Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian hyperstimulation?

Leiden University, Leyden, South Holland, Netherlands
Human Reproduction (Impact Factor: 4.57). 12/2006; 21(12):3228-34. DOI: 10.1093/humrep/del311
Source: PubMed


The primary objective of this study was to investigate whether subfertility explains poor perinatal outcome after assisted conception. A secondary objective was to test the hypothesis that ovarian hyperstimulation rather than the IVF procedure may influence the perinatal outcome.
Using data from a Dutch population-based historical cohort of women treated for subfertility, we compared perinatal outcome of singletons conceived after controlled ovarian hyperstimulation (COHS) and IVF (IVF + COHS; n = 2239) with perinatal outcome in subfertile women who conceived spontaneously (subfertile controls; n = 6343) and in women who only received COHS (COHS only; n = 84). Furthermore, we compared perinatal outcome of singletons conceived after the transfer of thawed embryos with (Stim + Cryo; n = 66) and without COHS (Stim - Cryo; n = 73).
The odds ratios (ORs) for very low birthweight (<1500 g) and low birthweight (1500-2500 g) were 2.8 [95% confidence interval (95% CI) 1.9-3.9] and 1.6 (95% CI 1.2-1.8) in the IVF + COHS group compared with the subfertile control group. The ORs for very preterm birth (<32 weeks) and for preterm birth (32-37 weeks) were 2.0 (95% CI 1.4-2.9) and 1.5 (95% CI 1.3-1.8), respectively. Adjustment for confounders did not materially change these risk estimates. The difference in risk between the COHS-only group and the subfertile group was significant only for very low birthweight (OR 3.5; 95% CI 1.1-11.4), but the association became weaker after adjustment for maternal age and primiparity (OR 3.1; 95% CI 1.0-10.4). No significant difference in birthweight and preterm delivery was found between the group of children conceived after ovarian stimulation/ovulation induction and (Stim + Cryo) and the group of children conceived after embryo transfer of thawed embryos in a spontaneous cycle without ovarian stimulation/ovulation induction (Stim - Cryo).
The poor perinatal outcome in this database could not be explained by subfertility and suggests that other factors may be important in the known association between assisted conception and poor perinatal outcome.

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    • "The etiology of these complications is likely diverse: the infertile population could be predisposed to diseases (Draper et al., 1999; Bahceci et al., 2005; Kapiteijn et al., 2006); epigenetic dysregulation, or altered placentation following in vitro culture are additional possibilities . Given the key role of the placenta throughout pregnancy, and the evidence of placental abnormalities in ART pregnancies, we hypothesized that ART may lead to suboptimal placentation that may cause impaired embryo development. "
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    ABSTRACT: Abnormal placentation is a potential mechanism to explain the increased incidence of low birthweight observed after IVF. This study evaluates, in a mouse model, whether the method of conception and embryo transfer affect placentation and fetal development. IVF blastocysts (CF1 x B6D2F1/J) were cultured in Whitten's medium (IVF(WM), n = 55) or K modified simplex optimized medium with amino acids (IVF(KAA), n = 56). Embryos were transferred to the uteri of pseudo-pregnant recipients. Two control groups were created: unmanipulated embryos produced by natural mating (in vivo group, n = 64) and embryos produced by natural mating that were flushed from uterus and immediately transferred to pseudo-pregnant recipients (flushed blastocysts, FB group, n = 57). At gestation age 12.5 days, implantation sites were collected and fixed; fetuses and placentas were weighed and their developmental stage (DS) evaluated. Placental areas and vascular volume fractions were calculated; parametric statistics were applied as appropriate. IVF fetuses showed a modest but significant delay in development compared with FB mice (P < 0.05). In addition, IVF conceptuses were consistently smaller than FB (P < 0.05). Importantly, these differences persisted when analyzing fetuses of similar DS. The placenta/fetus ratio was larger in the IVF group (IVF(WM) 0.95; IVF(KAA) = 0.90) than the FB group (0.72) (P < 0.05 for all comparisons). Gross morphology of the placenta and ratio labyrinth/fetal area were equivalent in the IVF and FB groups, as were percentage of fetal blood vessels, maternal blood spaces and trophoblastic components. In vitro embryo culture affects fetal and placental development; this could explain the lower birthweight in IVF offspring.
    Human Reproduction 08/2010; 25(8):2039-46. DOI:10.1093/humrep/deq165 · 4.57 Impact Factor
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    • "Potential IVF/ICSI associated adverse pregnancy outcomes that have been reported in previous studies include multiple births, birth defects, low birth weight, preterm birth, fetal growth restriction, maternal complications, and neonatal morbidity [5– 18]. However, except for multiple births, studies on the associations of IVF/ICSI with other adverse pregnancy outcomes have so far yielded inconsistent results [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]. Differences in study population and methodology are the main reasons for the inconsistent findings. "
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    ABSTRACT: To assess the association between in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) and adverse birth outcomes. Retrospective cohort study involved IVF/ICSI patients who were treated in the Ottawa Fertility Centre from 1996 to 2005 with a viable pregnancy (>20 weeks of gestation) and mothers who conceived naturally. Eleven of the 1044 infants conceived with IVF/ICSI (1.1%) and 7 of the 1910 naturally conceived infants (0.4%) had congenital heart defects (P<0.01). Five of the 138 infants (3.6%) born to mothers with a body mass index>30 and conceived by IVF/ICSI had congenital heart defects, compared with none in the 240 infants born to mothers with a body mass index>30 and conceived naturally (P<0.01). Infants conceived with use of IVF/ICSI have three times as high a risk of a congenital heart defect as naturally conceived infants.
    European journal of obstetrics, gynecology, and reproductive biology 03/2010; 150(2):160-5. DOI:10.1016/j.ejogrb.2010.02.028 · 1.70 Impact Factor
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    • "In order to determine the details of adverse birth events in children conceived by ART, the majority of studies mentioned above consulted national or regional registries (Wennerholm et al. 1997, Kallen et al. 2005a, 2005b, Wang et al. 2005, Griesinger et al. 2008, Jacod et al. 2008). The studies by Kapiteijn et al. (2006) and Reefhuis et al. (2009) were predominantly based on interviews of mothers, who were asked to recall information regarding the preconceptional and pregnancy periods (method of conception, ethnicity, parity, duration of gestation, birth weight, etc). This method of data collection can lead to significant biases, and therefore extrapolations based in this kind of analysis have to be moderate. "
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    ABSTRACT: The use of assisted reproductive technologies (ART) has been increasing over the past three decades, and, in developed countries, ART account for 1-3% of annual births. In an attempt to compensate for inefficiencies in IVF procedures, patients undergo ovarian stimulation using high doses of exogenous gonadotrophins to allow retrieval of multiple oocytes in a single cycle. Although ovarian stimulation has an important role in ART, it may also have detrimental effects on oogenesis, embryo quality, endometrial receptivity and perinatal outcomes. In this review, we consider the evidence for these effects and address possible underlying mechanisms. We conclude that such mechanisms are still poorly understood, and further knowledge is needed in order to increase the safety of ovarian stimulation and to reduce potential effects on embryo development and implantation, which will ultimately be translated into increased pregnancy rates and healthy offspring.
    Reproduction 09/2009; 139(1):23-34. DOI:10.1530/REP-09-0187 · 3.17 Impact Factor
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