Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTION: Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER: Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY: Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS: Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE: The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228-338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84-117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with 'male factor' as treatment indication (compared to 'tubal factor'). LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS: Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.

[Can I still get pregnant? Options for fertility preservation in young women diagnosed with cancer]. / Kan ik nog zwanger worden?

- In 2015 around 2300 women under the age of 40 years were diagnosed with cancer in the Netherlands.- Cancer treatment can have a negative effect on fertility.- Due to improving survival rates, discussing this effect and the options for fertility preservation has become an important part of counselling these patients.- Cryopreservation of oocytes and embryos is standard procedure in fertility preservation in the Netherlands.- Cryopreservation of ovarian tissue is a new, rapidly-developing technique. Recently, the first child following autotransplantation of thawed ovarian tissue was born in the Netherlands.- If gonadotoxic treatment has to be given, it is important to talk well in advance with the patient about fertility preservation.

The immunomodulating effect of seminal plasma on T cells.

Seminal plasma (SP) contains immunomodulatory factors that may contribute to the formation of a tolerogenic environment at the embryo implantation site. The main focus of this study was to investigate the influence of SP on female T cells in the presence and absence of antigen-presenting cells (APCs) in an in vitro model. Female PBMCs and T cells were incubated with SP from seminal fluid samples of known and variable sperm quality. The immediate effect of SP on the mRNA expression of CD25, IL-10, IFN-γ, and Foxp3 was measured. Furthermore, proliferative responses, cytokine production, and CD25 expression were determined. Exposure to SP leads to increased mRNA expression of CD25, IL-10, and Foxp3 in T cells. Induction of mRNA for IL-10 and CD25 was dependent on the presence of APCs. Both PBMCs and T cells exposed to SP showed a proliferative response and produced several cytokines. The proliferative effects of SP on T cells observed were independent of sperm quality parameters, cytokines or soluble HLA molecules in SP. Furthermore, the presence of SP induced a higher expression of CD25 on the membrane of CD4+ T cells. SP has a direct immunomodulatory effect on T cells, as reflected in a proliferative response and upregulation of Foxp3. The presence of APCs is needed to induce IL-10 and CD25 upregulation in T cells exposed to SP. In conclusion, SP has both a direct and an indirect effect mediated through APCs on T cells.

Maternal HLA-C2 and 14 bp insertion in HLA-G is associated with recurrent implantation failure after in vitro fertilization treatment.

The major rate-limiting step in in vitro fertilization (IVF) success appears to be the implantation of the semi-allogeneic embryo into the maternal endometrium. To determine possible risk factors of recurrent failure of embryos to implant, we investigated immunogenetic determinants as level of human leukocyte antigen (HLA) histocompatibility, frequency of killer-cell immunoglobulin-like receptors (KIR) and HLA-C alleles and HLA-G polymorphism. We DNA typed women with recurrent implantation failure (RIF) and their partners for classical HLA Class I, HLA Class II, HLA-G and KIR alleles and compared these results with couples with successful embryo implantation after their first IVF and normal fertile couples. No association was found between RIF and the degree of histocompatibility between partners or sharing of a specific antigen. Also, no significant difference in KIR haplotype or combination of HLA-C group and KIR was observed. We did find a higher frequency of HLA-C2 and a higher frequency of 14 base pair (bp) insertion in HLA-G in women with RIF. Therefore we conclude that the degree of histocompatibility between partners is not a determining factor for the occurrence of RIF. However, presence of the HLA-C2 allotype and the HLA-G allele with a 14 bp insertion is a significant risk factor.

Matched follow-up study of 5 8-year-old ICSI singletons: child behaviour, parenting stress and child (health-related) quality of life.

BACKGROUND: Psychosocial follow-up of ICSI children is scarce. We compared child behaviour, parenting stress and quality of life for singletons aged 5-8 years born after ICSI, IVF and natural conception (NC). METHODS: All singletons born between June 1996 and December 1999 after ICSI in the Leiden University Medical Center were invited (n = 110). Matched singletons born after IVF and NC were recruited. Parents completed the Child Behaviour Checklist (measures problem behaviour), the Parenting Stress Index (Nijmeegse Ouderlijke Stress Index) and two quality of life questionnaires (Dux25 and TACQOL). Children completed the Dux25 Child form. RESULTS: Eighty-seven ICSI children (79%), 92 IVF children (73%) and 85 NC children enrolled. Prevalence of behavioural disorders-as reported by the parents-was comparable in the three groups. Three of 87 ICSI children had autism or an autistic spectrum disorder (ASD). Problem behaviour scores were similar for ICSI and NC children; IVF children (mainly girls) scored less problem behaviour (P < 0.05) and their scores were less often in the (borderline) clinical range. Parenting stress was similar for ICSI and IVF, but lower for NC than ICSI parents, mainly on the child scale. Quality of life scores were similar in the three conception groups. CONCLUSIONS: Prevalence of autism/ASD seemed higher after ICSI, but this unexpected finding should be confirmed by future studies with larger group sizes. ICSI parents experienced more stress than NC parents, although selection bias cannot be ruled out. The majority of ICSI singletons assessed at age 5-8 years showed a normal psychosocial well-being.