Alastair Sutcliffe

Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples

Recent case reports have suggested that infertility treatment with intracytoplasmic sperm injection (ICSI) may increase the risk of imprinting defects leading to Angelman syndrome (AS). Although imprinting defects account for only 4% of patients with AS, we have found four cases among 16 AS patients born to subfertile couples, who conceived with or without infertility treatment (25%; relative risk (RR) 6.25; 95% confidence interval (CI) 1.68 to 16.00). The risk in untreated couples with time to pregnancy (TTP) exceeding 2 years was identical to that of those treated by ICSI or by hormonal stimulation alone (RR 6.25; 95% CI 0.70 to 22.57). It was twice as high in couples who had received treatment and also had TTP >2 years (RR 12.5; 95% CI 1.40 to 45.13). Our findings suggest that imprinting defects and subfertility may have a common cause, and that superovulation rather than ICSI may further increase the risk of conceiving a child with an imprinting defect.

Outcome of assisted reproduction

In-vitro fertilisation has been done for nearly 30 years; in developed countries at least 1% of births are from assisted reproductive therapies (ART). These children now represent a substantial proportion of the population but little is known about their health. Some of the morbidity associated with ART does not result from the techniques but from the underlying health risks of being subfertile. Much of the amplified risk associated with ART is related to high birth order. However, risk of intrauterine and subsequent perinatal complications is enhanced after ART, and urogenital malformations can be present in boys, even in singleton infants. No increase in discord or other difficulties within families has been recorded. Long-term follow-up of children born after ART to reproductive age and beyond is necessary.

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.

Minitablets: New Modality to Deliver Medicines to Preschool-Aged Children

OBJECTIVE. The goal was to assess the acceptability and suitability of placebo minitablets for preschool-aged children. METHODS. One hundred children 2 to 6 years of age were recruited from a major London hospital. How to swallow the minitablet was discussed with the child, and chewing was discouraged. The parents were asked to administer 1 minitablet (placebo, 3-mm diameter) to the child. The outcomes were recorded as (1) swallowed, (2) chewed, (3) spat out, or (4) refused to take. RESULTS. Of the youngest children (2 years of age), almost one half (46%) swallowed the minitablet. The proportion increased to 53% for children 3 years of age. Children ≥4 years of age were more likely to swallow the minitablet than not to swallow the minitablet, with 85% of 5-year-old children swallowing the minitablet. The ability to swallow the minitablet was not affected by gender. CONCLUSIONS. This study demonstrated the potential to use minitablets for the treatment of preschool-aged children and suggests that minitablets can be used as a potential new formulation for children in this age range.

Outcome for children born after in utero laser ablation therapy for severe twin-to-twin transfusion syndrome

Objective To examine the postnatal development of a group of children born after in utero laser ablation therapy for severe twin‐to‐twin transfusion syndrome.

Children born after intracytoplasmic sperm injection: population control study

Intracytoplasmic sperm injection is often successful for treatment of male infertility; over 20 000 children have been born as a result.1 This bypassing of natural barriers to sperm selection has raised concerns about the children conceived.2 We report a population control study of children born in the United Kingdom as a result of this treatment. Children between 12 and 24 months old who had been singleton births were identified from a list of couples who had received the treatment and their parents were invited to participate; 123 of 137 families (90%) agreed. Control children, conceived naturally, were recruited from associated nurseries (105/123) or were social peers of cases (18/123). Altogether, 123 children born after intracytoplasmic sperm injection (study children) and 123 control children were seen. Children were matched for social class, maternal educational level, region, sex, and race but not maternal age. Multiple births were excluded to avoid confounding factors. Primary outcome measures were developmental scoring on the Griffiths scales of mental development3 and rates of congenital abnormalities. The Griffiths scales are an objective method of assessing development which uses five subscales. All subscales …

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial.

Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders. Design 12 week double masked randomised placebo controlled phase III trial. Setting 19 hospitals across England and Wales. Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep. Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment. Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy. Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups. Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required. Trial registration ISRCT No 05534585.

Follow-up of children born after ART.

Assisted reproductive therapies (ART), namely in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), have become widely used in the treatment of human infertility. Children conceived using ART represent a substantial proportion of the population. Follow-up of these children is necessary in order to evaluate the risks of infertility treatment upon subsequently conceived offspring. In recent years there has been considerable work in this field. This review summarises current evidence regarding the health of children conceived following ART, encompassing neonatal outcomes, the risk of congenital malformations, neurodevelopmental outcome, physical health, psychosocial well being, and the risk of cancer. The main risks for the future well being of ART children remain multiple pregnancies and low birth weight. Evidence regarding the outcome of singletons born at term following ART is generally reassuring. It is essential that follow-up of ART children continues as they progress through adolescence into adulthood.

Outcome in children from cryopreserved embryos.

A cohort of 91 children from cryopreserved embryos and 83 control children who were conceived normally had their development assessed using the Griffithss scales of mental development. The controls (81 singletons and two twins) of a similar age, sex, and social class were selected from siblings, cousins, and peers of the cryopreserved embryo group (68 singleton, 20 twins, and three triplets). Children from cryopreserved embryos had a lower mean birth weight and mean gestational age and a higher proportion were born by caesarean section. One child from the cryopreserved embryo group had Downs syndrome, three had squints, and four had conductive hearing loss while in the control children, six had squints, and nine had conductive hearing loss. In both groups, including the child with Downs syndrome, the mean Griffithss quotient was greater than the standard 100. In the children from cryopreserved embryos, the singleton and multiple birth subgroups had statistically similar assessment results. The mean (SD) Griffithss quotient was 105.69 (13.55) in children from cryopreserved embryos and 108.18 (9.80) in controls at a chronological age of 25.08 (12.86) and 29.19 (14.65) months respectively. Overall, the development in children from cryopreserved embryos did not cause concern though formal testing had highlighted small differences compared with other children conceived normally and of a similar social class.

A retrospective case-control study of developmental and other outcomes in a cohort of Australian children conceived by intracytoplasmic sperm injection compared with a similar group in the United Kingdom

OBJECTIVE To investigate the possibility that children born after ICSI were at increased risk for neurodevelopmental delay. DESIGN Retrospective case-control study. SETTING IVF clinic. PATIENT(S) Fifty-eight singleton children born after ICSI and 38 normally conceived singleton children (controls), matched for relevant sociodemographic characteristics, from Australia and 208 case-patients and 221 controls from the United Kingdom. MAIN OUTCOME MEASURE(S) Antenatal and perinatal, and sociodemographic characteristics; physical health, including congenital abnormalities; and neurodevelopment by using the Griffiths scales of mental development. RESULT(S) Eighty-five percent of case-patients and 96% controls were assessed at a mean age of 13 months. Neurodevelopmental scores were similar in all children. Perinatal outcome was similar, apart from more caesarean sections in the case-patients. Rates of congenital anomalies were similar (5.6% among case-patients vs. 5.7% among controls). Children from fathers with oligozoospermia showed no extra problems. Children born after ICSI in the United Kingdom and Australia were similar. CONCLUSION(S) Children conceived after ICSI did not differ from their naturally conceived peers in physical health or development at ages up to 15 months.