Mental development of children conceived using intracytoplasmic sperm injection. The current evidence.

There are biologically plausible reasons why children conceived using intracytoplasmic sperm injection (ICSI) may be at increased risk for delayed mental development. The first controlled study of mental development in ICSI children which was published in 1998 found 1 year old ICSI children to be at significantly increased risk for developmental delay compared with both in vitro fertilization (IVF) and naturally conceived control children. These results encouraged several groups of investigators to further study developmental outcomes for ICSI children in order to clarify the level of risk, if any. This review considers the currently available evidence from published studies which included control groups and a standardized measure of infant or child development. The 9 publications included in the review include a total of 969 ICSI children and 828 controls (343 IVF, 485 naturally conceived). All studies indicate that the majority of children conceived using ICSI have normal mental development, and most have not found ICSI children to be at increased risk for developmental delay. The evidence to date suggests that ICSI per se is not an independent risk factor for delayed child development, but that demographic factors such as level of maternal education and social class are more important determinants of developmental outcome for ICSI children.

Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age.

BACKGROUND: Concerns about possible adverse outcomes for children conceived using ICSI were highlighted in 1998 when 1-year-old ICSI children were found to be at increased risk (relative risk = 9.2) of delayed mental development compared with children conceived naturally or using IVF. As the findings were biologically plausible, it was considered important to reassess child development when a more accurate measure of long-term cognitive ability could be obtained. METHODS: The mental development of 97 ICSI, 80 IVF and 110 naturally conceived (NC) children at 5 years of age was assessed using intelligence quotients (IQ) obtained from the Wechsler Preschool and Primary Scales of Intelligence. RESULTS: The mean full-scale IQ was 110 +/- 18 for ICSI, 111 +/- 13 for IVF and 114 +/- 13 for NC children (P = 0.21, non-significant). ICSI children were not at increased risk for delayed (full-scale IQ <85) cognitive development (ICSI 5.2%, IVF 2.5%, NC 0.9%; P = 0.18, non-significant). The only significant independent predictor of below-average full-scale IQ on multivariate analysis was lower maternal education level. CONCLUSIONS: These findings suggest that the genetic influence of parental cognitive ability is more important than the mode of conception in determining the long-term intellectual ability of children conceived using ICSI.

The mother-child relationship following in vitro fertilisation (IVF): infant attachment, responsivity, and maternal sensitivity.

Infant attachment and mother-child interaction were evaluated for 65 primiparous women and their singleton infants conceived through in vitro fertilisation (IVF) and a control group of 61 women and their infants conceived naturally. The sample was enrolled during pregnancy as part of a longitudinal study. At 12 months postpartum, security of infant attachment was assessed using the Strange Situation procedure, and mother-child interaction was assessed in a free play context using the Emotional Availability Scales. IVF children demonstrated predominantly secure attachment relationships with their mothers (64.6% IVF, 55.9% controls), and there were no significant between-group differences in the proportion of IVF compared to control group children classified in any of the secure or insecure attachment groups. Furthermore, there were no significant group differences on maternal (sensitivity, structuring, hostility) or child (responsivity, involving) dimensions of interaction during play. The majority of IVF mothers (86%) were sensitive and their infants responsive (91%). Contrary to expectation, mother's ratings of greater anticipated infant difficultness assessed during pregnancy and higher ratings of infant temperament and behaviour difficulty assessed at 4 and 12 months postpartum were associated with secure attachment relationships and more optimal mother-child interaction in both the IVF and control groups.

Antenatal glucocorticoids modulate the amplitude of pulsatile cortisol secretion in premature neonates.

We hypothesized that antenatal exposure to glucocorticoids influences subsequent pulsatile cortisol (F) secretion in premature neonates. To test this hypothesis, blood was sampled for plasma F determination via indwelling arterial lines at 15-min intervals for 6 h in 26 clinically stable neonates whose gestational ages were 25-33 wk. Deconvolution analysis was used to characterize F secretion and elimination. Pulsatile F secretion was observed in all neonates. Deconvolution estimates in eight neonates exposed to antenatal glucocorticoids (ANG group) were compared with those of 18 neonates not or only remotely exposed to ANG (No/RG group). The median amplitude of the F secretory burst of the ANG group was significantly less than that of the No/RG group [4.3 nmol/Lv x min and 9.2 nmol/Lv x min, respectively; p = 0.026 (Lv is liter of F distribution volume)]. The number and duration of F secretory bursts was similar for both groups: 5 bursts per 6 h, and 23 versus 16 min. By univariate linear regression analysis, mean arterial blood pressure correlated positively with F secretory burst frequency and F production rate (p = 0.0035, r = 0.55 and p = 0.0067, r = 0.52, respectively). We propose that ANG treatment modulates the amplitude of pulsatile F secretion in premature neonates.

Infants conceived using in-vitro fertilization do not over-utilize health care resources after the neonatal period.

Health outcomes during the first year for 95 infants born following in-vitro fertilization (IVF) were compared with those of 79 naturally conceived controls whose mothers were of identical parity and similar age. Primigravid women were enrolled prospectively at 30 weeks gestation, perinatal and neonatal data were collected during pregnancy and following birth, and details of health care resource use were obtained from mothers at 4 and 12 months. Median (range) number of medical problems during the first year tended to be less for IVF infants, 4 (0-41) versus 5 (0-12) (P = 0.07), whilst total number of visits to health care workers was similar for IVF and control infants, 19 (2-47) versus 19 (1-47). IVF infants were more likely to have an excessive number of visits to Early Childhood Health Care Centres [odds ratio (OR; 95% confidence interval, CI) = 2.44 (1.11-5.56)], but less likely to have an excessive number of visits to general medical practitioners [OR = 0.45 (0.22-0.93)] and other health care workers [OR = 0.48 (0.23-0.99)]. These data provide some degree of reassurance about medium-term health outcomes for children conceived using IVF. Although they are more likely to utilize the resources of neonatal intensive care units, IVF infants do not appear to have an increased number of medical problems or to over-utilize health care resources during the remainder of their first year of life.

Development, behaviour and temperament: a prospective study of infants conceived through in-vitro fertilization.

The development, behaviour and temperament of 65 singleton infants conceived through in-vitro fertilization (IVF) and 63 matched controls were compared at 1 year postpartum. Primiparous women were recruited during pregnancy and their infants' development was assessed at 1 year. In addition, test-taking behaviour was evaluated by an examiner using the Bayley behaviour rating scale and mothers completed a behaviour problem checklist and temperament scale. Mental, motor, speech and social development were appropriate for age, with no significant group differences. While receptive language development was in the normal range, IVF infants scored lower than control infants. Across both groups, mothers reported low levels of behaviour difficulty and mean temperament ratings were in the general population range. There were no group differences in observed test-taking behaviour. However, IVF mothers rated their children at a higher level of behaviour difficulty and more reactive than the ratings given by control mothers. Overall, singleton children conceived through IVF demonstrate appropriate general development at 1 year of age. The higher reported behaviour difficulty experienced by IVF mothers may reflect their concerns about the well-being and adjustment of their child during the first year.

Medical and developmental outcome at 1 year for children conceived by intracytoplasmic sperm injection.

BACKGROUND: Intracytoplasmic sperm injection (ICSI) was introduced as a new form of in-vitro fertilisation (IVF) in 1993 and is now accepted as the treatment of choice for severe male infertility in many centres around the world. However, there is little information about the long-term outcome of children conceived by ICSI. We aimed to find out the medical and developmental outcome of children conceived by ICSI at age 1 year. METHODS: In this prospective study, we compared the medical and developmental outcome at 1 year of 89 children conceived by ICSI with 84 children conceived by routine IVF, and with 80 children conceived naturally. Formal developmental assessment was done with Bayley Scales of Infant Development (2nd edition) from which a mental development index (MDI) was derived. FINDINGS: There was no significant difference in the incidence of major congenital malformations or major health problems in the first year of life. However, the mean Bayley MDI was significantly lower for the children conceived by ICSI than for the children conceived by routine IVF or naturally (95.9 [SD 10.7], 101.8 [8.5], and 102.5 [7.6], respectively, p < 0.0001). 15 (17%) of 89 children conceived by ICSI experienced mildly or significantly delayed development (MDI < 85) at 1 year compared with two (2%) of the 84 children conceived by IVF and one (1%) of the 80 children conceived by natural conception (p < 0.0001). INTERPRETATION: Although most children conceived by ICSI are healthy and develop normally, there is an increased risk of mild delays in development at 1 year when compared with children conceived by routine IVF or conceived naturally. These findings support the need for ongoing developmental follow-up of children conceived by ICSI to see whether they are at increased risk of intellectual impairment or learning difficulties at school age.

Ocular sequelae in extremely premature infants at 5 years of age.

OBJECTIVE: To report long-term ophthalmological sequelae in extremely premature infants at 5 years and to determine the relationship between neonatal variables (including retinopathy of prematurity; ROP) and the 5 year ophthalmological outcome of these infants. METHODOLOGY: The study cohort comprised 84 surviving infants born with a birthweight < 1000 g or gestational age < 28 weeks from June 1985 to December 1989. All infants had an ophthalmological assessment between 34 and 40 weeks post conceptional age to document grade of ROP and were assessed at 5 years of age for fundoscopy, visual acuity, refractive error and ocular mobility. RESULTS: Of the 84 long-term survivors 69 (82%) were formally assessed at 5 years. Overall, 30 (43%) had some form of ocular disorder. Nineteen (27%) had reduced visual acuity of < 6/6 and three of these were blind. Myopia > -0.5 dioptre was noted in eight (12%), hypermetropia > or = 2.0 dioptre in five (8%), astigmatism in seven (11%) and strabismus was present in nine (14%) of the cohort. There was a significant relationship (P < 0.0001) between the incidence of ocular disorders and ROP. However, even those premature children without ROP had a 31% incidence of ocular disorder at 5 years. CONCLUSION: Long-term ophthalmological follow-up is recommended in all extremely premature infants regardless of the presence of ROP in the neonatal period.

Survey of the definition and screening of neonatal hypoglycaemia in Australia.

OBJECTIVE: To determine the approach to identifying neonatal hypoglycaemia and the definition of neonatal hypoglycaemia used by neonatal paediatricians in Australian Level 3 neonatal intensive care units (NICU). METHODOLOGY: A questionnaire was sent to the 101 neonatal paediatricians in the 22 Level 3 NICU in Australia asking their method of screening for, and definition of, neonatal hypoglycaemia. RESULTS: Responses were received from 70 neonatal paediatricians, including all 22 directors. A bedside glucose meter is used in 19 of 22 NICU to screen for hypoglycaemia, whilst one NICU uses a glucose analyzer and another NICU uses a visual colour comparison method. One NICU does not screen, but has blood glucose measured in a satellite laboratory. If the screening method suggests hypoglycaemia, 62 of 63 neonatal paediatricians proceed to blood glucose determination in a laboratory, mostly using plasma samples. Based on the laboratory measurement, the definition of neonatal hypoglycaemia ranged from < 1.1 to 3.0 mmol/L. CONCLUSIONS: The majority of neonatal paediatricians in Australian NICU screen for neonatal hypoglycaemia using a bedside glucose meter. There is a wide range in the definition of neonatal hypoglycaemia from < 1.1 to 3.0 mmol/L.

The Neonatal Neurobiologic Risk Score: does it predict outcome in very premature infants?

OBJECTIVE: To examine the validity of the Neonatal Neurobiologic Risk Score (NBRS) for predicting neurodevelopmental outcome to 3 years in infants born at < 28 weeks gestation. METHOLDOLOGY: The NBRS was retrospectively determined for 56 consecutive infants cared for in our NICU and prospectively followed to 3 years. Neurodevelopmental assessments performed at 3 years were correlated with the NBRS, and the predictive powers of individual items in the NBRS determined. RESULTS: The mean (range) birth weight was 908 (514-1295) g and gestational age was 26 (24-27) weeks. Three-year outcome was abnormal in 12 (21%) infants. A high NBRS at discharge was associated with an increased risk of abnormal 3-year outcome (odds ratio 2.56; 95% C.I. 1.4-4.7, p = 0.002). A modified NBRS using only significantly predictive items (acidosis, hypoxemia, hypotension, intraventricular hemorrhage, infection and hypoglycemia) demonstrated high sensitivity (1.00), specificity (0.98), positive predictive value (0.92) and negative predictive value (1.00) for abnormal 3-year outcome. CONCLUSIONS: This study confirms the validity of the NBRS as a simple and objective means of identifying very premature infants at highest risk of abnormal neurodevelopmental outcome, and of identifying specific events which may contribute to such outcomes.

Predictive value of the Griffiths assessment in extremely low birthweight infants.

OBJECTIVE: To assess the relationship between the Griffiths Mental Development Scales at 1 and 3 years and the Stanford-Binet Intelligence Scale (S-B) and Beery Test of Visual-Motor Integration (VMI) at 5 years in extremely low birthweight (ELBW) children. METHODOLOGY: Prospective study of 45 ELBW infants, without severe neurosensory impairment, cared for in a single Level III neonatal intensive care unit. RESULTS: At 5 years, 36 (80%) children were of average intelligence, 8 (18%) had borderline intelligence and one was mentally retarded. The Griffiths general quotient (GQ) at 1 year had a weak correlation with the 5 year IQ (corr. coeff. = 0.47), with only 17% of children with a GQ < -1 s.d. at 1 year receiving an IQ < -1 s.d. at 5 years. In contrast, the Griffiths GQ at 3 years correlated strongly with 5 year IQ (corr. coeff. = 0.78). Among those children with a 3 year GQ < -1 s.d., 67% had a 5 year IQ < -1 s.d. and all had a 5 year 1Q < 89. The 3 year hearing and speech subscale correlated strongly with the 5 year S-B verbal comprehension factor (corr. coeff. = 0.753) and the 3 year combined eye/hand co-ordination/performance quotient had a moderate correlation with the S-B non-verbal reasoning factor (corr. coeff. = 0.597) and with the Beery VMI (corr. coeff. = 0.49). CONCLUSIONS: The 3 year Griffiths GQ is a good predictor of 5 year S-B IQ in ELBW children and can be used to identify children who may benefit from intervention prior to school entry.

An unusual congenital dorsal midline thoracic mass.

OBJECTIVE: To describe the presentation and investigation of an unusual form of congenital dorsal midline thoracic mass. RESULTS: An infant born by emergency Caesarean section at 34 weeks gestation was found to have a large dorsal midline thoracic mass. The infant had normal neurological function in all limbs. Radiological investigation showed no abnormality in the vertebrae. Ultrasonographic investigation suggested the mass to consist of subcutaneous oedema. The mass resolved completely within the first 2 weeks. CONCLUSIONS: The lesion observed in this infant represents a very unusual location for a benign condition caused by cervical pressure on the presenting fetal part. The use of ultrasonography enabled rapid exclusion of the more common, potentially serious, causes of a congenital midline dorsal thoracic mass.

Neonatal outcome in a randomized, controlled trial of low-dose aspirin in high-risk pregnancies.

OBJECTIVE: To determine the value of low-dose aspirin in high-risk pregnancies, and assess its impact on fetal growth, as well as on perinatal mortality and morbidity. METHODOLOGY: One hundred and eight women with singleton pregnancies were enrolled in a randomized, double-blind, placebo-controlled trial of 100 mg/day aspirin from 17 to 19 week gestation. Enrolment criteria included pre-existing chronic essential hypertension or renal disease, or a history of previous early, severe pre-eclampsia. RESULTS: There were four stillbirths (all aspirin) and two neonatal deaths (both placebo), to yield respective perinatal mortality rates of 69/1000 and 40/1000 (P = 0.499). Liveborn infants in the aspirin group were significantly more mature (P = 0.017) and of heavier birthweight (P = 0.034) but had similar length (P = 0.091) and head circumference (P = 0.257). Fewer infants in the aspirin group were liveborn prematurely (5/54 vs 14/50; P = 0.016) or were of low birthweight (3/54 vs 9/50; P = 0.052). There were no significant between-group differences for standard deviation (Z) scores for weight, length or head circumference, or for skinfold thickness measurements. There was no significant difference in occurrence of low Apgar scores or in neonatal intensive care unit use between the groups. CONCLUSIONS: Low-dose aspirin does not appear to have a significant effect on perinatal morbidity. The increase in weight at birth associated with low-dose aspirin therapy is due to prolongation of pregnancy rather than prevention of intra-uterine growth retardation.

Risk factors for sensorineural hearing loss in extremely premature infants.

OBJECTIVE: To identify potentially preventable risk factors for sensorineural hearing loss (SNHL) in extremely premature infants. METHODOLOGY: A case control study of survivors with gestational age (GA) < 28 weeks or birthweight (BW) < 1000 g using data collected prospectively in our Neonatal Intensive Care Unit database. Each subject with bilateral SNHL > 40 dB was matched according to GA, BW and sex with two controls who had neither sensorineural nor conductive hearing loss. RESULTS: Infants with SNHL had increased mean (+/- s.d.) days ventilated (53 +/- 21 vs 37 +/- 23 days, P = 0.006) and in oxygen (107 +/- 44 vs 69 +/- 28 days, P = 0.02) compared with controls. The risk for SNHL was increased for infants who spent > 90 days in oxygen (OR 4.0 [95% CI 1.1-15.6]), had maximum FiO2 > 0.90 (5.6 [1.2-26.9]), minimum plasma Na < 125 mmol/L (5.6 [1.1-27.8] or maximum pH > 7.60 (5.6 [1.1-89.0]). Neither maximum serum bilirubin nor exposure to ototoxic drugs was associated with SNHL. CONCLUSIONS: Avoidance of severe hyponatraemia and extreme alkalosis, as well as use of surfactant to minimize the severity of hyaline membrane disease, may result in a decreased incidence of SNHL in extremely premature infants.

Vitamin A status in preterm neonates with and without chronic lung disease.

It has been proposed that there is an association between vitamin A (VA) deficiency and the development of chronic lung disease (CLD) in preterm infants. This study was designed to measure the VA status in preterm infants and to compare the results in the group of babies who developed CLD with the group who did not. Vitamin A status was assessed by measuring plasma VA, retinol binding protein (RBP) and the plasma VA:RBP molar ratio in 25 infants of less than 31 weeks gestation during the first 28 days of life. Eleven babies developed CLD and 14 did not. There was no significant difference in plasma VA levels between the CLD and non CLD groups during the first 28 days. The majority of infants had adequate VA status, with a subgroup being deficient.

Extremely low birthweight infants at 3 years: a developmental profile.

This study documents the neurodevelopmental outcome at 3 years of 52 of 55 extremely low birthweight (ELBW) survivors (survival rate 49%) born in a tertiary maternity centre from July 1985 through December 1988, and examines more closely the developmental profile of the neurologically normal survivors. At 3 years, 6 (12%) children had severe neurodevelopmental impairment (severe cerebral palsy, blindness, deafness or a General Quotient (GQ) < 70 on the Griffiths Scales), 11 (21%) had mild to moderate impairment and 35 (67%) had no neurosensory impairment and normal development (GQ > or = 85). Significant risk factors for severe impairment were stage 3 or 4 retinopathy of prematurity (odds ratio [OR] 21.5), treatment with postnatal steroids (OR 21), grade III or IV intraventricular haemorrhage (OR 11) and supplemental oxygen at 'term' (OR 6.4). The developmental profile of the 35 neurologically normal children revealed a significant weakness in eye and hand coordination skills and a relative strength in hearing and speech skills. Early recognition of this developmental profile may allow implementation of more appropriate preschool programmes for ELBW children.

Longitudinal study of plasma ACTH and cortisol in very low birth weight infants in the first 8 weeks of life.

There are few published data on plasma ACTH and cortisol in very low birth weight (VLBW) infants beyond the first week of life. We therefore measured plasma ACTH and cortisol longitudinally in 25 infants (mean birth weight 1025 g, mean gestational age 28 weeks) at 1, 2, 4 and 8 postnatal weeks to document normative values for infants not receiving dexamethasone. We also examined the influence of clinical state and dexamethasone treatment on plasma ACTH and cortisol levels. Median plasma ACTH increased significantly with advancing postnatal age from 1 week to 8 weeks (21.0 vs. 40.0 ng/l; P = 0.01) but did not correlate with postconceptional age. Median plasma cortisol decreased significantly with advancing postnatal age from 1 week to 8 weeks (216 vs. 50 nmol/l; P = 0.001) and correlated inversely with postconceptional age (P = 0.004). At 8 weeks infants who were clinically well (n = 6) had lower plasma ACTH values compared with sick (n = 6) infants (median: 37.0 vs. 63.5 ng/l; P = 0.033). Plasma ACTH did not correlate with clinical state at 1, 2 and 4 weeks. At none of the postnatal ages studied was plasma cortisol influenced by the degree of sickness. Five infants received dexamethasone to assist weaning from mechanical ventilation. Their median plasma ACTH level, at 8 weeks, was significantly lower than that of the 12 infants who did not receive dexamethasone (11.0 vs. 40.0 ng/l; P = 0.0006). Plasma cortisol was not significantly influenced by dexamethasone treatment (P = 0.27). These data provide further information on the evolution of adrenocortical function in VLBW infants in the first months of life.

In-vitro fertilisation and neonatal ventilator use in a tertiary perinatal centre.

OBJECTIVE: To determine the contribution of livebirths resulting from in-vitro fertilisation and related technologies (IVF) to the use of neonatal ventilator beds. DESIGN: A retrospective review of records of all livebirths from our hospital's IVF program and all IVF infants receiving mechanical ventilation in our neonatal intensive care unit for the period 1985-1989. We also reviewed records of labour ward deliveries, neonatal intensive care unit admissions and transfer requests in order to obtain comparative data for livebirths of non-IVF infants whose mothers had been booked to deliver in our hospital. SETTING: A tertiary perinatal centre with a large IVF program and a Level 3 neonatal intensive care unit. RESULTS: IVF livebirths accounted for 5.1% of total ventilator bed days. Compared with non-IVF booked livebirths, IVF babies were more likely to require ventilation (odds ratio, 7.41; P less than 0.0001) and used more ventilator bed days per 100 livebirths (rate ratio, 9.63; P less than 0.0001), largely due to preterm delivery of multiple pregnancies; 42.3% of IVF babies who required ventilation were from triplet births and 38.5% from twin births. Nevertheless, even IVF singletons used more ventilator bed days per 100 livebirths than non-IVF booked livebirths (rate ratio, 2.78; P less than 0.0001). IVF livebirths accounted for 9.9% of the 78% increase in ventilator bed days used in 1989 compared with 1985. CONCLUSIONS: IVF livebirths accounted for only a small percentage of the overall use of neonatal ventilator beds, but consumed relatively more of such resources per livebirth than did non-IVF livebirths. The degree of risk of requiring ventilation is directly related to the number of infants in a multiple pregnancy, but even IVF singletons are at a relatively high risk of requiring ventilation.

Hyaline membrane disease and early neonatal aldosterone metabolism in infants of less than 33 weeks gestation.

We studied urine excretion of free and conjugated aldosterone by 12 control infants and 14 infants with hyaline membrane disease (HMD) on the first and seventh days after birth. Both groups had a mean gestational age of 29 weeks. Total urine aldosterone excretion (UAE) and percent excreted as conjugate were similar for both groups on both study days, and did not relate to the severity of respiratory failure in infants with HMD. Sodium intake was higher for infants with HMD on both study days (p less than 0.02), but their urine sodium excretion was only significantly (p less than 0.01) higher on day 7. For total UAE values greater than 3 nmol/kg/d, there was no significant difference between estimated sodium-potassium exchange by control (22 +/- 5%, n = 8) and HMD (31 +/- 5%, n = 10) groups. These data suggest that neither the magnitude of excretion of aldosterone in the urine, the ability to conjugate aldosterone nor the degree of relative distal tubular unresponsiveness to aldosterone are related to the severity of pulmonary immaturity in preterm infants.