Pregnancy and child outcome after assisted reproduction techniques

The introduction and widespread application of assisted reproduction techniques have raised major concern about the outcome of resulting pregnancies, as well as about the offspring's health. It seems that pregnancies achieved after standard in-vitro fertilization (IVF) bear an increased risk for prematurity and low birth weight. On the other hand, pregnancy outcome of singletons achieved after intracytoplasmic sperm injection (ICSI) and after the transfer of frozen-thawed embryos is similar to that of spontaneously conceived singletons, and pregnancy complications are related only to gestation multiplicity. The incidence of congenital and chromosomal anomalies after standard IVF seems to be similar to that expected in the general population. The prevalence of congenital malformations does not seem to be higher after ICSI. On the other hand, there is a slightly increased risk for transmission of chromosomal aberrations of paternal origin and a higher risk of de novo, mainly sex-chromosomal aberrations. Postnatal growth and development of children born after standard IVF and cryopreservation seem to be within the normal ranges. Growth of ICSI children is also normal while their mental development needs further investigation. Family functioning in assisted reproduction families is better.     

Uterine junctional zone contractions during assisted reproduction cycles. VIDEO

This study was designed to assess junctional zone contractions(JZ) during cycles of in-vitro fertilization (IVF) and embryotransfer in oocyte donors exposed to a long protocol regimefor ovarian stimulation. Real-time transvaginal ultrasound andadvanced audio-visual and computer technology were used to evaluatethe contraction pattern, frequency and velocity. At the timeof down-regulation JZ contractions were not observed. After7 days of superovulation all patients displayed cervico-fundal,fundo-cervical and random contractions. Cervico-fundal wavesdominated the picture at the time of human chorionic gonadotrophininjection. However, the activity was strongest on the day ofoocyte retrieval. At the time the percentage of opposing wavesincreased and fundo-cervical waves disappeared. The highestwave frequency and velocity (4.29±0.68 waves/min and2.73±0.54 mm/s respectively) were observed at the timeof oocyte retrieval. All patients had some JZ activity on days2, 3, and 4 after oocyte retrieval but regular wave-like contractilitygradually decreased and only single random movements were seenon day 4 after oocyte retrieval. In conclusion, JZ activitythroughout the IVF cycle is more exaggerated when compared tothe results reported from observations of the natural cyclebut follows a similar pattern. This fact can probably be explainedby the vastly different hormone levels. Higher JZ activity andcorrespondingly increased mobility of the endometrium may impairits receptivity and affect implantation.     

First-trimester bleeding and pregnancy outcome in singletons after assisted reproduction

BACKGROUND: First-trimester bleeding is frequent in assisted reproductive technique (ART) pregnancies. It is unknown whether first-trimester bleeding, if not ending in a spontaneous abortion, negatively influences further pregnancy outcome in ART in singletons. METHODS: Data were obtained from our ART database (1993-2002), with 1432 singleton ongoing pregnancies being included in this study. The outcome measures-second-trimester and third-trimester bleeding, preterm contraction rates, pregnancy duration, birthweight, Caesarean section rates, intrauterine growth retardation (IUGR), preterm prelabour rupture of membranes (P-PROM), neonatal intensive care unit (NICU) admission and perinatal mortality-were compared in the groups with and without first-trimester bleeding. RESULTS: Significantly more singleton pregnancies resulted from a vanishing twin in the group with first-trimester bleeding (8.7%) than in the controls (4.0%). A correlation was found between the incidence of first-trimester bleeding and the number of embryos transferred. First-trimester bleeding led to increased second-trimester [odds ratio (OR)=4.56; confidence interval (CI)=2.76-7.56] and third-trimester bleeding rates (OR=2.85; CI=1.42-5.73), P-PROM (OR=2.44; CI=1.38-4.31), preterm contractions (OR=2.27; CI=1.48-3.47) and NICU admissions (OR=1.75; CI=1.21-2.54). First-trimester bleeding increased the risk for preterm birth (OR=1.64; CI=1.05-2.55) and extreme preterm birth (OR=3.05; CI=1.12-8.31). CONCLUSIONS: First-trimester bleeding in an ongoing singleton pregnancy following ART increases the risk for pregnancy complications. The association between first-trimester bleeding, the number of embryos transferred and adverse pregnancy outcome provides a further argument in favour of single-embryo transfer.     

Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome

BACKGROUND: The sperm chromatin structure assay (SCSA) has beensuggested as a predictor of fertility in vivo as well as invitro. The available data however, have been based on limitednumbers of treatments. We aimed to define the clinical roleof SCSA in assisted reproduction. METHODS: A total of 998 cycles[387 intrauterine insemination (IUI), 388 IVF and 223 ICSI]from 637 couples were included. SCSA results were expressedas DNA fragmentation index (DFI) and high DNA stainable (HDS)cell fractions. Outcome parameters were biochemical pregnancy(BP), clinical pregnancy (CP) and delivery (D). RESULTS: ForIUI, the odds ratios (ORs) for BP, CP and D were significantlylower for couples with DFI >30% as compared with those withDFI 30%. No statistical difference between the outcomes of ICSIversus IVF in the group with DFI 30% was seen. In the DFI >30%group, the results of ICSI were significantly better than thoseof IVF. CONCLUSIONS: DFI can be used as an independent predictorof fertility in couples undergoing IUI. As a result, we proposethat all infertile men should be tested with SCSA as a supplementto the standard semen analysis. When DFI exceeds 30%, ICSI shouldbe the method of choice.     

HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment

The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA-G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART.     

Endometrial pattern and thickness associated with pregnancy outcome after assisted reproduction technologies.

The endometrial pattern and thickness was analysed prospectively on the day of administration of human chorionic gonadotrophin (HCG) in 200 in-vitro fertilization (IVF), gamete intra-Fallopian transfer (GIFT) and tubal embryo transfer (TET) cycles. Increasing maturity of the endometrial pattern was positively correlated with oestradiol levels (r = 0.20; P = 0.005), number of mature eggs (r = 0.13; P less than 0.05) and the number of top quality embryos (r = 0.40; P less than 0.001). The endometrial thickness was positively correlated with the number of follicles greater than or equal to 15 mm (r = 0.15; P less than 0.02) and the cycle day on which HCG was administered (r = 0.14; P less than 0.03). It was unaffected by the dose of human menopausal gonadotrophin and was negatively correlated with the use of clomiphene citrate (r = 0.40; P less than 0.001). Fecundity was increased for IVF when the endometrial thickness was greater than or equal to 9 mm (P less than 0.05) and for GIFT and TET when a Type C triple-line endometrial pattern was present (P less than 0.05). Biochemical pregnancies for the combined methods increased from 2.5% of all pregnancies when the endometrial thickness was 9-13 mm, to 27.8% when the thickness was less than 9 mm or greater than 13 mm (P less than 0.01). Biochemical pregnancies occurred in 67% of IVF pregnancies when the endometrial thickness was greater than or equal to 3 mm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uterine leiomyomas reduce the efficacy of assisted reproduction cycles: results of a matched follow-up study

A matched follow-up study design was used to test the hypothesis that pregnancy rates following assisted reproduction procedures do not differ between women with or without intramural or sub-serosal uterine leiomyomas. Women undergoing their first in-vitro fertilization (IVF)- embryo transfer or zygote intra-Fallopian transfer (ZIFT) cycle between January 1993 and June 1995 were included. Cases (women with leiomyomas) were matched 1:1 with the next consecutive control (women without leiomyomas) according to age, number of embryos transferred, embryo grade, and the route of embryo transfer (uterine or Fallopian). Assisted reproduction cycles were performed in an identical manner, independent of the presence or absence of uterine leiomyomas. The main outcomes measured were clinical pregnancy and delivery rates. A total of 182 cycles was evaluated. Of the 91 assisted reproduction cycles performed in the leiomyoma group, there were 34 clinical pregnancies (37%) and 30 deliveries (33%). Of the 91 assisted reproduction cycles in the control group, there were 48 clinical pregnancies (53%) and 44 deliveries (48%). The Mantel-Haenszel estimate of relative risk indicated that the presence of a uterine leiomyoma significantly reduced the chance for a clinical pregnancy or delivery. These findings suggest that leiomyomas are associated with a reduction in the efficacy of assisted reproduction cycles.      

Maternal exposure to second-hand tobacco smoke and pregnancy outcome among couples undergoing assisted reproduction

BACKGROUND: Exposure to second-hand tobacco smoke is preventable, yet common. This study assessed relationships between maternal exposure to second-hand tobacco smoke and adverse pregnancy outcomes. METHODS: We measured cotinine (a biomarker of tobacco smoke) in urine from 921 women undergoing assisted reproductive technologies (ARTs) between 1994 and 1998. We also collected information on self-reported exposure to second-hand smoke at home or at work, in addition to parental smoking during the women's childhood. RESULTS: In crude analysis, creatinine-adjusted cotinine levels were associated with a slight decrease in implantation rate among non-smoking women (11.1% in the lowest cotinine quintile versus 8.2% in the highest cotinine quintile; P=0.13). However, in multivariate logistic regression, cotinine levels above the median were not associated with failed fertilization, failed implantation or spontaneous abortion, nor was there evidence of a dose-response relationship among cotinine quintiles. After excluding women in couples diagnosed with male factor infertility, there were increased odds of having a spontaneous abortion among non-smoking women who reported that both parents smoked while they were children growing up compared with women reporting that neither parent smoked [adjusted odds ratio (OR) = 4.35; 95% confidence interval (CI) = 1.04-18.1]. CONCLUSIONS: Female exposure to second-hand smoke as a child or in utero may be associated with an increased risk of spontaneous abortion in adulthood. However, this may be a chance finding due to multiple comparisons. Similar associations should be explored in additional studies with more refined estimates of childhood and in utero exposure to tobacco smoke.     

关于辅助生殖技术中HBV感染者胚胎发育和IVF结局的研究

目的探讨HBV感染夫妇的胚胎的发育情况和IVF结局。方法病例对照研究:将仅一方感染HBV的夫妻与未感染的夫妻进行1∶2配对,配对指标为:女方年龄,月经周期,基础FSH,不孕原因,原发还是继发不孕,不孕年限,第几次周期,卵巢刺激方案是长方案还是短方案,IVF还是ICSI。比较这两组人群的胚胎在受精率,卵裂率,着床率,临床妊娠率,流产率和活产率方面有无差异。结果仅一方感染HBV的夫妻与未感染的夫妻在配对指标方面没有显著性差异。除了较低的卵裂率外(97.7%比98.8%;P<0.05),仅一方感染HBV的夫妻的胚胎的受精率,着床率,临床妊娠率,流产率和活产率方面与对照组比较没有差异(P均>0.05)。结论HBV感染夫妇和未感染夫妇比较,除了卵裂率较低外,HBV感染夫妇的胚胎继续发育的潜能和IVF结局与未感染者相似。     

Antithyroid antibodies do not affect pregnancy outcome in women undergoing assisted reproduction.

The purpose of this study was to determine the association of antibodies to thyroglobulin and thyroid peroxidase and pregnancy outcome in women undergoing assisted reproductive techniques. The study included three centres and retrospectively evaluated patient sera for antithyroid antibodies, then related the results to pregnancy outcome. Enzyme-linked immunosorbant assays for thyroglobulin and thyroid peroxidase antibodies were performed using two different commercially available kits. Controls included 200 healthy women of reproductive age. Women (n = 873) who were undergoing assisted reproductive techniques for pelvic adhesions, endometriosis, ovarian dysfunction, or unexplained/other were included. All women utilized a standard regimen of gonadotrophin releasing hormone agonist down-regulation followed by ovulation induction. Embryos were cultured for 3 days, at which time embryo transfer occurred. Statistical analysis utilized the two-tailed Fisher's exact test. Antithyroid antibodies were positive in 143 of 873 (16.4%) women undergoing assisted reproductive techniques while 29 of 200 (14.5%) normal controls were positive (not significant). Deliveries were achieved in 396 of 730 (54.2%) of women who had no thyroid antibodies versus 78 of 143 (54.5%) of women who had thyroid antibodies (not significant). No difference in biochemical pregnancies (not significant) or clinical pregnancy losses (not significant) were detected. Antithyroid antibodies were found no more frequently in women undergoing assisted reproductive techniques than in normal controls. There were no differences in pregnancy outcome based on antithyroid antibody positivity in women undergoing assisted reproductive techniques. These data do not support the testing or treatment for antithyroid antibodies of women undergoing assisted reproductive techniques.     

Intrafamilial medically assisted reproduction

For different motives, couples in need of third party assisted reproduction sometimes prefer the help of a family member over an unrelated collaborator. Quantitative (frequency) and qualitative (experience) data about this practice are lacking or scarce. Forms of intrafamilial medically assisted reproduction (IMAR) are different with respect to (i) familial closeness between the collaborator and the person whose reproductive contribution he or she replaces and whether assistance would be intra- or intergenerational, (ii) the relationship between the collaborator and the fertile partner (this relationship may or may not be consanguineous) and (iii) with regard to the material (sperm and oocytes) that is donated and the services (surrogacy) that are offered. This document aims at providing guidance to the professional handling of requests for IMAR. It briefly sketches the background of this practice and discusses a variety of relevant normative aspects.     

Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome

Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P: < 0.01 and P: < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P: < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P: < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.     

Paired human chorionic gonadotrophin determinations for the prediction of pregnancy outcome in assisted reproduction

The aim of this study was to determine the prognostic value of single and paired measurements of serum concentrations of human chorionic gonadotrophin (HCG) for successful pregnancy following in-vitro fertilization (IVF) and tubal embryo transfer (TET). We analysed serum HCG concentrations 15 and 22 days after IVF or TET in 198 conception cycles. Cut-off values of serum HCG were determined by a receiver operating characteristic (ROC) curve. On the basis of single HCG samples on day 15 (HCG15) after transfer, using a cut-off value of HCG15 = 150 mIU/ml, the sensitivity was 71% and the specificity was 77%. The positive predictive value (HCG15 > or = 150 mIU/ml indicating a normal pregnancy) was 89%, while the negative predictive rate (HCG15 < 150 mIU/ml indicating an abnormal pregnancy) was 51%. Patients with HCG15 < 150 mIU/ml but HCG22/HCG15 ratio > or = 15, still had a 90% chance of normal pregnancy. However, in patients with HCG15 < 150 mIU/ml and an HCG22/HCG15 ratio < 15, there was an 84% chance of an abnormal pregnancy. We conclude that a single HCG15 determination combined with the ratio of HCG22 to HCG15 has a higher diagnostic accuracy for prediction of pregnancy outcome than either analysis alone.      

Perinatal complications of assisted reproduction

The main perinatal complications of assisted reproduction include congenital malformation, chromosomal aberrations, multiple pregnancy, and prematurity. Earlier studies and in vitro fertilization (IVF) registries showed that there was no increased incidence of congenital malformations in children conceived by IVF/intracytoplasmic sperm injection (ICSI). However, a large Australian study has found that by one year of age, the incidence of congenital malformations in IVF/ICSI children is increased in comparison with those naturally conceived. Several investigators found a slight but increased risk of chromosomal aberrations in ICSI children. Multiple pregnancy is a major cause of increased perinatal mortality due to increased incidence of both prematurity and congenital malformations. Even in singleton pregnancies conceived by assisted reproductive technologies, the risk of prematurity and newborns small for gestational age is increased. In this article, recently published work on perinatal complications associated with assisted reproductive technologies is reviewed.     

Microscopical advances in assisted reproduction

In a series of papers carried out by this laboratory it was demonstrated that the quality of sterile males sperm, assessed submicroscopically and mathematically, is closely correlated with the success of the various procedures of assisted reproduction. If we attempt to select hypothetically optimal spermatozoa destined to the ICSI by light inverted microscopy, a considerable amount of ultrastructural information is lost and our selection is merely based on the motility. In this study we apply polarization microscopy to the ICSI technique, introducing polarizing and analyzing lenses in an inverted microscope model, operating in a transparent container. The retardation of the birefringence in the various organelles is evaluated by compensators, and the images are transmitted to a video system, and stored in a computer. Spermatozoa are maintained alive and perfectly motile in this polarizing inverted microscope, and the character of the birefringence is the same as in fixed and sectioned biological material examined by polarization microscopy. The birefringence of the sperm structures allows a sperm analysis closer to TEM than to phase contrast light microscopy analysis.     

Cytoplasmic transfer in assisted reproduction

This report details the use of cytoplasmic transfer in human oocytes. The introduction of a small amount of ooplasm from a donor oocyte or zygote may alter the function of oocytes, with probable deficiencies. Cytoplasmic transfer from fertile donor oocytes or zygotes into compromised oocytes from patients with recurrent implantation failure after assisted reproduction has now led to the birth of nearly 30 healthy babies worldwide. Transfer of small amounts of cytoplasm probably involves mRNAs, proteins and mitochondria, as well as other factors and organelles. Even though the use of cytoplasmic transfer has been employed in several IVF clinics--and pregnancies have resulted--it is not known definitively whether the physiology of the early embryo is affected. This review outlines the experimental cytoplasmic transfer techniques and postulates the future impact in assisted reproduction.     

Safety issues in assisted reproduction technology: the children of assisted reproduction confront the responsible conduct of assisted reproductive technologies

Neurological sequelae and multiple birth defects have been observed in children conceived by IVF and ICSI. Multiple pregnancy is the most important risk factor. These health problems challenge the responsible practice of medicine. The core values of medicine and the deontology of the profession have been reviewed to define the responsible conduct of research and clinical practice. Professional associations have proposed guidelines to reduce health problems in assisted reproductive technology. Although these health problems could have been prevented, this response by the medical community is nonetheless an important step towards improving responsible medical practices that have become questionable over the years. Professional associations must find out means, not only to implement their guidelines, but also to prevent the recurrence of such episodes in the history of medicine.