performance of a variety of gross- and fine-motor tasks. Leg coordination, arm coordination, and imitative action tests provide measures of gross-motor ability. Draw-a-design and draw-a-child assess fine-motor coordination, as revealed by the levels of hand coordination and finger dexterity. The mean score for this test is 50, with a SD of 10. Results. No differences were identified among ICSI, IVF, and NC children with respect to VIQ, PIQ, or FSIQ scores of the WPPSI-R. Furthermore, there were no differences between groups regarding the discrepancy between VIQ and PIQ scores. These results were not influenced by gender, country, or maternal educational level. However, in the subgroup of firstborn children with mothers who gave birth at an older age (33–45 years), NC children obtained significantly better VIQ and FSIQ scores than did children conceived through assisted reproductive technologies. These differences in VIQ and FSIQ scores between ICSI/IVF and NC children were relative, because NC children scored <1 IQ point higher than ICSI/IVF children. Therefore, these scores show no clinical relevance. For Verbal Scale subtests, variables such as age of the mother at the time of the birth, educational level of the mother, and gender and nationality of the child interacted with mode of conception, resulting in clinically irrelevant differences between scores for the ICSI/IVF and NC groups on the arithmetic, vocabulary, and comprehension subtests. For Performance Scale subtests, these same demographic factors interacted with mode of conception for the block design, object assembly, and animal pegs subtests, again resulting in clinically irrelevant differences among groups. In the 3 groups (ICSI, IVF, and NC), we observed equal numbers of children scoring below 1 SD from the mean on the WPPSI-R and the MSCA. Conclusions. This study includes a substantial number of children from several European countries. Apart from a few interaction effects between mode of conception and demographic variables, no differences were found when ICSI, IVF, and NC scores on the WPPSI-R and MSCA Motor Scale were compared. Nevertheless, the aforementioned interaction effects could indicate that demographic variables such as maternal age at the time of the birth and maternal educational level play different roles in the cognitive development of IVF and ICSI children, compared with NC children. Additional research is needed to explore and verify this finding. Previous studies revealed that ICSI children, in comparison with NC children, more frequently obtained scores below 1 SD from the mean on 3 subtests of the Performance Scale (object assembly, block design, and mazes) or showed a trend of 5.2% of ICSI children, compared with 2.5% of IVF children and 0.9% of NC children, obtaining a score below 1 SD from the mean, but those findings were not confirmed in this study. Here no differences were found among the 3 groups in the numbers of children scoring below 1 SD from the mean on the VIQ, PIQ, and FSIQ tests and the Verbal and Performance Scale subtests. Motor development results were somewhat more conclusive. There were no differences between the scores of ICSI, IVF, and NC children on the MCSA Motor Scale. No interaction effects were found between mode of conception and demographic variables, indicating that these results are not influenced by gender, nationality, maternal educational level, or maternal age at the time of the birth. Furthermore, equal proportions of children in all 3 groups scored below 1 SD from the mean. The results of this study are reassuring for parents who conceived through ICSI (or IVF). The findings indicate that the motor and cognitive development of their offspring is very similar to that of NC children. However, demographic factors such as maternal educational level and maternal age at the time of the birth might play different roles in the cognitive development of ICSI and IVF children, compared with NC children.

Anal sphincter tears: prospective study of obstetric risk factors

Objective To evaluate intrapartum risk factors for anal sphincter tear.

Sequelae of chorioamnionitis.

Chorioamnionitis correlates to preterm delivery prior to 30 weeks of gestation. In most studies, proxies of intrauterine infection (clinical chorioamnionitis, histological chorioamnionitis, intra-amniotic increase in cytokines) are associated with acute neonatal morbidity and mortality and, at least to some degree, with neurological impairments (periventricular leukomalacia, intraventricular hemorrhage, cerebral palsy, polymicrogyria), chronic lung disease, and involution of the thymus in the preterm infant. The connection to visual impairment and cognitive deficits is uncertain or unknown. Full-term babies exposed to intrauterine infection often present with depressed Apgar scores and neonatal encephalopathy, and are at markedly increased risk of developing cerebral palsy. The infectious/inflammatory mechanisms involved are incompletely understood, and the types of microbes, as well as the genetic characteristics of the host adaptive and innate immune response, need to be better characterized.

Infertility therapy associated-multiple pregnancies (births): an ongoing epidemic

Multiple gestation is now recognized as a major problem associated with both assisted reproductive technologies (ART) and also with ovulation induction therapies. Although some countries are beginning to adopt measures to address this issue, either through legislation or the development of clinical guidelines, there is a clear need to ensure recognition and a consistent approach to this problem worldwide. In particular, there is a need to educate both healthcare professionals and the lay population that multiple gestations are not a desirable outcome for the infertile couple.

Postnatal growth and health in children born after cryopreservation as embryos

BACKGROUND There is uncertainty about the health of children born from in-vitro fertilisation (IVF) with cryopreserved embryos. We investigated the postnatal growth and health (up to 18 months) of these children compared with those born after standard IVF with fresh embryos and those from spontaneous pregnancies. METHODS 255 children from cryopreserved embryos were matched by maternal age, parity, single or twin pregnancy, and date of delivery with 255 children born after IVF with fresh embryos, and 252 children from spontaneous pregnancies. The main endpoint was growth; secondary endpoints were the prevalence of chronic illness, major malformations, cumulative incidence of common diseases, and development during the first 18 months. Growth was assessed by comparison with standard Swedish growth charts and by standard deviation scores. FINDINGS Growth features were similar for both singletons and twins in the three groups. There were 6 (2.4%) of 255, 9 (3.5%) of 255, and 8 (3.2%) of 252 major malformations in the cryopreserved group, standard IVF, and spontaneous groups, respectively (p=0.6 between the cryopreserved and standard IVF group). The prevalence of chronic diseases did not differ between the three groups, with 18.0%, 15.3%, and 16.7% of children with a chronic illness in the cryopreserved group, standard IVF, and spontaneous groups, respectively. INTERPRETATION The cryopreservation process does not adversely affect the growth and health of children during infancy and early childhood. Minor handicaps, behavioural disturbances, learning difficulties, and dysfunction of attention and perception cannot be ruled out at this age.

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.

Obstetric outcomes after transfer of vitrified blastocysts

BACKGROUND It has been claimed that the risks to the child resulting from vitrification as compared with the slow-freezing technique, may be higher owing to the high concentrations of potentially toxic cryoprotectants. We therefore retrospectively compared the obstetric and neonatal outcomes in a cohort of children born after transfer of vitrified blastocysts, fresh blastocysts and slow-frozen early cleavage stage embryos. METHODS All children born after transfer of vitrified blastocysts (n = 106), fresh blastocysts (n = 207) and slow-frozen early cleavage stage embryos (n = 206) during the period January 2006 to May 2008 at Fertility Center Scandinavia were included. Data on obstetric and neonatal outcomes were obtained from medical records from the antenatal and delivery clinics. RESULTS For singletons, there were no significant differences between the groups in gestational age, mortality or birth defects. After adjustment for parity and BMI, birthweight was significantly higher in singletons born after transfer of vitrified blastocysts as compared with after transfer of fresh blastocysts (median 3560 versus 3510 g, P = 0.0311). More singletons born after transfer of fresh blastocysts were small for gestational age compared with singletons born after transfer of vitrified blastocysts (12.1 versus 3.0%, P = 0.0085). A higher rate of major post-partum haemorrhage was observed in the vitrified blastocyst group as compared with the other two groups (25.0 versus 6.0 and 7.5%). CONCLUSIONS No adverse neonatal outcomes were observed in children born after transfer of vitrified, as compared with fresh blastocysts or after transfer of slow-frozen early cleavage stage embryos.