Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review.

PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.

IVF procedures are not, but subfertility is associated with neurological condition of 9-year-old offspring.

In vitro fertilization (IVF) is not associated with neurological abnormalities in offspring's early childhood. Yet, it is unclear whether this is also true for school age. Neither do we know the role of parental subfertility in offspring's neurological development. The present study examined neurological condition at 9 years of 57 singletons born after controlled ovarian hyperstimulation IVF (COH-IVF), 46 singletons born after modified natural cycle IVF (MNC-IVF) and 66 singletons born to subfertile parents after natural conception (Sub-NC). To assess the effect of subfertility, the groups were pooled to form a subfertile group, and compared with a prospectively followed fertile reference group (n = 282). The sensitive Minor Neurological Dysfunction (MND) examination was used, resulting in the detailed Neurological Optimality Score (NOS) and the prevalence of the clinically relevant complex MND. Neurological condition of the three subfertile groups did not differ significantly: median NOS was 53 in each subfertile group and the prevalence of complex MND in the three subfertile groups was 30%, 37% and 36%, respectively. However, the NOS was lower and the prevalence of complex MND higher in children born to subfertile couples than in children of fertile couples (adjusted mean difference [95% CI]: -4.48 [-5.53 to -3.42]) and adjusted OR [95% CI]: 5.13 [2.60-10.16], respectively). We conclude that ovarian hyperstimulation, in vitro procedures, and the combination of both were not associated with a less favourable neurological outcome of 9-year-old singletons. However, the presence of parental subfertility was associated with less favourable neurological outcome of offspring at 9 years follow up.

In-utero cigarette smoke exposure and the risk of earlier menopause.

OBJECTIVE: Cigarette smoking is a risk factor for earlier menopause. Animal studies show that in-utero smoke exposure is toxic to developing ovaries. Our aim was to evaluate whether in-utero smoke exposed women reach menopause earlier compared with nonexposed women. METHODS: This is a cohort study within the Avon Longitudinal Study of Parents and Children. Participants included in this study were followed from 1991/1992 until 2010. Participant characteristics for the current analysis were obtained from obstetric records and from annual follow-up questionnaires. When not available, age at natural menopause was estimated by age at filling in the questionnaire minus 1 year. Cox proportional hazards modeling was used to estimate hazard ratios of menopause for in-utero exposed and nonexposed women. RESULTS: There were 695/2,852 postmenopausal women, of whom 466 had natural menopause, 117 had hormonal therapy, and 112 had surgical menopause. Age at natural menopause was 50.6 ±â€Š3.7 years. Of all participants, 20.2% (577/2,852) were exposed to smoke in-utero. Participants who were in-utero exposed but were not smokers did not have higher hazards of menopause (adjusted hazard ratio [HR] 0.92, 95% CI 0.72-1.18), whereas participants who were ever smokers (current or previous) and were in-utero exposed (adjusted HR 1.41, 95% CI 1.01-1.95) or were ever smokers but not exposed (adjusted HR 1.24, 95% CI 1.00-1.53) did have higher hazards of earlier menopause. CONCLUSIONS: In-utero smoke exposure was not associated with earlier menopause, but the effect of in-utero smoke exposure was modified by the smoking habits of the participants themselves increasing the risk for smokers who were in-utero exposed.

Predictive value of general movements' quality in low-risk infants for minor neurological dysfunction and behavioural problems at preschool age.

BACKGROUND: General movement (GM) assessment is a well-established tool to predict cerebral palsy in high-risk infants. Little is known on the predictive value of GM assessment in low-risk populations. AIMS: To assess the predictive value of GM quality in early infancy for the development of the clinically relevant form of minor neurological dysfunction (complex MND) and behavioral problems at preschool age. STUDY DESIGN: Prospective cohort study. SUBJECTS: A total of 216 members of the prospective Groningen Assisted Reproductive Techniques (ART) cohort study were included in this study. ART did not affect neurodevelopmental outcome of these relatively low-risk infants born to subfertile parents. OUTCOME MEASURES: GM quality was determined at 2 weeks and 3 months. At 18 months and 4 years, the Hempel neurological examination was used to assess MND. At 4 years, parents completed the Child Behavior Checklist; this resulted in the total problem score (TPS), internalizing problem score (IPS), and externalizing problem score (EPS). Predictive values of definitely (DA) and mildly (MA) abnormal GMs were calculated. RESULTS: DA GMs at 2 weeks were associated with complex MND at 18 months and atypical TPS and IPS at 4 years (all p<0.05). Sensitivity and positive predictive value of DA GMs at 2 weeks were rather low (13%-60%); specificity and negative predictive value were excellent (92%-99%). DA GMs at 3 months occurred too infrequently to calculate prediction. MA GMs were not associated with outcome. CONCLUSIONS: GM quality as a single predictor for complex MND and behavioral problems at preschool age has limited clinical value in children at low risk for developmental disorders.

Asthma and asthma medication use among 4-year-old offspring of subfertile couples--association with IVF?

This study evaluated the prevalence of asthma and asthma medication use in 213 4-year-old singletons followed from birth onwards, including three groups of children born following: (i) controlled ovarian hyperstimulation IVF/intracytoplasmic sperm injection (ICSI); (ii) modified natural cycle IVF/ICSI; and (iii) natural conception in subfertile couples. The rate of asthma medication was higher in the ovarian hyperstimulation-IVF/ICSI than in the subfertile group (adjusted odds ratios [aOR]: 1.96 [1.00-3.84]). Time to pregnancy, a proxy for the severity of subfertility, was not associated with asthma and asthma medication. In conclusion, controlled ovarian hyperstimulation-IVF/ICSI is associated with the use of asthma medication in 4-year-old offspring of subfertile couples.

Congenital anomalies in offspring of subfertile couples: a registry-based study in the northern Netherlands.

OBJECTIVE: To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Case-only analyses. SETTING: Not applicable. PATIENT(S): We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n = 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder. RESULT(S): We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05-5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58-27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06-2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93-62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39-16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43-17.65). CONCLUSION(S): In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands.

Dysmorphic features and developmental outcome of 2-year-old children.

AIM: The aim of this study was to assess the associations between dysmorphic features and neurological, mental, psychomotor, and behavioural development in order to improve our understanding of aetiological pathways leading to minor developmental problems. METHOD: In our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39 weeks, [range 30-43wks]), born after a parental history of subfertility either with or without fertility treatment, were examined. Dysmorphic features were classified as abnormalities (clinically relevant or not), minor anomalies, or common variants according to Merks' classification system. Hempel's neurological assessment resulted in a neurological optimality score (NOS) and fluency score. Mental and psychomotor development were assessed with the Dutch version of the Bayley Scales of Infant Development and behavioural development with the Achenbach Child Behaviour Checklist. RESULTS: Of the different types of dysmorphic feature, clinically relevant abnormalities were most strongly associated with a lower NOS (difference -2.53, 95% confidence interval [CI] -4.23 to -0.83) and fluency score (difference -0.62, 95% CI -1.1 to -0.15). The presence of one or more abnormalities (clinically relevant or not) or one or more common variants was significantly associated with a lower NOS, and the presence of three or more minor anomalies was associated with lower fluency scores. Dysmorphic features were not associated with mental, psychomotor, or behavioural development. INTERPRETATION: As dysmorphic features originate during the first trimester of pregnancy, the association between dysmorphic features and minor alterations in neurodevelopment may suggest an early ontogenetic origin of subtle neurological deviations.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part I: multivariable regression analysis.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? SUMMARY ANSWER: Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient. MAIN RESULTS AND THE ROLE OF CHANCE: SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53). LIMITATIONS, REASONS FOR CAUTION: Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach.

STUDY QUESTION: What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children? SUMMARY ANSWER: Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown. STUDY DESIGN, SIZE, DURATION: In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. MAIN RESULTS AND THE ROLE OF CHANCE: Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. LIMITATIONS, REASONS FOR CAUTION: Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Blood pressure and anthropometrics of 4-y-old children born after preimplantation genetic screening: follow-up of a unique, moderately sized, randomized controlled trial.

BACKGROUND: Recent studies suggest that in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are associated with suboptimal cardiometabolic outcome in offspring. It is unknown whether preimplantation genetic screening (PGS), which involves embryo biopsy, affects blood pressure (BP), anthropometrics, and the frequency of received medical care. METHODS: In this prospective multicenter follow-up study, we assessed BP, anthropometrics, and received medical care of 4-y-old children born to women who were randomly assigned to IVF/ICSI with PGS (n = 49) or without PGS (controls; n = 64). We applied linear and generalized linear mixed-effects models to investigate possible effects of PGS. RESULTS: BP in the PGS and control groups was similar: 102/64 and 100/64 mm Hg, respectively. Main anthropometric outcomes in the PGS vs. control group were: BMI: 16.1 vs. 15.8; triceps skinfold: 108 vs. 98 mm; and subscapular skinfold: 54 vs. 53 mm (all P values > 0.05). More PGS children than controls had received paramedical care (speech, physical, or occupational therapy: 14 (29%) vs. 9 (14%); P = 0.03 in multivariable analysis). The frequency of medicial treatment was comparable. CONCLUSION: PGS does not seem to affect BP or anthropometrics in 4-y-old children. The higher frequency of received paramedical care after PGS may suggest an effect of PGS on subtle developmental parameters.

Increased time to pregnancy is associated with suboptimal neurological condition of 2-year-olds.

OBJECTIVE: To evaluate whether time to pregnancy (TTP) is associated with neurological condition of 2-year-old children born to subfertile parents. DESIGN: Data collected in a prospective, assessor-blinded follow-up study were used for cross-sectional analyses. PATIENTS: Participants were the singletons of the Groningen assisted reproductive technique cohort study: all children were born to subfertile couples (n=209). The active waiting TTP of the couples obtained from fertility charts was recorded in years and months, and was converted to decimal years. MAIN OUTCOME MEASURE: The presence of minor neurological dysfunction (MND), assessed with the Hempel examination. RESULTS: MND was present in 16 (7.7%) children. TTP of children with MND (median 4.1, range 1.6-13.2) was significantly longer than that of children without MND (median 2.8, range 0.1-13.3; Mann-Whitney U test p=0.014). Logistic regression analysis on the contribution of TTP to MND resulted in a crude OR of 1.27 (95% CI 1.06 to 1.54). After correction for gestational age, parental age and parental level of education, the association remained statistically significant: OR=1.30 (95% CI 1.05 to 1.61). CONCLUSIONS: Increased TTP was associated with suboptimal neurological development in 2-year-old children. This suggests that subfertility and its determinants are involved in the genesis of neurodevelopmental problems.

Dysmorphic features in 2-year-old IVF/ICSI offspring.

BACKGROUND: An increased risk of major congenital abnormalities after IVF and ICSI has been described, but underlying mechanisms are unclear. This study evaluates the effects of ovarian hyperstimulation, the in vitro procedure and time to pregnancy (TTP) - as proxy for the severity of subfertility - on the prevalence of dysmorphic features. DESIGN/METHODS: Participants were singletons born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI; n=66), or modified natural cycle-IVF/ICSI (MNC-IVF/ICSI; n=56), or to subfertile couples who conceived naturally (Sub-NC; n=86). Dysmorphic features were assessed according to the method of Merks et al., and are classified into 'minor variants' (minor anomalies or common variants) and 'abnormalities' (clinically relevant or irrelevant abnormalities). We focussed on minor anomalies as they indicate altered embryonic development and because they have the advantage of a higher prevalence. RESULTS: The prevalences of any of the outcome measures were similar in the three groups. One or more minor anomalies, our primary outcome measure, occurred in 50% of COH-IVF/ICSI, 54% of MNC-IVF/ICSI and 53% of Sub-NC children. TTP in years was significantly associated with abnormalities (adjustedOR=1.20; 95%CI=1.02-1.40), especially with clinically relevant abnormalities (adjustedOR=1.22; 95%CI=1.01-1.48). CONCLUSIONS: The study indicates that ovarian hyperstimulation and the in vitro procedure are not associated with an increase in dysmorphic features. The positive association between TTP and clinically relevant abnormalities suggests a role of the underlying subfertility and its determinants in the genesis of dysmorphic features.

Early menopause in mothers of children with Down syndrome?

OBJECTIVE: To investigate whether having a Down syndrome pregnancy at a relatively young age is associated with lower ovarian reserve as reflected by lower antimüllerian hormone (AMH) levels and the occurrence of earlier menopause. DESIGN: Retrospective, case control study. SETTING: Not applicable. PATIENT(S): Two hundred twenty mothers (118 trisomy cases, 102 controls). INTERVENTION(S): Questionnaire and serum AMH measurement. MAIN OUTCOME MEASURE(S): Serum AMH levels and menopause, defined as not having a menstrual cycle for at least 1 year. RESULT(S): The participant response rate was 93%. After applying the exclusion criteria, 144 women were evaluable (73 trisomy cases, and 71 controls). The baseline characteristics of the women were not statistically significantly different. More women with a Down syndrome pregnancy had an AMH level below 0.5 µg/L, a difference that was statistically significant. Eleven women (15.1%) in the Down syndrome group had reached menopause compared with 9 (12.7%) of the controls. CONCLUSION(S): Women who have had a Down syndrome pregnancy at a younger age show signs of limited ovarian reserve, as evidenced by their frequently having lower AMH levels. The study has found no obvious signs of early menopause thus far. Whether their age at menopause is within the normal range remains to be determined.

Miscarriage risk for IVF pregnancies in poor responders to ovarian hyperstimulation.

The increasing miscarriage rate with advancing female age is attributed to a decline in oocyte quality. A poor response to ovarian hyperstimulation is often an expression of a decrease in oocyte quantity. Although oocyte quality and quantity both decrease as a result of ovarian ageing, it is unclear whether these two processes are related to each other. To investigate the relationship between oocyte quantity and quality, we compared miscarriage rates between IVF treated women with a poor and normal response, respectively. Data were studied from a retrospective nationwide cohort of Dutch women undergoing IVF treatment from 1983 to 1995. Women achieving an ongoing pregnancy after their first complete IVF cycle (n=1468) were compared with those experiencing miscarriage (n=357) with respect to their ovarian response. Logistic regression analysis showed a statistically significant association between poor response (fewer than four retrieved oocytes) and miscarriage (P=0.001). Due to interaction, this association became stronger with increasing female age. Among women < 36 years, miscarriage rates between poor and normal responders did not differ, whereas among women 36 years poor responders had a statistically significant increased miscarriage rate compared with normal responders (P=0.001). These results support the hypothesis of a relationship between quantitative ovarian reserve and oocyte quality.

Neurological condition of infants born after in vitro fertilization with preimplantation genetic screening.

UNLABELLED: Aim of this study was to evaluate the effect of preimplantation genetic screening (PGS) on neurodevelopmental outcome in children. We conducted a prospective follow-up study of children born to women randomly assigned to in vitro fertilization with or without PGS. Primary outcome was adverse neurologic outcome at 18 mo; secondary outcomes were types of minor neurologic dysfunction (MND), neurologic outcome before 18 mo, neonatal intensive care admission, and congenital malformations. Twenty women in the PGS group participated with 25 children and 26 women in the control group participated with 31 children. Five PGS pregnancies (25%) and four control pregnancies (15%) resulted in birth of at least one child with an adverse neurologic outcome (adjusted odds ratio: 2.3 [0.4-12.0]). Dysfunction in fine motor abilities and posture and muscle tone dysregulation tended to be present more frequently after PGS. Neurologic outcome before 18 mo, neonatal intensive care admission, and prevalence of congenital malformations were similar in study and control pregnancies. Nevertheless, at child level, rates of adverse outcome were higher after PGS. In conclusion, outcome in pregnancies after in vitro fertilization (IVF) with and without PGS was similar. The small sample size precludes the conclusion that PGS is not associated with less favorable neurologic outcome. Safety of new assisted reproductive techniques should be evaluated before large-scale implementation. ABBREVIATIONS: :

Ovarian hyperstimulation and the in vitro fertilization procedure do not influence early neuromotor development; a history of subfertility does.

OBJECTIVE: To evaluate specific effects of ovarian hyperstimulation, the in vitro procedure, and a history of subfertility on neuromotor development at 3 months of age. DESIGN: Prospective, cohort study. SETTING: University Medical Center Groningen, The Netherlands. PATIENT(S): Singletons conceived after controlled ovarian hyperstimulation-IVF/intracytoplasmic sperm injection (COH-IVF; n = 68) or modified natural cycle-IVF/intracytoplasmic sperm injection (MNC-IVF; n = 57), and naturally conceived singletons of subfertile couples (NC; n = 90). Data from a reference population were available (n = 450). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Quality of general movements (GMs), classified as normal-optimal, normal-suboptimal, mildly abnormal, or definitely abnormal. Definitely abnormal GMs indicate brain dysfunction, mildly abnormal GMs normal but non-optimal brain function. RESULT(S): Mildly abnormal and definitely abnormal GMs were observed equally frequently in COH-IVF, MNC-IVF, and NC singletons. The three subfertile groups showed a reduction in GM quality, in particular more mildly abnormal GMs, in comparison with the reference population. CONCLUSION(S): Singletons born after IVF (with or without ovarian hyperstimulation) are not at increased risk for abnormal GMs compared with naturally conceived peers of subfertile parents. Mildly abnormal GMs occur more often in infants of subfertile parents than in the general population, suggesting that factors associated with subfertility rather than those related to IVF procedures may be associated with less-optimal early neurodevelopmental outcome. These results need confirmation through replication and follow-up at older ages.

Preimplantation genetic screening as an alternative to prenatal testing for Down syndrome: preferences of women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment.

OBJECTIVE: Although the primary goal of preimplantation genetic screening (PGS) is to increase pregnancy rates in women undergoing IVF/intracytoplasmic sperm injection treatment, it has been suggested that it may also be used as an alternative to prenatal testing for Down syndrome. DESIGN: Trade-off questionnaires. SETTING: Two university centers for reproductive medicine. PATIENT(S): Two hundred forty-four subfertile women. INTERVENTION(S): Scenarios with different pregnancy chances after PGS and with different risk reductions of a Down syndrome pregnancy were presented. MAIN OUTCOME MEASURE(S): Willingness to have PGS performed in the various scenarios. RESULT(S): In case PGS would discover all Down syndrome embryos without affecting pregnancy chances, 83% of the women would have PGS performed. If PGS lowered pregnancy chances from one in five to one in seven, 36% of the women preferred to have PGS performed. If PGS reduced the chance of a Down syndrome pregnancy with 80% without affecting pregnancy chances, 75% of the women would have PGS performed, and 31% of them would refrain from prenatal testing afterward. CONCLUSION(S): Most women favor PGS for Down syndrome screening, even if it is not 100% sensitive. The acceptability depends on the effect PGS has on pregnancy chances, and, to a lower extent on its sensitivity to detect Down syndrome embryos.

Evaluation of the WHO clinical case definition for pediatric HIV infection in Bloemfontein, South Africa.

The WHO clinical case definition for pediatric HIV infection has been designed to be used in countries where diagnostic laboratory resources are limited. We evaluated the WHO case definition to determine whether it is a useful instrument to discriminate between HIV-positive and HIV-negative children. In addition, clinical features not included in this case definition were recorded. We recorded clinical data from 300 consecutively admitted children in a state hospital in Bloemfontein, South Africa, and tested these children for HIV infection. A total of 222 children were included in the study; 69 children (31.1 per cent) were HIV positive. The sensitivity of the WHO case definition in this study was 14.5 per cent, the specificity was 98.6 per cent. Apart from weight loss and generalized dermatitis, the signs of the WHO case definition were significantly more often seen in HIV-positive than in HIV-negative children. Of the clinical signs not included in the WHO case definition, marasmus and hepatosplenomegaly especially occurred more frequently in HIV-positive children. Based on these findings we composed a new case definition consisting of four signs: marasmus, hepatosplenomegaly, oropharyngeal candidiasis, and generalized lymphadenopathy. HIV infection is suspected in a child presenting with at least two of these four signs. The sensitivity of this case definition was 63.2 per cent, the specificity was 96.0 per cent. We conclude that in this study the WHO case definition was not a useful instrument to discriminate between HIV-positive and HIV-negative children, mainly because its sensitivity was strikingly low. The simplified case definition we propose, proved to be more sensitive than the WHO case definition (63.2 vs. 14.5 per cent), whilst its specificity remained high.