Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8-18 years of IVF children and spontaneously conceived controls born to subfertile parents.

BACKGROUND: Little is known about post-natal growth in IVF offspring and the effects of rates of early post-natal growth on blood pressure and body fat composition during childhood and adolescence. METHODS: The follow-up study comprised 233 IVF children aged 8-18 years and 233 spontaneously conceived controls born to subfertile parents. Growth data from birth to 4 years of age, available for 392 children (n = 193 IVF, n = 199 control), were used to study early post-natal growth. Furthermore, early post-natal growth velocity (weight gain) was related to blood pressure and skinfold measurements at follow-up. RESULTS: We found significantly lower weight, height and BMI standard deviation scores (SDSs) at 3 months, and weight SDS at 6 months of age in IVF children compared with controls. Likewise, IVF children demonstrated a greater gain in weight SDS (P < 0.001), height SDS (P = 0.013) and BMI SDS (P = 0.029) during late infancy (3 months to 1 year) versus controls. Weight gain during early childhood (1-3 years) was related to blood pressure in IVF children (P = 0.014 systolic, 0.04 diastolic) but not in controls. Growth during late infancy was not related to skinfold thickness in IVF children, unlike controls (P = 0.002 peripheral sum, 0.003 total sum). Growth during early childhood was related to skinfold thickness in both IVF and controls (P = 0.005 and 0.01 peripheral sum and P = 0.003 and 0.005 total sum, respectively). CONCLUSIONS: Late infancy growth velocity of IVF children was significantly higher compared with controls. Nevertheless, early childhood growth instead of infancy growth seemed to predict cardiovascular risk factors in IVF children. Further research is needed to confirm these findings and to follow-up growth and development of IVF children into adulthood.

Cardiometabolic differences in children born after in vitro fertilization: follow-up study.

CONTEXT: Increasing evidence suggests that adverse conditions during early prenatal life are associated with cardiometabolic dysfunction in postnatal life. In vitro fertilization (IVF) conception may be an early prenatal life event with long-term health consequences. OBJECTIVE: Our objective was to investigate several cardiometabolic measures in 8- to 18-yr-old IVF singletons and spontaneously conceived controls born from subfertile parents. DESIGN AND SETTING: This follow-up study was conducted at the VU University Medical Center, Amsterdam, The Netherlands. PARTICIPANTS: Blood pressure was examined in 225 IVF-conceived children and 225 age- and gender-matched spontaneously conceived control children. Several indicators of insulin resistance were studied in a pubertal subpopulation (131 IVF children and 131 controls). MAIN OUTCOME MEASURES: Blood pressure, fasting glucose, and fasting insulin were determined. RESULTS: Systolic and diastolic blood pressure levels were higher in IVF children than controls (109 +/- 11 vs. 105 +/- 10 mm Hg, P < 0.001; and 61 +/- 7 vs. 59 +/- 7 mm Hg, P < 0.001, respectively). Children born after IVF were also more likely to be in the highest systolic and diastolic blood pressure quartiles (odds ratio = 2.1, 95% confidence interval 1.4, 3.3; odds ratio = 1.9, 95% confidence interval 1.2, 3.0, respectively). Furthermore, higher fasting glucose levels were observed in pubertal IVF children (5.0 +/- 0.4 vs. 4.8 +/- 0.4 mmol/liter in controls; P = 0.005). Blood pressure and fasting glucose differences could not be explained by current body size, birth weight, and other early life factors or by parental characteristics, including subfertility cause. CONCLUSIONS: These findings highlight the importance of continued cardiometabolic monitoring of IVF-conceived children and might contribute to current knowledge about periconceptional influences and their consequences in later life.

Pubertal development in children and adolescents born after IVF and spontaneous conception.

BACKGROUND: Previous studies demonstrated a link between adverse conditions during prenatal life and the development of diseases in adult life. It is still unclear whether IVF conception could permanently affect early prenatal development in humans, with post-natal health consequences. The objective of the present study is to examine pubertal development in 8-18-year-old IVF singletons and controls born from subfertile parents who attended one Dutch fertility clinic were included. METHODS: IVF singletons and controls born from subfertile parents who attended one clinic in the Dutch OMEGA study were included. Pubertal stage by Tanner's classification, age at menarche and menstrual cycle characteristics were studied in the total population (n = 233: 115 IVF-conceived boys and 118 IVF-conceived girls, each with age-matched comparison groups). Bone age and sex hormone levels were examined in two distinct pubertal subpopulations. RESULTS: Pubertal stage and age at menarche were not significantly different between IVF and control children. In the pubertal subpopulation, a higher bone age-chronological age (BA-CA) ratio and a larger BA-CA difference were observed in IVF-conceived girls compared with controls (1.04 +/- 0.07 versus 1.02 +/- 0.08, P = 0.022; 0.54 +/- 0.82 versus 0.18 +/- 1.00 year, P = 0.021, respectively). Furthermore, dehydroepiandrosterone sulphate (DHEAS) and LH levels were significantly higher in IVF-conceived girls than in control subjects (2.5 versus 1.9 micromol/l, P = 0.017, and 1.5 versus 0.6 U/l, P = 0.031, respectively). CONCLUSIONS: Bone age appeared to be advanced in pubertal IVF-conceived girls, but not in boys, compared with controls. Increased DHEAS and LH concentrations were found among IVF girls.

Body composition in children and adolescents born after in vitro fertilization or spontaneous conception.

CONTEXT: Increasing evidence suggests that adverse conditions during prenatal life are associated with the development of chronic diseases in adult life. It is still unclear whether in vitro fertilization (IVF) conception could affect the vulnerable developmental processes in humans occurring during early prenatal development with long-term perturbations of developmental pathways. OBJECTIVE: Our objective was to examine body composition in 8- to 18-yr-old IVF singletons and spontaneously conceived controls born from subfertile parents. DESIGN AND SETTING: This follow-up study was conducted at the VU University Medical Center in Amsterdam, The Netherlands. PARTICIPANTS: Participants included 233 IVF children (139 pubertal children) and 233 age- and gender-matched control children (143 pubertal children). MAIN OUTCOME MEASURES: Body composition measures were assessed by anthropometry and dual-energy x-ray absorptiometry in the pubertal subpopulation. RESULTS: IVF children had a significantly lower subscapular-triceps skinfold ratio and a significantly higher sum of peripheral skinfolds, peripheral body mass, and percentage of peripheral body fat as compared with controls. Although not reaching statistical significance, both dual-energy x-ray absorptiometry and skinfold measurements suggested that total body fat in IVF children is increased. Neither current and early risk factors nor parental factors, such as subfertility cause, could explain the differences in peripheral fat assessed by anthropometry between IVF children and controls. No differences in bone mineral composition between IVF children and controls were found. CONCLUSIONS: Our observations indicate that body fat composition in IVF children is disturbed. Follow-up of IVF children to monitor body fat pattern and potentially related health problems from adolescence into adulthood is of great importance.

Particle distribution in low-volume capillary-loaded chambers.

Accurate determination of sperm concentration in fluid suspension is a critical component in a semen analysis. Inaccurate estimations can lead to misinterpretation of the spermiogram and, in the case of livestock production, can lead to faulty insemination doses, which can adversely affect stud power, fertility, fecundity, and cost effectiveness of breeding programs. Capillary-loaded slides, like the hemacytometer, have been the standard for calibration of other concentration estimation modalities such as photometry, Coulter counter, flow cytometry, and computer-automated semen analysis (CASA). Single-use capillary-loaded slides, much smaller than the hemacytometer, are frequently used by many of the current CASA systems. As the use of CASA increases, more field reports are suggesting differences between CASA results and hemacytometry. In this article, we establish that these differences are, in large part, due to the Segre-Silberberg effect, which occurs during Poiseuille flow in high-gradient fluid flow in thin capillary-loaded slides. We develop the theory of this phenomenon and derive the scaling and significance of the effect. Finally, we graphically provide a means for predicting the necessary compensation factor when using capillary-loaded slides to determine sperm concentration.

Capillary-loaded particle fluid dynamics: effect on estimation of sperm concentration.

Capillary loaded chambers are frequently used for semen analysis. Poiseuille flow of specimen into these chambers causes migration of suspended particles or cells in a direction transverse to the flow, which results in their preferential accumulation in the Segre-Silberberg (SS) planes. This SS effect depends on the transverse velocity gradient in the laminar flow. For semen analysis in thin capillary-loaded slides, the SS effect can lead to erroneous estimation of sample sperm-cell concentration. To better understand chamber flow dynamics and SS effect significance, we assessed flow uniformity, inflow cell velocity, and results of concentration measurements under different flow conditions for latex bead and porcine and human sperm suspensions. Overall, a concentration peak was present at the meniscus, which continued through chamber loading. High-velocity SS preferred planes, which channeled particles toward the meniscus, were located at the fractional positions of beta = .27 and beta = .73, where beta is the distance from wall to plane normalized to the chamber depth. In computer-automated semen analysis, a standard 20-microm x 18-mm x 6-mm chamber is commonly used, and these studies supported our previously published fluid-flow theory for this type of chamber. Conversely, the SS effect does not appear to have time to develop in the 100-microm-depth hemacytometer, which is deeper than the standard slide, has lower transverse velocity gradient, and consequently does not exhibit concentration variation due to the SS effect. These findings provide further support that hemacytometry, when performed properly, remains the gold standard. Applicability of our findings to routine semen analyses was then tested in 2 studies performed with independent boar studs. These studies compared diluted boar semen concentrations estimated by standard hemacytometry and in capillary-loaded 20-microm slides, using a computer-automated semen-analysis system designed to compensate for the SS effect. Good numerical agreement for sperm concentration with a high degree of correlation (r(2) = .936) was found between the 2 techniques. These findings reaffirm the need to critically assess new technologies for accuracy, repeatability, and precision.

Migraine associated with gastrointestinal disorders: review of the literature and clinical implications.

Recent studies suggest that migraine may be associated with gastrointestinal (GI) disorders, including irritable bowel syndrome (IBS), inflammatory bowel syndrome, and celiac disease. Here, an overview of the associations between migraine and GI disorders is presented, as well as possible mechanistic links and clinical implications. People who regularly experience GI symptoms have a higher prevalence of headaches, with a stronger association with increasing headache frequency. Children with a mother with a history of migraine are more likely to have infantile colic. Children with migraine are more likely to have experienced infantile colic compared to controls. Several studies demonstrated significant associations between migraine and celiac disease, inflammatory bowel disease, and IBS. Possible underlying mechanisms of migraine and GI diseases could be increased gut permeability and inflammation. Therefore, it would be worthwhile to investigate these mechanisms further in migraine patients. These mechanisms also give a rationale to investigate the effects of the use of pre- and probiotics in migraine patients.

Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection?

OBJECTIVE: To review the literature and present original data to answer the question of whether in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is associated with an increase in imprinted diseases in offspring. If the answer is positive, to investigate whether there is a causal relationship between IVF or ICSI and the imprinted diseases. DESIGN: Review study. RESULT(S): Eight epidemiologic studies were suitable to calculate the weighted relative risk for the birth of a child with Beckwith-Wiedemann syndrome following IVF or ICSI compared with the risk in the normal population. This relative risk was 5.2 (95% CI 1.6-7.4). In one study the relative risk was corrected for parents' fertility problems and no significant association was found. Data on the Silver-Russell syndrome are too sparse to draw conclusions, but a positive association with IVF or ICSI treatment is probable. No significant associations were found between the incidences of the Angelman and Prader-Willi syndromes and IVF or ICSI treatments. Children with Prader-Willi syndrome or Angelman syndrome are more likely to be born to parents with fertility problems. All retinoblastomas in children born after IVF or ICSI could be explained by de novo mutations in the RB1 gene and were not associated with imprinted genes. Imprinted diseases result from methylation errors already present in sperms or oocytes. There is no proof of a causal relationship between imprinted diseases and IVF or ICSI treatments. CONCLUSION(S): Imprinting disorders are more prevalent after human IVF or ICSI. Future studies should correct for fertility problems in the affected and comparison groups. It is highly improbable that assisted reproduction technologies cause imprinted diseases in humans.

Growth and development of children born after in vitro fertilization.

OBJECTIVE: To evaluate growth and development of children born after IVF treatment. DESIGN: Literature review. CONCLUSION(S): At present there is substantial evidence that children born after IVF are at increased risk for adverse perinatal outcome, congenital malformations, and rare epigenetic defects. It is still unclear whether observed health problems originate from the IVF procedure itself or the underlying subfertility problems of the parents. Current follow-up studies regarding postnatal growth and morbidity rates are scarce with conflicting results and other areas of long-term research in children born after IVF are still in its infancy. The importance of the worldwide continuing monitoring of children born after IVF to investigate potential long-term consequences including the development of cardiovascular diseases is therefore highlighted.

Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study.

BACKGROUND: Evaluation of relationships between assisted reproduction technologies (ART), fertility problems and disorders caused by disturbed genetic imprinting such as Angelman syndrome (AS) and Beckwith-Wiedemann syndrome (BWS). METHODS: A nation-wide questionnaire survey was performed regarding ART in families with a child with AS, BWS or Prader-Willi syndrome (PWS) including questions on fertility. Molecular data on the genetic disorder in affected children were gathered. RESULTS: Of the 220 affected children in this study, 14 (6.4%) were born following any form of ART compared with 83 818 (2.1%) in the Dutch population. Of AS, PWS or BWS children 15 (6.8%) were born after a fertility problem (Time To Pregnancy > 12 months, no forms of ART) compared to 141,340 (3.5%) in the Dutch population. Maternal age in the individual syndromes was higher than in the Dutch population. Families with affected children were three times more likely to experience fertility problems than the general population. All three syndromes were also individually associated with increased fertility problems in the families. CONCLUSIONS: After correction for the increased fertility problems of the parents, there is no increased incidence of ART related birth of AS, PWS or BWS children. ART does not seem to have a direct effect on the increase of imprinted diseases.

The place of the crossover design in infertility trials: a maximum likelihood approach.

BACKGROUND: For some years, there has been a debate as to the place of the crossover trial in assisted reproduction technology (ART). We aimed to investigate whether crossover and parallel designs result in different estimates of treatment effects. METHODS: We carried out computer simulation of cohorts of patients undergoing either intra-uterine insemination (IUI) or IVF under both parallel and crossover designs, under scenarios involving censoring and carryover effects. Results of the simulation were analysed using a maximum likelihood approach. RESULTS: No relevant difference was found between the designs. The crossover design resulted in slightly more pregnancies than the parallel design. Carryover effects may slightly distort the estimates of treatment effects. Crossover and parallel designs will produce essentially the same statistical estimates of treatment effect and percentage of pregnancies. The crossover design is an acceptable design in infertility research provided the data are analysed correctly.

Multivariate Markov chain analysis of the probability of pregnancy in infertile couples undergoing assisted reproduction.

BACKGROUND: Estimating the probability of pregnancy leading to delivery and the influence of clinical factors on that probability is of fundamental importance in the treatment counselling of infertile couples. A variety of statistical techniques have been used to analyse fertility data, many borrowed from survival analysis. METHODS AND RESULTS: We propose an alternative method of analysis which is based on a discrete time Markov chain approach, with states 'pregnancy (leading to a delivery)', 'not pregnant', and 'censored' and in which the transition probabilities are dependent both on the clinical characteristics of the patient and the treatment given. CONCLUSIONS: We believe that the method of analysis presented here may be preferable to standard analyses in that it better reflects the clinical situation, it is a truly discrete time analysis applied to a discrete time situation, it explicitly models the censoring process (a process which in itself provides information of interest to the physician) and can be readily extended to a variety of clinical situations.

High level of alpha1-acid glycoprotein in human seminal plasma is associated with high branching and expression of Lewis(a) groups on its glycans: supporting evidence for a prostatic origin.

BACKGROUND: Changes in concentration of seminal plasma alpha(1)-acid glycoprotein (AGP) have been studied in detail before. However, the source of high levels of AGP as well as the glycosylation of seminal plasma AGP has not been elucidated yet. METHODS: The glycosylation of AGP was studied by crossed affinity immunoelectrophoresis using fucose-specific lectins and immunostaining. Glycan structure and monosaccharide analyses were performed by high pH anion exchange chromatography with pulsed amperometric detection. Fucosyltransferases were analyzed for activity and their substrate specificity was determined. RESULTS: Two types of fucosylation were detected; Lewis(x) and Lewis(a). Lewis(a) groups were only present on AGP of individuals with a high concentration and were completely absent when the AGP concentration in seminal plasma was low. Lewis(a) expression coincides with a higher degree of branching of the glycans and a relative increased alpha4-fucosyltransferase activity. The molecular weight of all seminal plasma AGP was slightly higher than of blood plasma AGP (approx. 47 vs. 41-43 kDa). CONCLUSIONS: The results indicate that AGP in seminal fluid most likely originates from the prostate and that it is either alpha3- or alpha4-fucosylated.

The impact of the embryo transfer catheter on the pregnancy rate in IVF.

BACKGROUND: The aim was to assess whether the type of embryo transfer set used for embryo transfer affects the ongoing pregnancy rate in IVF. METHODS: The TDT set was compared with the K-soft 5000 in a large, prospective, randomized study. Patients were randomized moments before transfer by drawing a consecutively numbered, sealed, opaque envelope indicating the catheter to be used. RESULTS: 2059 embryo transfers in 1296 patients were analysed. The ongoing pregnancy rate was significantly higher in the K-soft group. If the first transfer of a patient (n = 1296) within this study period was analysed, the ongoing pregnancy rates were 27.1 versus 20.5% (P = 0.006). If the analysis is limited to patients that underwent their very first transfer ever (n = 607), the ongoing pregnancy rates were 30.3 versus 20.0% (P = 0.003) in favour of the K-soft. CONCLUSION: We conclude from these data that the type of embryo transfer set used for embryo transfer does affect the ongoing pregnancy rate and that the impact of the variable transfer catheter on the ongoing pregnancy rate increases when the a priori chance of pregnancy increases.