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Neonatal and obstetric outcome of pregnancies conceived by ICSI or IVF.

Intracytoplasmic sperm injection (ICSI) is currently widely used despite concern regarding pregnancy complications and outcome, specifically congenital malformations. The aim of this study was to compare the obstetric and neonatal outcome of pregnancies conceived by IVF and ICSI. Long-term follow-up was achieved through questionnaires sent to women who conceived after IVF/ICSI treatment. Information was obtained regarding 219 pregnancies (322 children) conceived after ICSI and 145 pregnancies (201 children) conceived after IVF. There were no significant differences between the ICSI and regular IVF pregnancies in regard to the couple's characteristics and the obstetric complications. The mean +/- SD birth weight of the singletons conceived after ICSI was similar to that of singletons conceived after IVF: 3001 +/- 703 versus 3059 +/- 643 g respectively. In both groups there was a high incidence of multiple pregnancies, Caesarean sections, prematurity and low birth weights. The incidence of congenital malformations following IVF or ICSI pregnancies was similar, 6.3 and 7.7% respectively, but was increased compared with the general Israeli population. In summary, concern remains regarding the incidence of congenital malformations after IVF and the long-term outcome of ICSI pregnancies. However, the present results are reassuring with regard to the obstetric and neonatal outcome of pregnancies conceived by ICSI compared with those achieved by IVF.

Abnormalities, Multiple↗

Efficacy of IVF using frozen donor semen in cases of previously failed DI cycles compared with tubal infertility: a cohort study.

A cohort follow-up study was designed to compare the efficacy of IVF using frozen donor semen (IVF-D) following previously failed DI cycles (unexplained female infertility) and direct IVF-D treatment because of tubal infertility (control group). The cohort comprised 189 couples initiating IVF-D after previously failed DI cycles (n = 126) or directly (n = 63). Couples were followed until completion (success or drop-out for personal or medical reasons). Live births and drop-out were expressed both as rate per cycle and crude cumulative rate. Characteristics of IVF-D cycles were similar between the two groups. Moreover, overall outcome was also similar in terms of crude cumulative live birth rate (54.0 versus 57.1% for failed DI cycles and tubal infertility groups respectively). This is the first report on crude cumulative live birth rate based on a cohort follow-up study in unexplained previously failed DI cycles and tubal infertility. Previously failed DI cycles did not impair the chances of achieving a successful pregnancy using IVF-D in this series. Slight oocyte dysfunction, which might underlie the failure of DI cycles, might be overcome using IVF-D.

Adult↗

How animal embryo research led to the first documented human IVF.

Research studies using animal gametes led to the first documented human IVF in 1969. A key contribution was the development of a reliable culture medium for IVF of hamster oocytes, which was then used successfully with human gametes in the laboratory. This article describes how this was accomplished. Hamster IVF was obtained using a bicarbonate-buffered culture medium based on Tyrode's solution. A dose-response experiment showed that IVF in this species was highly dependent on the pH of the culture medium. At pH 7.2 or less, very few oocytes were penetrated and spermatozoa did not undergo acrosome reactions. Over the pH range 7.3-7.5, 40% of oocytes were fertilized in vitro, while at pH 7.6 or higher, more than 75% of oocytes were fertilized and most spermatozoa exhibited acrosome reactions. There was no apparent effect of pH on sperm motility. These experiments showed that in the hamster, fertilization in vitro is highly pH dependent, most likely through pH effects on the sperm acrosome reaction and sperm:zona binding. The data led to formulation of a culture medium, Tyrode-B, that consistently supported high levels of IVF of hamster oocytes. When this medium was used for human gametes, IVF was observed and documented for the first time. Spermatozoa penetrating through the zona pellucida and sperm components within the ooplasm were detected, and some oocytes exhibited two pronuclei. These observations suggested that human IVF might be useful for alleviation of infertility.

Animals↗

Different antiphospholipid antibody specificities are found in association with early repeated pregnancy loss versus recurrent IVF-failure patients.

PROBLEM: Patients having in vitro fertilization and embryo transfer (IVF-ET) failures show an increased incidence of antiphospholipid (aPL) antibodies; but controversy exists whether aPL can induce IVF-failure. This study was designed to compare aPL specificities between recurrent IVF-failure patients versus repeated early pregnancy loss (RPL) patients. METHOD OF STUDY: Anticardiolipin (aCL), lupus anticoagulant (LA), antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE), and antinuclear antibodies (ANA) were measured in 74 recurrent IVF-ET failure patients and compared with 273 early RPL patients ( < 10 weeks). RESULTS: An increased incidence of IgG-aPE and ANA was observed for both groups in comparison with controls. Patients with recurrent IVF-ET failure showed a significantly higher prevalence of IgG-aPS (P = 0.02) and IgG-aCL (P = 0.02) when compared with early RPL patients or controls. CONCLUSIONS: IgG-aPS and IgG-aCL may be responsible for some IVF-failures. Additional studies are needed to clarify the pathogenic role of IgG-aPS and IgG-aCL on IVF-ET failure.

Abortion, Habitual↗

Treatment of male infertility due to sperm surface antibodies: IUI or IVF?

This prospectively designed study was aimed at comparing the results of two different treatment protocols in 29 infertile couples with proven male immunological infertility, i.e. a positive (>50%) mixed antiglobulin reaction (MAR) test (IgG and/or IgA). In the first protocol (group I, n = 14) couples were treated with ovarian stimulation/ intrauterine insemination (IUI), followed by in-vitro fertilization (IVF) if no pregnancy occurred after three IUI cycles. In the second protocol (group II, n = 15), patients were treated with IVF as a first choice procedure. The decision to follow protocol 1 or 2 was made by the couples after information about financial costs and expected success rates (according to the literature) for both treatment options. In group I, nine patients (64.3%) conceived after a maximum of three IUI cycles whereas seven patients (46.6%) of group II became pregnant during the first IVF cycle. The take-home baby rate per started IUI or IVF cycle was 27.3% (9/33) and 44.4% (16/36) respectively with a take-home baby rate of 64.3% after three IUI cycles and 93.3% after three IVF attempts. To conclude, both IUI and IVF yielded unexpectedly high pregnancy rates in this selected group of patients with long-standing infertility due to sperm surface (predominantly IgG) antibodies. Since cost benefit analysis comparing superovulation IUI with IVF may favour a course of four IUI cycles, we advocate superovulation IUI as the first line therapy in male immunological infertility.

Adult↗

Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals.

In singleton pregnancies after IVF a high rate of preterm deliveries and an increased rate of small-for-gestational age (SGA) children in comparison to the general parturient population have been reported. However, due to differences between IVF mothers and their peers who conceived naturally, careful selection of the control group is necessary to assess whether IVF pregnancies really carry increased risks of adverse outcome. In our study 307 IVF pregnancies were compared with 307 control pregnancies after elaborate matching for an extensive number of maternal characteristics, as well as for the hospital that provided the obstetric care. Four Dutch university hospitals contributed to the study. In cases with spontaneous onset of labour, gestational age at delivery was 3 days shorter in the IVF group (275 versus 278 days, P = 0.05). The proportion of SGA was higher in the IVF group (16.2 versus 7.9%, P < 0.001). The combination of these two results denotes a distinct difference between IVF and control pregnancies. Placental weight was comparable in both groups.

Abnormalities, Multiple↗

The course of pregnancy and delivery and the use of maternal healthcare services after standard IVF in Northern Finland 1990-1995.

BACKGROUND: The objective of this study was to evaluate the course of pregnancy and delivery and the use of maternal healthcare after IVF. METHODS: This population-based cohort study included all women who had undergone IVF treatment in Northern Finland leading to delivery in 1990-1995 (n = 225) and control pregnancies derived from the Finnish Medical Birth Register (n = 671) matched for sex of the child, year of birth, area, maternal age, parity, social class and fetal plurality. The analyses were stratified by plurality. Outcome measures were pregnancy complications, mode of delivery, gestational length and the level of use of antenatal care. RESULTS: The results showed an increased risk for vaginal bleeding throughout pregnancy [relative risk (RR) 4.1, 95% confidence interval (CI) 2.5-6.7 for singletons; RR 6.9, 95% CI 2.5-19.2 for twins], threatened preterm birth (RR 1.8, 95% CI 1.1-2.9, singletons) and intrahepatic cholestasis of pregnancy (RR 3.8, 95% CI 1.0-15.0, singletons) in IVF pregnancies, as well as an increase in the use of specialized antenatal care. CONCLUSIONS: IVF pregnancies following standard, fresh ova IVF treatments are at greater risk of obstetric problems than spontaneously conceived pregnancies, and hence IVF mothers use more specialized antenatal care than others. The pregnancy complications after IVF are likely to be due to maternal characteristics regarding infertility and to a high incidence of multiple pregnancies.

Adult↗

Obstetric outcome among women with unexplained infertility after IVF: a matched case-control study.

BACKGROUND: Infertility itself and also assisted reproductive treatment increase the incidence of some obstetric complications. Women with unexplained infertility are reported to be at an increased risk of intrauterine growth restriction during pregnancy, but not for other perinatal complications. METHODS: A matched case-control study was performed on care during pregnancy and delivery, obstetric complications and infant perinatal outcomes of 107 women with unexplained infertility, with 118 clinical pregnancies after IVF or ICSI treatment. These resulted in 90 deliveries; of these, 69 were singleton, 20 twin and one triplet. Two control groups were chosen from the Finnish Medical Birth Register, one group for spontaneous pregnancies (including 445 women and 545 children), matched according to maternal age, parity, year of birth, mother's residence and number of children at birth, and the other group for all pregnancies after IVF, ICSI or frozen embryo transfer treatment (FET) during the study period (including 2377 women and 2853 children). RESULTS: Among singletons, no difference was found in the mean birthweight, and the incidence of low birthweight (<2500 g) was comparable with that of the control groups. No differences were found in gestational duration, major congenital malformations or perinatal mortality among the groups studied. Among singletons in the study group, there were more term breech presentations (10.1%) compared with both spontaneously conceiving women and all IVF women (P < 0.01). The rate of pregnancy-induced hypertension was significantly lower among singletons in the study group (P < 0.05) compared with other IVF singletons. The multiple pregnancy rate was 23.3% in the study group. The obstetric outcome of the IVF twins was similar to both control groups. CONCLUSIONS: The overall obstetric outcome among couples with unexplained infertility treated with IVF was good, with similar outcome compared with spontaneous pregnancies and IVF pregnancies generally.

Adult↗

Maternal serum hCG and alpha-fetoprotein levels in pregnancies conceived after IVF or ICSI with fresh and frozen-thawed embryos.

BACKGROUND: Studies have shown that levels of serum markers of Down's syndrome were altered in pregnancies conceived after IVF, though the reason for this remains unknown. METHODS: Second-trimester maternal serum levels of hCG and alpha-fetoprotein (AFP) in pregnancies conceived with fresh and frozen-thawed embryos after assisted reproduction were compared with those conceived spontaneously. RESULTS: There were 203 pregnancies with fresh embryo transfers (130 IVF cases, 73 ICSI cases) and 98 pregnancies with frozen-thawed embryo transfers (61 IVF cases, 37 ICSI cases). The controls consisted of 17 145 spontaneous pregnancies. The median hCG multiples of the median (MoM) was significantly increased to 1.24 in 98 pregnancies conceived after frozen embryo transfer. This elevation was observed only in the IVF-frozen embryo transfer subgroup (P < 0.001), but not in the ICSI-frozen embryo transfer subgroup. The median AFP MoM for 203 pregnancies after fresh embryo transfer was 0.90. Among the subgroups, the median AFP MoM was significantly reduced to 0.90 and 0.86 in IVF-embryo transfer (P = 0.04) and ICSI-embryo transfer (P = 0.001) pregnancies respectively, and significantly raised to 1.20 in the IVF-frozen embryo transfer subgroup. CONCLUSIONS: The degree of alterations in maternal serum hCG and AFP levels varied between fresh and frozen-thawed embryos, and also between the mode of fertilization. Pregnancies resulting from ICSI or frozen embryo transfer should be regarded as distinct entities from those of IVF-embryo transfer.

Case-Control Studies↗

Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment.

BACKGROUND: Our aim was to examine whether women who had a low number of retrieved oocytes at their first IVF attempt reach the menopausal transition and/or the natural menopause earlier than women of similar ages with a high number of retrieved oocytes. METHODS: We conducted a retrospective cohort study among women in The Netherlands who received IVF treatment between 1983 and 1995. For the present study, we selected all cohort members who had a regular menstrual cycle at the time of the first visit to the gynaecologist (n = 4601). After a median follow-up of 5.5 years, 3871 (84%) women still had a regular menstrual cycle pattern, 547 (12%) women had entered the menopausal transition (i.e. no menses for 3-11 months, use of HRT or irregular menstrual cycles) and 27 (1%) women had reached natural menopause. We examined whether the quantity and the quality of the retrieved oocytes were related to an early menopausal transition and early menopause. The live birth rate per embryo transfer was used as indicative of the quality of the oocytes. RESULTS: The age-adjusted odds ratio (OR) for having entered the menopausal transition/natural menopause for women with a poor response (0-3 oocytes) at their first IVF attempt was 3.1 [95% confidence interval (CI) 2.4-3.8] compared with women with a normal response (>3 oocytes). Women who were stimulated with gonadotrophins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (cancelled IVF cycle) had an age-adjusted OR of 3.2 (95% CI 2.3-4.3). There was no significant difference in the odds of reaching the menopausal transition/natural menopause, after adjustment for age and the number or retrieved oocytes, between women who did and did not have a live birth following their first embryo transfer (OR = 1.3; 95% CI 0.95-1.7). CONCLUSIONS: These results indicate that a low remaining quantity of oocytes, as reflected by a low number of retrieved oocytes at first IVF treatment, is an important predictor of the risk of an early menopausal transition/natural menopause. The quality of the oocytes did not affect the risk of an early menopausal transition/natural menopause once the number of retrieved oocytes had been taken into account. Our findings support the concept that the number of remaining follicles in the ovaries is one of the main aspects of reproductive ageing.

Adult↗

The effectiveness of IVF in unexplained infertility: a systematic Cochrane review. 2002,.

BACKGROUND: IVF is an accepted treatment for unexplained infertility. The objective of this review was to determine whether, for unexplained infertility, IVF improves the probability of live birth compared with: (i) expectant management; (ii) clomiphene citrate (CC); (iii) intrauterine insemination (IUI); (iv) IUI with controlled ovarian stimulation; and (v) gamete intra-Fallopian transfer (GIFT). METHODS: This was based on a Cochrane review. Randomized controlled trials (RCTs) which compared the effectiveness of IVF with expectant management, CC, IUI with or without controlled ovarian stimulation and GIFT were included. Patients included couples with unexplained infertility. Live birth rate per woman/couple was the main outcome measure. RESULTS: Nine RCT were identified. Five RCTs were included in the final meta-analysis. There were no comparative data for CC and live birth rates for expectant management or GIFT. There was no significant difference in clinical pregnancy rates between IVF and expectant management. There was no evidence of a difference in live birth rates between IVF and IUI either without (OR 1.96, 95% CI 0.88 to 4.36) or with (OR 1.15, 95% CI 0.55 to 2.42) ovarian stimulation. Clinical pregnancy rates with IVF were significantly higher compared with GIFT (OR 2.14, 95% CI 1.08 to 4.22) as were the multiple pregnancy rates (OR 6.25, 95% CI 1.70 to 23.00). Clinical heterogeneity was present among the studies. There was no evidence of statistical heterogeneity. CONCLUSIONS: The effectiveness of IVF in unexplained infertility remains unproven. Larger trials with adequate power are warranted.

Female↗

A multicentre randomized controlled trial of expectant management versus IVF in women with Fallopian tube patency.

BACKGROUND: Although observational studies suggest that IVF is more effective than no treatment for women with Fallopian tube patency, this has not been tested rigorously in a randomized controlled trial (RCT). METHODS: Eligible consenting couples planning their first treatment cycle in five Canadian fertility clinics received either IVF, within 90 days of randomization, or a period of 90 days with no treatment. Random allocation was stratified by female age and sperm quality, and administered using numbered, opaque, sealed envelopes. Follow-up assessed live birth and associated morbidity. RESULTS: Sixty-eight couples were randomized to a first cycle of IVF and 71 couples had 3 months without treatment. The live birth rates were 20/68 (29%) and 1/71 (1%), respectively. The single delivery in the untreated group was of twins, as were six of the 20 IVF deliveries (30%). An average of 2.0 embryos were transferred and no triplet pregnancies resulted. The relative likelihood of delivery after allocation to IVF was 20.9-fold higher than after allocation to no treatment [95% confidence interval (CI) 2.8-155]. The presence of abnormal sperm did not reduce this likelihood. Treating four women (95% CI 3-6) with one cycle of IVF is required to achieve a single additional birth. CONCLUSIONS: This study provides a valid and up-to-date comparison for policy makers and patients as they make choices around IVF, accurately measuring and confirming a major benefit from treatment.

Birth Rate↗

IVF versus ICSI in sibling oocytes from patients with polycystic ovarian syndrome: a randomized controlled trial.

BACKGROUND: This study compares the fertilization rate and embryonic development of oocytes randomly inseminated by conventional IVF or ICSI in patients with polycystic ovarian syndrome (PCOS) and normozoospermic semen during IVF cycles. METHODS: Sibling oocytes were randomized to be inseminated either by ICSI or IVF. Fertilization rate (two pronuclei/COC), day 2 embryonic morphology and rate of development were assessed. RESULTS: A total of 1089 cumulus-oocyte complexes (COC) were collected in 60 cycles (mean+/-SD, 18.2 +/- 7.2). Totals of 541 and 548 COC were inseminated by IVF and ICSI respectively, with a significantly higher fertilization rate in the ICSI group (ICSI versus IVF, 72.3 +/- 15.5 versus 44.8 +/- 25.1%). No fertilization failure occurred in the group of oocytes inseminated by ICSI, whereas the COC in nine patients (15%) inseminated by IVF had complete fertilization failure. The day 2 embryonic morphology and rate of development were not different regardless of the insemination method. CONCLUSIONS: Our results suggested that another randomized controlled study, randomizing patients instead of sibling oocytes, should be undertaken to compare the pregnancy rate per started cycle and to see whether ICSI should be performed on all, or at least on a portion of, oocytes for patients with PCOS undergoing IVF cycles.

Adult↗

Comparison of outcome of pregnancy after intra-uterine insemination (IUI) and IVF.

INTRODUCTION: Pregnancy outcome after IVF has been shown to be worse than after spontaneous conception. There is discussion as to whether this results from the technique itself or the patient characteristics. This study compares pregnancy outcome after IVF and intra-uterine inemination (IUI) in a matched patient group. METHODS: Data were obtained from our IVF and IUI databases (1997-2001). Matching was performed for maternal age, parity and plurality, and 126 IUI pregnancies were compared with 126 IVF pregnancies. Outcome variables were pregnancy duration, birth weight, Caesarean section rates, preterm contraction rates, neonatal intensive care unit admission, Apgar score, blood loss rates and maternal hypertension. RESULTS: None of the analysed parameters was statistically different between the groups. CONCLUSION: This matched case-control study does not show different pregnancy outcomes after IVF and IUI. Since there is no reason to believe that the IUI technique in itself leads to an increased obstetric or neonatal risk, this study suggests that the worse pregnancy outcome after IVF as compared with spontaneous conceptions is due to the specific patient characteristics, rather than to the use of IVF itself.

Adult↗

Lack of seasonal variations in fertilization, pregnancy and implantation rates in women undergoing IVF.

BACKGROUND: Several studies have investigated seasonal variations during IVF. Their results are contradictory, especially concerning fertilization and pregnancy rates. The aim of the present study was to re-evaluate these parameters using a large number of IVF cycles. METHODS: A total of 7368 IVF cycles conducted in Switzerland between 1995 and 2003 were retrospectively analysed. To avoid a bias in the evaluation of the fertilization rate, only IVF cycles without ICSI were considered for analysis. Cycles were assigned to seasons according to the date of the beginning of stimulation. RESULTS: There were no statistically significant differences between the seasons concerning the fertilization, the pregnancy and the implantation rates. However, statistically significant variables deciding on the outcome of an IVF cycle are age, centre, aetiology of infertility and day of transfer. CONCLUSIONS: There were no statistically significant seasonal differences in central Europe (Switzerland) that influenced the outcome of IVF treatment. The only statistically significant variables of IVF outcome were age, centre, aetiology of infertility and day of transfer. A change to routine fertility treatment concerning the different seasons should therefore not be taken into account.

Adult↗

IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch.

Recent studies suggest that IVF and assisted reproduction technologies (ART) may result in abnormal genomic imprinting, leading to an increased frequency of Angelman syndrome (AS) and Beckwith-Weidemann syndrome (BWS) in IVF children. To learn how ART might alter the epigenome, we examined morulas and blastocysts derived from C57BL/6J X M. spretus F1 mice conceived in vivo and in vitro and determined the allelic expression of four imprinted genes: Igf2, H19, Cdkn1c and Slc221L. IVF-derived mouse embryos that were cultured in human tubal fluid (HTF) (Quinn's advantage) media displayed a high frequency of aberrant H19 imprinting, whereas in vivo and IVF embryos showed normal maternal expression of Cdkn1c and normal biallelic expression of Igf2 and Slc221L. Embryonic stem (ES) cells derived from IVF blastocysts also showed abnormal Igf2/H19 imprinting. Allele-specific bisulphite PCR reveals abnormal DNA methylation at a CCCTC-binding factor (CTCF) site in the imprinting control region (ICR), as the normally unmethylated maternal allele acquired a paternal methylation pattern. Chromatin immunoprecipitation (ChIP) assays indicate an increase of lysine 4 methylation (dimethyl Lys4-H3) on the paternal chromatin and a gain in lysine 9 methylation (trimethyl Lys9-H3) on the maternal chromatin at the same CTCF-binding site. Our results indicate that de novo DNA methylation on the maternal allele and allele-specific acquisition of histone methylation lead to aberrant Igf2/H19 imprinting in IVF-derived ES cells. We suggest that ART, which includes IVF and various culture media, might cause imprinting errors that involve both aberrant DNA methylation and histone methylation at an epigenetic switch of the Igf2-H19 gene region.

Animals↗

Relative ability of modified versions of the hamster oocyte penetration test, incorporating hyperosmotic medium or the ionophore A23187, to predict IVF outcome.

This study was designed to assess the relationship between IVF outcome and the results obtained with two modified versions of the zona-free hamster oocyte penetration test in which the spermatozoa were pre-incubated with either hyperosmotic medium or the divalent cation ionophore A23187. When the former system was used, a poor correlation with IVF outcome was observed. Samples screened prior to IVF exhibited a 60% false negative rate (failed penetration test, successful IVF), while for those assessed concurrently with IVF, the equivalent figure was 85.7%. Addition of A23187 optimized the penetration system giving higher levels of sperm--oocyte fusion and a more accurate prediction of the capacity of the spermatozoa to fertilize human ova in vitro. With this system the false negative rate was 4.3% for screened samples and 0% for those assessed simultaneously with IVF. These results suggest that the A23187-enhanced system may be of value as a screening criterion for IVF.

Animals↗

Does in vitro fertilization (IVF) influence the levels of sperm and zona pellucida (ZP) antibodies in infertile women?

The levels of sperm and zona pellucida antibodies in 250 women divided into four groups according to number of recurrent IVF failures (1-4) were analysed and compared with results of a control group of 211 unexplained infertile women never treated by IVF. Sperm antibodies in serum and in ovulatory cervical mucus were determined by mixed antiglobulin reaction (MAR) test, serum zona pellucida antibodies were detected using passive haemagglutination and ELISA. These tests showed increased occurrence of zona pellucida antibodies in women after repeated IVF. Zona pellucida antibodies were found in 20% after on unsuccessful IVF (similarly to 27% in the control group), but in 64% after two, in 91% after three and in 4 of 5 cases after four IVF failures. Sperm IgG, A, M, and E antibodies in serum and in ovulatory cervical mucus do not seem to be influenced by IVF procedure. The results show evolution of autoimmune process due to repeated ovarial intervention during oocyte collections. Presence of zona pellucida antibodies, on the other hand, may become a cause of IVF failure.

Adult↗