M. J. Heineman

Perinatal outcome in singletons after modified natural cycle IVF and standard IVF with ovarian stimulation

OBJECTIVE Singletons born after IVF treatment are at risk for adverse pregnancy outcome, the cause of which is unknown. The aim of the present study was to investigate the influence of ovarian stimulation on perinatal outcome. STUDY DESIGN In this single-centre retrospective study, perinatal outcome of singleton pregnancies resulting from IVF treatment with (n=106) and without ovarian stimulation (n=84) were compared. For IVF without ovarian stimulation, a modified natural cycle protocol was used. RESULTS No differences were found in pregnancy duration, proportion of prematurity and proportion of low birth weight. Mean birth weight of modified natural cycle vs standard IVF singletons was 3485 (+/-527) vs 3218 (+/-670)g; P=0.003. After adjustment for prognostic factors by linear regression analysis, the difference in birth weight remaining was 134 g; P=0.045. CONCLUSIONS Birth weights of modified natural cycle IVF singletons found in this study are higher than standard IVF singletons, suggesting that ovarian stimulation may be a causative factor in the occurrence of low birth weight in standard IVF.

Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation

BACKGROUND In modified natural cycle IVF (MNC-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH-antagonist together with gonadotrophins in the late follicular phase only. The MNC-IVF is of interest because of its low-risk and patient-friendly profile. The effect of application of MNC-IVF preceding standard IVF with ovarian stimulation on overall results is unknown. METHODS This single-center cohort study provides follow-up of an earlier study in which nine cycles of MNC-IVF were offered to 268 patients. Ongoing pregnancy rates and live birth rates, as well as time-to-pregnancy after controlled ovarian stimulation-IVF (COS-IVF) following MNC-IVF, were evaluated. RESULTS Actual observed cumulative ongoing pregnancy rates and live birth rates after sequential treatment with MNC-IVF followed by COS-IVF were 51.5 (95% CI: 45.4-57.6) and 50.0% (95% CI: 43.9-56.1) per patient, of which 8.0 and 6.7% were twins. Median time to ongoing pregnancy was 28.8 weeks. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7-62.8). CONCLUSIONS Sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is low. Because of its patient-friendly and low-risk profile, it seems appropriate to perform MNC-IVF preceding COS-IVF.

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

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

The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy

BACKGROUND Due to the growing number of children born following assisted reproduction technology, even subtle changes in the childrens health and development are of importance to society at large. The aim of the present study was to evaluate the specific effects of ovarian hyperstimulation and the in vitro procedure on neurological outcome in 4-18-month-old children. METHODS In this prospective assessor-blinded cohort study, we included singletons born following controlled ovarian hyperstimulation in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) (COH-IVF; n = 68) or modified natural cycle-IVF/ICSI (MNC-IVF; n = 57) or naturally conceived singletons of subfertile couples (NC; n = 90). Children were assessed with standardized, age-specific and sensitive neurological assessments (TINE and Hempel assessment) at 4, 10 and 18 months. Neurological examination resulted in a neurological optimality score (NOS), a fluency score and a clinical neurological classification. Fluency of movements is easily affected by neurological dysfunction and is therefore a sensitive measure for minimal changes in neuromotor development. RESULTS The NOS and the fluency score were similar in COH-IVF, MNC-IVF and NC children. None of the children showed major neurological dysfunction and rates of minor neurological dysfunction at the three ages were not different between the three conception groups. CONCLUSIONS We found no effects of ovarian hyperstimulation or the in vitro procedure itself on neurological outcome in children aged 4-18 months. The findings of our study are reassuring, nevertheless it should be kept in mind that subtle neurodevelopmental disorders may emerge when children grow older. Continuation of follow-up in older and larger groups of children is therefore still needed.

Is the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures

Singletons born after IVF are at risk of adverse pregnancy outcome, the cause of which is unknown. The present study investigated the influence of ovarian stimulation and IVF laboratory procedure on birthweight. Birthweight of singleton pregnancies resulting from IVF treatment with (n=161) and without ovarian stimulation (using a modified natural cycle (MNC) protocol; n=158), and spontaneous conceptions in subfertile patients (n=132) were compared. Mean+/-SD birthweight of singletons after conventional IVF with ovarian stimulation, MNC-IVF and natural conception were 3271+/-655, 3472+/-548 and 3527+/-582 g (P=0.001). After adjustment for biological and social confounders, the difference in birthweight between conventional IVF and MNC-IVF was reduced to 88 g and the differences between conventional IVF and MNC-IVF versus spontaneous conceptions to 123 and 23 g, respectively. The results lead to three conclusions. First, a major part of the crude differences in birthweight between the three groups is related to patient and pregnancy characteristics. Second, the IVF laboratory procedure has no influence on birthweight. Third, although a trend towards lower birthweight after ovarian stimulation was found, an adverse effect of ovarian stimulation on birthweight was not substantiated.

The Groningen ART cohort study: the effects of ovarian hyperstimulation and the IVF laboratory procedures on neurological condition at 2 years

BACKGROUND Up to 4% of children are born following assisted reproduction techniques (ART) yet relatively little is known on neurodevelopmental outcome of these children after 18 months of age. Only a limited number of long-term follow-up studies with adequate methodological quality have been reported. Our aim was to evaluate the effects of ovarian hyperstimulation, IVF laboratory procedures and a history of subfertility on neurological condition at 2 years. METHODS Singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 66), modified natural cycle IVF (MNC-IVF, n = 56), natural conception in subfertile couples (Sub-NC, n = 87) and in fertile couples (reference group, n = 101) were assessed (using Hempel approach) by neurological examination at 2 years of age. This resulted in a neurological optimality score (NOS), a fluency score and the prevalence of minor neurological dysfunction (MND). Primary outcome was the fluency score, as fluency of movements is easily affected by subtle dysfunction of the nervous system. RESULTS Fluency score, NOS and prevalence of MND were similar in COH-IVF, MNC-IVF and Sub-NC children. However, the fluency score (P < 0.01) and NOS (P < 0.001) of the three subfertile groups were higher, and the prevalence of MND was lower (P = 0.045), than those in the reference group. CONCLUSIONS Neurological condition of 2 year olds born after ART is similar to that of children of subfertile couples conceived naturally. Moreover, subfertility does not seem to be associated with a worse neurological outcome. These findings are reassuring, but we have to keep in mind that subtle neurodevelopmental disorders may emerge as children grow older.

Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization

OBJECTIVE To study the implantation potential of unselected embryos derived from modified natural cycle IVF according to their morphological characteristics. DESIGN Cohort study. SETTING Academic department of reproductive medicine. PATIENT(S) A series of 449 single embryo transfers derived from modified natural cycle IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Ongoing implantation rate according to embryo characteristics. RESULT(S) The best implantation was found in embryos with 4 and 8 cells on day 2 and 3 respectively, <or=10% fragmentation, and absence of multinucleated blastomeres. In contrast to findings from other studies, we found embryos with fewer than four blastomeres on day 2 to do relatively well. Furthermore, we found the implantation potential of embryos containing multinucleated blastomeres to be less severely impaired than expected. CONCLUSION(S) Findings from this study suggest that in currently used embryo scoring systems, the implantation potential of embryos with low numbers of blastomeres on day 2, as well as embryos containing multinucleated blastomeres, is underestimated. However, it is unclear whether the results of our study apply to embryos derived from controlled ovarian hyperstimulation cycles.

The predictive value of ovarian reserve tests for miscarriage in a population of subfertile ovulatory women

BACKGROUND The increase in miscarriage rate with female age is attributed to a decline in oocyte quality. This age-related decrease of oocyte quality is accompanied by a decrease in oocyte quantity. Assessment of the number of oocytes by ovarian reserve tests (ORTs) may therefore also represent their quality. The objective of our study was to assess the predictive value of ORTs for miscarriage in subfertile women. METHODS This study was a subanalysis within a prospective cohort study of 474 subfertile ovulatory couples in two hospitals in Groningen, The Netherlands. The ORTs performed were: antral follicle count (AFC), basal and stimulated levels of follicle-stimulating hormone (FSH) and inhibin B, and the clomiphene citrate challenge test (CCCT). Women who achieved an ongoing pregnancy (n = 233) were compared with women experiencing miscarriage (n = 72) on the results of their ORTs and patient characteristics. RESULTS In univariate analysis, the outcome of the ORTs did not differ between the groups. Logistic regression analysis including patient characteristics such as female age did not reveal an association between the ORT results and miscarriage either. CONCLUSIONS Neither AFC, basal and stimulated levels of FSH and inhibin B, nor the CCCT have a statistically significant predictive value for miscarriage in subfertile ovulatory women.

The Groningen assisted reproductive technologies cohort study: developmental status and behavior at 2 years

OBJECTIVE To evaluate whether childrens cognitive and psychomotor development and behavior at 2 years are affected by ovarian hyperstimulation and the IVF laboratory procedures or subfertility. DESIGN Prospective longitudinal cohort study. SETTING University Medical Center Groningen, the Netherlands. PATIENT(S) Singletons born after controlled ovarian hyperstimulation (COH)-IVF (n=66) and modified natural cycle-IVF (n=56), singletons born to subfertile couples who conceived naturally (subfertile-naturally conceived, n=87), and a reference group of 101 2-year-old singletons born to fertile couples. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Bayley Scales of Infant Development and Achenbach Child Behavior Checklist. RESULT(S) Mental and psychomotor development and behavioral outcome in COH-IVF, modified natural cycle-IVF, and subfertile-natural cycle groups was not different. Developmental outcome and behavior of the subfertile groups were largely similar to those of the fertile reference group. Nevertheless, the subfertile groups scored higher on the scale of anxious-depressed behavior than the reference group. CONCLUSION(S) This present relatively small study found no differences in cognitive and psychomotor development and behavior at 2 years in children born after COH-IVF or modified natural cycle-IVF or naturally conceived children of subfertile parents. Replication of the study is needed before firm conclusions can be drawn. Furthermore, long-term follow-up is needed to confirm these findings in older children.