Psychosocial health and quality of life in ICSI and naturally conceived adolescents: a cross-sectional comparison.

PURPOSE: Psychosocial health (PH) and quality of life (QoL) are important health outcomes. We compared PH and QoL of adolescents conceived with intrazytoplasmatic sperm injection (ICSI) and of naturally conceived controls. The impact of disclosure of ICSI-conception on QoL and PH was quantified. METHODS: The cross-sectional sample consisted of 545 ICSI-conceived adolescents and 427 unmatched singleton controls aged 14-18 years. Adolescents reported PH with the 'Strengths and Difficulties Questionnaire' (low values indicating high PH), and QoL with the KINDL questionnaire (high values indicating high QoL). Because of clustering of multiples within families, adjusted linear regressions with generalized estimating equations were used to compare ICSI- and naturally conceived adolescents. Missing values were treated by multiple imputation. Minimal importance was defined as half a standard deviation. RESULTS: Both ICSI and control adolescents had high PH (low mean 'total difficulties' score: 9 of 40) and high QoL (mean 'total KINDL' score: 75 of 100). Differences were generally in favour of the ICSI group. Significant differences occurred for 'impact of behavioural problems' (p = 0.033), the 'total KINDL' score (p = 0.021) and the dimensions 'physical wellbeing' (p = 0.031) and 'school' (p = 0.005), but all differences were far below minimal importance. About 80% of ICSI adolescents were informed about their mode of conception. PH and QoL were slightly higher in informed adolescents; behavioural difficulties ('total behavioural problems' and 'conduct problems') were significantly lower (p = 0.013 and p = 0.003), behavioural strengths ('prosocial behaviour') and 'physical QoL' significantly higher (p = 0.004 and p = 0.018), but differences remained clearly below minimal importance. CONCLUSIONS: Our results are reassuring for parents using ICSI and their children. Speaking openly about an ICSI conception in the family may be beneficial.

Pubertal development and reproductive hormone levels of singleton ICSI offspring in adolescence: results of a prospective controlled study.

STUDY QUESTION: Are there any differences in the pubertal development and reproductive hormone status during adolescence between singletons following ICSI therapy or spontaneous conception (SC)? SUMMARY ANSWER: Pubertal development and reproductive hormone levels are largely similar between ICSI and SC adolescents, except for a tendency towards lower inhibin B levels as well as significantly higher estradiol levels and a lower testosterone-to-estradiol-ratio in male adolescents. WHAT IS KNOWN ALREADY: Previous data are scarce and partly inconclusive regarding pubertal development in female ICSI adolescents as well as demonstrating a tendency towards lower inhibin B serum levels in male ICSI offspring. STUDY DESIGN, SIZE, DURATION: Prospective controlled study including 274 singleton ICSI-conceived adolescents (141 girls, 133 boys) followed up for the third time, and 273 SC controls (142 girls, 131 boys) from seven German registration offices (Aachen, Eichstätt, Erfurt, Lübeck, Hamburg, Heidelberg and Schwerin). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pubertal development assessed by Tanner staging (breast, genital and pubic hair development), age at menarche and reproductive hormone levels were analyzed in ICSI and SC adolescents at the mean age of 16.5 years. Differences were analyzed by multinomial regression (Tanner stages) or t test and linear regression for hormonal assessments. MAIN RESULTS AND THE ROLE OF CHANCE: Both female and male ICSI and SC adolescents showed adequate pubertal maturation according to their age, and the mean age at menarche (at 12.7 versus 12.8 years) was similar. Tanner stages as well did not display any relevant or significant differences between the groups. Reproductive hormone levels in female adolescents not using hormonal contraception were largely similar before and after adjustment for several factors such as preterm birth, Tanner stages, BMI or physical activity. In male ICSI adolescents, a tendency towards lower inhibin B (-14.8 pg/ml, 95% CI: -34.2 to 4.6 pg/ml), significantly higher estradiol (2.6 ng/l, 95% CI: 0.0 to 5.2 ng/l) and a significantly lower testosterone-to estradiol ratio (-0.047, 95% CI: -0.089 to -0.004) was found. LIMITATIONS, REASONS FOR CAUTION: The all-over response rate and the willingness to participate in the blood test and medical examination were very low in the control group. Participating control families may have greater health awareness, and selection bias cannot be ruled out. Hormonal data in the females were measured irrespective of the cycle day and restricted to those not using hormonal contraception. Some parameters from the questionnaire data such as usage of hormonal contraception might suffer from reporting bias. As this is an observational study, we can draw only limited causal conclusions from the findings. WIDER IMPLICATIONS OF THE FINDINGS: Differences in male reproductive hormones may indicate altered testicular function. However, at this time possible consequences for later reproductive success are unknown. STUDY FUNDING/COMPETING INTEREST(S): DFG research grant KA 1643/4-1. The authors declare no conflict of interest.

Oral contraception enhances growth hormone responsiveness to hyper- and hypoglycaemia.

AIMS: Plasma glucose levels influence growth hormone concentrations. Oral contraceptives are known to affect circulating growth hormone levels and glucose metabolism. While growth hormone plays an important role in hypoglycaemia counter-regulation, it has been shown that oral contraceptives increase growth hormone concentrations. In this context, we tested if serum growth hormone concentrations display a differential response on glycaemic variations in healthy women using oral contraceptives and those not using contraceptives. METHODS: Fifteen healthy women with oral contraceptive treatment and 10 without participated in a stepwise hyper- and hypoglycaemic glucose clamp procedure. Serum growth hormone concentrations were measured at euglycaemic baseline and subsequently at plasma glucose plateaus of 8.8, 6.8, 4.8 and 2.8 mmol/l. RESULTS: Growth hormone values were significantly higher in women using oral contraceptives throughout the experiments (P = 0.001). Hyperglycaemia decreased growth hormone concentrations in women using oral contraceptives (P = 0.009), but not in those who were not using oral contraceptives (P = 0.241). Hypoglycaemia significantly elevated growth hormone concentrations in women using oral contraceptives (P = 0.009), but not in those not using oral contraceptives (P = 0.094). Maximum growth hormone values were reached at the end of the hypoglycaemic plateau, with significantly higher concentrations in the group using oral contraceptives than in the group not using oral contraceptives (P = 0.016). CONCLUSION: Healthy women on oral contraceptive treatment display an increased responsiveness of growth hormone to hypoglycaemic, as well as hyperglycaemic conditions and generally higher serum growth hormone concentrations than women without oral contraceptives. Given the known boosting effects of growth hormone on hypoglycaemic hormonal counter-regulation, oral contraceptives may thus be a pharmacological candidate contributing to combat hypoglycaemia unawareness in women with diabetes in the future.

Assessment of vision and hearing in children conceived spontaneously and by ICSI: a prospective controlled, single-blinded follow-up study.

Long-term follow-up studies on the health of children born after assisted reproduction technologies are mandatory. Vision and hearing are the most important senses that continue to develop during childhood. There are few reports on vision and hearing in preschool children born after assisted conception. This prospective controlled blinded follow-up study examined 276 term-born singleton intracytoplasmic injection (ICSI) children and 273 spontaneously conceived controls at a mean age of 5.5 years and performed detailed vision and hearing test and clinically examined eyes and ears. There was no significant difference between ICSI and control children regarding the occurrence of vision or hearing impairments. Unsurprisingly, children with abnormalities in otoscopy were more likely to have an abnormal hearing test compared with children without abnormalities. Only 8.5% of ICSI parents and 25.4% of control parents whose children showed an abnormal hearing test knew about the hearing problems of their child. In conclusion, there was no difference in the development of hearing and vision in ICSI children and spontaneously conceived controls. But only few parents knew about hearing problems of their child after undergoing routine screening examinations. Parental interviews would therefore not be sufficient in order to assess vision and hearing in follow-up studies.

[Follow-up of children with prenatal diagnosis of supraventricular extrasystole]. / Langzeitoutcome von Kindern mit pränatal diagnostizierter supraventrikulärer Extrasystolie.

PURPOSE: The aim of this study was the follow-up of children with a prenatal diagnosis of supraventricular extrasystole (SVES) up to an age of 5 years in order to assess the long term outcome of these children and in order to characterize factors influencing the outcome. MATERIALS AND METHOD: All fetuses diagnosed with prenatal SVES between April 1993 and August 2005 were identified and the children's parents and pediatricians contacted for data regarding the children's health. Follow-up data about the children's health up to the age of 5 years could be obtained in 77 (46.1%) children. RESULTS: 0.5% (167/34,770) of all fetuses were diagnosed with prenatal SVES. In 70% of cases the SVES resolved before or at birth. 30% of children presented with arrhythmia postpartum. 31% of children were diagnosed with cardiac anomalies postpartum. 87% of children were healthy at the age of 2 - 5 years. In the subgroup of children with isolated fetal SVES without further anomalies, 95% of children were healthy at the age of 2 - 5 years. In children with persisting arrhythmia and in children with cardiac anomalies, the prognosis was worse. CONCLUSIONS: Overall, by the long-term follow-up of 77 children with prenatal SVES we could show that prenatal SVES has a good prognosis. However, 30% of children develop arrhythmia postpartum and 31% of children present with cardiac anomalies. These children still have a worse prognosis than children with isolated prenatal SVES.

Spontaneous pregnancy after successful ICSI treatment: evaluation of risk factors in 899 families in Germany.

There are only scarce data on the incidence of spontaneous pregnancy in infertility patients. Contraception after infertility treatment is another topic that has been neglected so far. Therefore, a questionnaire was sent to 1614 couples with a child conceived by intracytoplasmic sperm injection (ICSI) aged 4-6 years. A total of 899 couples responded (response rate 55.7%). A total of 10.9% of couples had used contraception. Of the couples that had actively tried to conceive, 20.0% had conceived spontaneously, resulting in a live-birth rate of 16.4%. 74.5% of these pregnancies were conceived within 2 years after delivery. A further 26.6% of couples conceived again by ICSI, with a live-birth rate of 20.9%. Maternal age was the only prognostic factor for spontaneous conception. Parents of multiples after ICSI did not have a higher chance of spontaneous conception than parents of singletons. Couples can be counselled that one out of five couples conceive spontaneously after successful ICSI. Even when assuming that none of the families that were lost to follow-up had conceived spontaneously, one out of eight couples would have conceived spontaneously. Therefore, it is important to counsel patients about the possibility of natural conception and necessity to use contraception despite their history of subfertility.

Influence of hypo- and hyperglycaemia on plasma leptin concentrations in healthy women and in women with polycystic ovary syndrome.

BACKGROUND: Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia. METHODS: We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l. RESULTS: The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04). CONCLUSIONS: Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.

Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study.

BACKGROUND: A bolus dose of GnRH agonist can substitute for hCG as a trigger for the resumption of meiosis in ovarian stimulation with GnRH antagonists, which has been suggested to reduce the risk of ovarian hyperstimulation syndrome (OHSS). As the efficacy of this measure in fresh embryo transfer (ET) cycles is unclear, we evaluated a new clinical concept of GnRH-agonist triggering. METHODS: In this prospective, observational proof-of-concept study, 20 patients considered at increased risk of developing OHSS (> or = 20 follicles > or = 10 mm or estradiol > or = 4000 pg/ml, or a history of cycle cancellation due to OHSS risk or the development of severe OHSS in a previous cycle) after ovarian stimulation and concomitant GnRH-antagonist administration had final oocyte maturation triggered with 0.2 mg triptorelin s.c. All two pronucleate (2 PN) oocytes were cryopreserved by vitrification, and frozen-thawed ETs (FT-ETs) were performed in an artificial cycle. Main outcome measures were the cumulative ongoing pregnancy rate per patient and the ongoing pregnancy rate per first ET. Secondary outcomes included the incidence of moderate-to-severe OHSS. RESULTS: Of the 20 patients triggered with GnRH agonist, 19 patients underwent 24 FT-ETs in the observational period. The cumulative ongoing pregnancy rate was 36.8% (95% confidence interval: 19.1-59.0%). The ongoing pregnancy rate per first FT-ET was 31.6% (15.4-54.0%). No cases of moderate or severe OHSS were observed. CONCLUSIONS: The present study is the proof of the concept that GnRH-agonist triggering of final oocyte maturation in combination with elective cryopreservation of 2 PN oocytes offers OHSS risk patients a good chance of pregnancy achievement, while reducing the risk of moderate and severe OHSS.

Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of >1000 oocyte retrievals.

BACKGROUND: Although transvaginal ultrasound-guided oocyte retrievals (OR) are performed routinely worldwide, there is very little systematic data about its complications. METHODS: We performed a prospective cohort study following the perioperative and post-operative complications of over 1058 ORs. Additionally, we assessed the pain experienced during the OR. RESULTS: A total of 1166 OR were performed during the study period, of which 1058 (90.7%) ORs were included prospectively. Incomplete data meant that the remaining 9.3% were excluded. No complications were caused by sedation or general anaesthesia. Vaginal bleeding was observed in 2.8% of procedures, without any cases of intra-abdominal bleeding. An injury of pelvic structures (a ureteral lesion) occurred in one case. No case of pelvic infection, but one case of unexplained fever, was observed. A severe ovarian hyperstimulation syndrome (OHSS) occurred in 2.7% of cases. Although most patients tolerated the OR well, 3% of patients experienced severe to very severe pain after the OR and 2% of patients were still suffering from severe pain 2 days after the procedure. The pain level increased with the number of oocytes retrieved. About 0.7% of patients required hospitalization for pain treatment. CONCLUSIONS: Patients can be reassured that overall OR is a safe procedure. However, patients have to be counselled about the minor risks of the OR. The literature on complications is reviewed in the article.

Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.

Long-term follow-up studies on the health and the development of children conceived by assisted reproduction (ART) are mandatory to assess the safety of ART. Meanwhile, different aspects of health of these children have been studied. To put these results together, we performed a systematic review of these publications. A Pubmed search and a hand-search of the abstract books from the annual meeting of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine were performed for controlled studies on the developmental outcome of children after ART, which include a matching for plurality of gestation. Regarding general health, growth, mental and psychomotor development IVF children do not differ from spontaneously conceived (SC) children. An increased need for surgical interventions may be due to an increase in the malformation rate. However, a lower birth weight and lower gestational age compared to matched controls may contribute to some health problems observed. The increased risk of neurological problems found in some large registry-based studies can partly be explained by the higher frequency of twins born, by low birth weight, and by low gestational age also found in singletons. But an effect of IVF, the parents' infertility or other factors not adjusted for in the studies cannot be excluded. In addition to this reporting bias caused by concerned parents cannot be excluded, either. To conclude, children born after assisted reproductive techniques are generally healthy and are developmentally similar to children born after SC. However, low birth weight and prematurity contributes to health care problems. An increase of neurological problems by IVF cannot be excluded. Further prospective studies on the neurological outcome are needed.

The value of pronuclear scoring for the success of IVF and ICSI-cycles.

BACKGROUND: Pronuclear scoring helps to identify good quality embryos already at the pronuclear stage. There are no data available, however, to demonstrate whether patients benefit from a higher pregnancy rate after pronuclear scoring. METHODS: In a retrospective, matched cohort study 338 cycles in which patients chose to score their oocytes at the pronuclear stage (scoring group) were compared with 338 cycles without scoring (control group). The cycles were matched for maternal age, number of previous IVF and ICSI cycles, cryopreservation (yes/no) and diagnosis of primary infertility. RESULTS: The pregnancy rate was not significantly different between the scoring group and the control group (24.0 vs. 21.0%, NS) in spite of more cycles with grade A embryos and a higher number of embryos transferred. The presence of a Z1 pronuclear oocyte was found to be associated with the retrieval of more oocytes, a higher fertilization rate and more grade A embryos, as well as a non-significant increase in pregnancy rates (25.1 vs. 18.8%). CONCLUSIONS: Benefit from pronuclear scoring seems to be small. Apparently, experienced biologists are able to select "good-quality" pronuclear oocytes in the same way they would do after scoring. However, the results might be biased by differences between the groups.

Antenatal care in singleton pregnancies after ICSI as compared to spontaneous conception: data from a prospective controlled cohort study in Germany.

BACKGROUND: The aim was to compare the antenatal care and the intake of vitamins and medications of infertility patients with singleton pregnancies after ICSI to women with a spontaneously conceived singleton pregnancy. METHODS: The data on the antenatal care of 2055 singleton pregnancies after ICSI from a prospective controlled multicentre study in Germany were analysed. The prospectively collected data of the control group of 7861 singletons were retrospectively assessed for the present analysis. RESULTS: The ICSI patients were significantly older (32.9 versus 27.0 years, P<0.019) and more likely to be obese (body mass index>or=30 kg/m2: 13.9 versus 4.8%, P<0.001) than the controls. The control mothers were significantly more likely to smoke (19.2%) or to consume alcohol (23.5%) during pregnancy than the ICSI mothers (7.4 and 0.6% respectively). Only 38.1% of ICSI patients took folic acid before conception. Only 61.7% of ICSI patients received an iodine supplementation at some point during pregnancy. ICSI patients went more regularly to the routine antenatal care consultations at the gynaecologist and had ultrasound examinations performed more regularly than the controls. The absolute number of ultrasound examinations was significantly higher in the ICSI group (13.6+/-6.0 versus 4.1+/-2.4). CONCLUSION: In spite of the intensive use of antenatal medical care by patients pregnant after ICSI, simple methods, such as the use of supplementary iodine and periconceptional folic acid, were used rarely. This indicates that counselling pregnant patients after ICSI about periconceptional and antenatal care seems to be insufficient in Germany and must be improved.