IVF Singletons Research Articles

In Vitro fertilization and adverse obstetric and perinatal outcomes

Most IVF-conceived children are healthy, but IVF has also been associated with adverse obstetric and perinatal outcomes as well as congenital anomalies. There is also literature suggesting an association between IVF and neurodevelopmental disorders as well as potentially long-term metabolic outcomes. The main driver for adverse outcomes is the higher risk of multiple gestations in IVF, but as the field moves toward single embryo transfer, the rate of multiple gestations is decreasing. Studies have shown that singleton IVF pregnancies still have a higher incidence of adverse outcomes compared to unassisted singleton pregnancies. Infertility itself may be an independent risk factor. Animal models suggest that epigenetic changes in genes involved in growth and development are altered in IVF during the hormonal stimulation and embryo culture. Further animal research and prospective human data are needed to elucidate the mechanisms by which IVF may contribute to adverse outcomes and to decrease risks.

Do Early Fetal Measurements and Nuchal Translucency Correlate With Term Birth Weight?

Traditionally, physiological variation in fetal weight is believed to emerge during the latter half of pregnancy. Although recent evidence suggests that crown-rump length (CRL) and nuchal translucency (NT) measured at 11-14 weeks correlate with abnormal fetal growth, findings have been limited by dating accuracy in spontaneous gestations. Therefore, we sought to determine whether CRL or NT measurements correlated with term birth weight (BW) or BW ratio in a cohort of IVF pregnancies, in which the date of conception is precisely known. This retrospective cohort study included 227 term, singleton IVF pregnancies. Subjects were included if they had an early first-trimester ultrasound examination and subsequent nuchal translucency (NT) screening. The difference between the measured and the expected CRL and the biparietal diameter (BPD) and NT measurement were calculated and correlated with the actual term BW or BW ratio. The BW ratio was calculated using the actual BW and the expected BW for GA. The difference between measured and expected mid-first-trimester CRL, and the BPD at NT assessment, correlated with BW ratio at delivery (rSpearman= 0.15, P= 0.023 and rSpearman= 0.27, P< 0.001, respectively). Absolute NT measurements and NT percentiles (adjusted for CRL) correlated with BW ratio at delivery (rSpearman= 0.18, r= 0.14, and P= 0.005 and 0.038, respectively). In this well-dated IVF population, we report a significant correlation between BW ratio and first-trimester CRL, BPD, and NT measurements. These findings support the hypothesis that physiological variation in BW can be reflected by variation in first-trimester fetal measurements.

Paternal and maternal urinary phthalate metabolite concentrations and birth weight of singletons conceived by subfertile couples

BackgroundPrenatal phthalate exposure has been inconsistently associated with fetal growth and infant birth weight. However, the effect of exposure during the paternal and maternal preconception period remains understudied. ObjectivesTo investigate associations of paternal and maternal preconception and maternal prenatal urinary phthalate metabolite concentrations with birth weight. MethodsThe study comprised 364 singletons born to 364 mothers and 195 fathers (195 couples) from the EARTH Study, a prospective cohort of couples from Boston, MA. Births were categorized by mode of conception: in-vitro fertilization based (IVF) (n=208) or non-IVF based (n=156, intrauterine insemination or non-medically assisted/natural conception). We measured urinary concentrations of eleven phthalate metabolites in maternal (n=1425) and paternal (n=489) preconception and maternal prenatal (n=781) samples. Birth weight was abstracted from delivery records. Covariate-adjusted associations between loge-phthalate metabolite concentrations and birth weight were evaluated separately by mode of conception using multivariable linear regression. ResultsEach loge-unit increase in paternal urinary concentration of the sum of di(2-ethylhexyl) phthalate (ΣDEHP) metabolites was associated with a 90 gram (95% CI: −165, −15) decrease in birth weight among IVF singletons, but not among non-IVF singletons (18g; 95% CI: −76, 113). Additional adjustment for maternal prenatal ΣDEHP concentrations modestly strengthened findings among IVF singletons. While few associations were found with maternal preconception phthalate metabolites, we observed an inverse relationship between several maternal prenatal urinary phthalate metabolite concentrations and birth weight among IVF singletons in covariate-adjusted models. However, with further adjustment for specific paternal phthalate metabolite concentrations, these associations were attenuated and no longer significant. ConclusionsPaternal preconception urinary concentration of ΣDEHP metabolites was associated with a decrease in birth weight among IVF-conceived singletons. These results, if replicated, highlight the importance of preconception health, especially among subfertile couples.

High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births

A higher risk of pregnancy complications occurs after assisted reproductive techniques compared with spontaneously conceived pregnancies. This is attributed to the underlying infertility and assisted reproduction technique procedures involved during treatment. It is a matter of interest whether use of donor oocytes affects perinatal outcomes compared with pregnancies after autologous IVF. Anonymized data were obtained from the Human Fertilization and Embryology Authority. The analysis included 5929 oocyte donation and 127,856 autologous IVF live births. Data from all women who underwent donor oocyte recipient or autologous IVF cycles, both followed with fresh embryo transfer, were analysed to compare perinatal outcomes of preterm birth (PTB) and low birthweight (LBW) after singleton and multiple live births. The risk of adverse perinatal outcomes after oocyte donation was increased: adjusted OR (aOR) 1.56, 99.5% CI 1.34 to 1.80 for PTB and aOR 1.43, 99.5% CI 1.24 to 1.66 for LBW were significantly higher after oocyte donation compared with autologous IVF singletons. The adjusted odds PTB (aOR 1.21, 99.5% CI 1.02 to 1.43) was significantly higher after oocyte donation compared with autologous IVF multiple births. Analysis of this large dataset suggests significantly higher risk of PTB and LBW after ooctye donation compared with autologous IVF pregnancies.

Supraphysiologic estradiol is an independent predictor of low birth weight in full-term singletons born after fresh embryo transfer.

Is supraphysiologic estradiol (E2) an independent predictor of low birth weight (LBW) in singletons born after fresh IVF-embryo transfer (ET) cycles? Our results suggest that E2 > 2500 pg/ml is an independent predictor for LBW in full-term singletons born to normal responder patients undergoing fresh IVF-ET cycles. The pathogenesis of LBW in IVF singletons remains unknown. However, recent studies have suggested that the hyperestrogenic milieu generated during ovarian stimulation may create a sub-optimal peri-implantation environment, leading to placental dysfunction, and therefore, LBW. Retrospective cohort study of normal responder patients, <40 years old, undergoing fresh IVF-ET cycles resulting in live singleton births between January 2005 and June 2014. A total of 6419 patients had live births after fresh IVF-ET during the study period,of which 2348 (36.6%) patients were excluded due to multiple gestation, vanishing twins or incomplete records. Perinatal outcomes recorded for all patients included birth weight, gestational age (GA) at delivery, mode of delivery and gender. Term birth, preterm birth (PTB) and LBW incidence proportions were plotted against E2 level on the day of trigger. The term LBW incidence proportion (i.e. singletons born at GA ≥ 37 weeks with birth weight <2500 g) was considered the primary outcome of interest. A total of 4071 patients with live singleton births were included. The median age, BMI, E2 level and birth weight for the study cohort was 36 (33-39) years, 22.3 (20.4-25.0) kg/m2, 1554 (1112.7-2179) pg/ml and 3289 (2920-3628) g, respectively. The incidence proportion of LBW rose from 6.4% (E2 2001-2500 pg/ml) to 20.7% (E2 3501-4000 pg/ml), without a corresponding rise in the incidence proportion of PTB. The odds of term LBW with E2 > 2500 pg/ml were 6.1-7.9 times higher compared to the referent E2 group. Multivariable logistic regression analysis revealed that E2 was an independent predictor for term LBW, even after adjusting for age, BMI, race, parity, infertility diagnosis, duration of ovarian stimulation, gonadotropin dosage and method of insemination (adjusted odds ratio 10.8, 95% CI 9.2-12.5). Receiver operating characteristic analysis generated an AUC estimate of 0.85 for E2 level as a predictor of LBW. The current study did not include analyses of hypertensive disorders of pregnancy or placental abnormalities. Furthermore, all patients were normal responders and of normal BMI, possibly limiting the overall generalizability of the study. Finally, as with any retrospective study, prospective data are required to validate the role of E2 in predicting LBW. Our results emphasize the importance of minimizing the supraphysiologic elevations of E2 levels during ovarian stimulation in fresh IVF-ET cycles. This, in turn, can optimize the early peri-implantation environment and mitigate adverse perinatal outcomes such as LBW. Dr Paul J. Christos was partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06). N/A.

Neurodevelopmental and cardiometabolic outcome in 4-year-old twins and singletons born after IVF

This prospective cohort study evaluated whether the cognitive development, neurological condition, anthropometrics and blood pressure of 4-year-old IVF twins differed from those of 4-year-old IVF singletons; 103 IVF singletons and 48 IVF twins born after conventional IVF treatment were included. Primary outcome was total intelligence quotient (IQ). Secondary outcomes were minor neurological dysfunction, anthropometrics and blood pressure. Unadjusted analyses found that the total IQ score of twins was lower than that of singletons, with a mean difference of −5.4 (–9.7 to −1.0). Weight (singletons: 18.6 [18.1 to 19.1] kg; twins: 16.9 [16.0 to 17.9] kg) and height (singletons: 108.8 [107.9 to 109.8] cm; twins: 105.9 [104.0 to 107.7] cm) of twins were lower than those of singletons (mean values [95% CI]). All differences disappeared after adjusting for mediators and confounders. Neurological outcome, systolic and diastolic blood pressure of twins and singletons were similar. Four-year-old IVF twins had a lower total IQ (−5.4 points), lowerbodyweight (−1.7 kg) and were shorter (−2.9 cm) than 4-year-old IVF singletons. After adjustment, the adverse twin effect disappeared, implying that increased risk for impaired health and development in twins also holds true for IVF twins, and is not altered by IVF.

Prediction of fetal loss by first-trimester crown-rump length in IVF pregnancies.

To evaluate the association between small crown-rump length (CRL) and fetal loss ≤22weeks in IVF pregnancies. A retrospective analysis of prospectively collected data at a university-affiliated medical center. All singleton IVF pregnancies within a 5-year period, with a live embryo on first-trimester ultrasound and verified pregnancy outcome were included. Rates of fetal loss ≤22weeks were compared between pregnancies with a CRL ≤tenth percentile and above the tenth percentile of our population. Overall, 397 pregnancies met inclusion criteria. Ninety-five percent of CRL measurements were performed at 40-80 gestational days. All live-embryo's CRL measurements, from 40 to 80mm, were plotted against expected gestational age (in 5-day clusters), with calculation of the tenth percentile for every gestational age. Total of 64 pregnancies had CRL ≤tenth percentile for gestational age. The rate of fetal loss in this group was significantly higher than in pregnancies with CRL >tenth percentile (17.2 vs. 6.6%, p=0.005, OR=2.93, 95% CI 1.2-6.7). In both groups, the majority of fetal losses occurred ≤10weeks of gestation. In IVF pregnancies with a live embryo, a small CRL at 40-80days' gestation may predict fetal loss. Repeated ultrasound should be considered after 1-2weeks.

Twins conceived using IVF: a follow-up of the family environment and psychosocial adjustment in adolescence.

Compared to families with IVF singletons, what are parental depressive, parent-adolescent interaction and adolescent adjustment outcomes in families with 11-17-year-old IVF twins? No differences were detected for any measured outcome between families with 11-17-year-old IVF twins and those with IVF singletons, despite high statistical power. When IVF twins are younger than 5-years-old, parents tend to have more mental health difficulties and poorer parent-child interactions relative to IVF singletons. By middle childhood, these differences may no longer exist and available studies with middle childhood-aged IVF twins challenge the expected long-term implications of the early concerns. IVF twins may even have more optimum adjustment than IVF singletons in middle childhood. Study of 280, 11-17-year-old IVF children (n=122 twins and n=158 singletons) from 195 families at a US reproductive endocrinology clinic. At Wave 1, clinic patients with an IVF child born between 1998 and 2004 were invited to participate in an online survey. In this follow-up study, mothers and fathers provided information on each of their 11-17-year-old IVF adolescents. There were no differences between 11- and 17-year-old IVF twins and IVF singletons in parent depressive symptoms, parent-adolescent interactions or adolescent adjustment outcomes. Although the family demographics are representative ofIVF patients, participants were drawn from one US clinic. Study results provide reassurance that by adolescence IVF twins and their families function as well as IVF singletons and their families. University of Minnesota (UMN) Agriculture Experiment Station (MN-52-107), UMN Grant-in-Aid of Research, Artistry and Scholarship, UMN College of Education and Human Development Research Development Investment Grant, UMN Women's Philosophic Leadership Circle Award, UMN Eva Miller Endowed Fellowship. The authors have no conflicts of interest to declare.

Pregnancy outcome in women with endometriosis achieving pregnancy with IVF.

Are women with endometriosis who conceive with IVF at increased risk of preterm birth? Women with endometriosis who conceive with IVF do not face an increased risk of preterm birth. The eutopic endometrium of women with endometriosis has been repeatedly shown to present molecular and cellular alterations. On this basis, it has been hypothesized that pregnancy outcome may be altered in affected women. However, to date, available evidence from epidemiological studies is scanty and conflicting. Data tended to be partly consistent only for an increased risk of preterm birth and placenta previa. Retrospective matched case-control study of women achieving an IVF singleton pregnancy progressing beyond 12 weeks' gestation. Women achieving IVF singleton pregnancies that progressed beyond 12 weeks' gestation at two infertility units were reviewed. Cases were women with a history of surgery for endometriosis and/or with a sonographic diagnosis of the disease at the time of the IVF cycle. Controls were women without current or past evidence of endometriosis who were matched to cases by age (±6 months), type of cycle (fresh or frozen cycle) and study period. Male factor and unexplained infertility were the most common diagnoses in the control group. Two hundred and thirty-nine women with endometriosis and 239 controls were selected. The main outcome of the study was the rate of preterm birth (birth<37 weeks' gestation) regardless of the cause. Secondary analyses were performed for the most common obstetrical complications. The rate of preterm birth was similar in the two study groups (14% and 14%, respectively, p=0.89). The rate of live birth and the incidence of hypertensive disorders, gestational diabetes, small and large for gestational age newborns and neonatal problems also did not differ. In contrast, placenta previa was more common in women with endometriosis than controls (6% versus 1%, respectively; p=0.006): The adjusted odds ratio was 4.8 (95% confidence interval: 1.4-17.2). As for all observational studies, confounders cannot be totally excluded. Moreover, the retrospective study design exposes the findings to some inaccuracies. For example, the independent role of adenomyosis could not be reliably assessed because this diagnosis is complex and would necessitate a prospective recruitment. Second, the selection of controls may also be a matter of concern because some affected women may have been erroneously included in this group. Third, even if the sample size is significant, it is insufficient for robust subgroup analyses. Finally, it is mandatory to point out that our conclusions are valid for IVF pregnancies only, and specific data from properly designed studies are required to support any inference for natural pregnancies. The results of our study suggest that women with endometriosis conceiving with IVF can be reassured regarding the risk of preterm birth. The observed association with placenta previa requires further investigation and may open a new avenue of research. No external funding was used for this study. None of the authors have any conflict of interest to declare.

Maternal and paternal preconception phthalate exposure and birthweight of IVF singletons

Maternal and paternal preconception phthalate exposure and birthweight of IVF singletons

How does ART singletons differ from naturally conceived (NC) singletons; comparison of perinatal data of 872 ART to 19317 (NC) singleton babies

It has been suggested that the fresh transfer of single embryo following ovarian stimulation is associated with smaller birth weight than naturally conceived singleton for a similar gestational age. Perinatal outcomes from a large Danish database (Henningsen A. et al, March 2011) showed that the birth weight of stimulated IVF singleton babies is significantly smaller than naturally conceived ones. There is limited data on the birth weight and the average gestational age at birth of modified natural in vitro-fertilization (mnIVF) conceived babies.

No change in live birthweight of IVF singleton deliveries over an 18-year period despite significant clinical and laboratory changes.

Has live birthweight changed over 18 years of autologous fresh and frozen IVF? Regardless of changes in clinical care and laboratory practice over 18 years, birthweight has remained stable. Birthweight has historically been used as a marker of neonatal health. Frozen embryo transfers lead to heavier live birthweights compared with fresh embryo transfers. This retrospective cohort study included 7295 singletons from autologous fresh (n = 6265) and frozen (n = 1030) IVF cycles from 1996 to 2013. All patients undergoing autologous IVF cycles between 1996 and 2013 resulting in a singleton live born with a birthweight recorded were included. One-way ANOVA and t-tests compared mean live birthweight in fresh and frozen cycles in 6-month increments over 18 years. Linear regression analysis was performed to investigate predictors of birthweight. Mean birthweight after fresh (3283 ± 601 g) and frozen (3462 ± 621 g) cycles were significantly different (P < 0.001). ANOVA demonstrated no significant difference in mean weight from fresh or frozen cycles over 6-month intervals. No difference in weight was noted between Days 3 and 5 transfers or between ICSI and standard IVF. No difference was found across known changes when comparing media, laboratory location, cryopreservation method or gonadotrophins. Limitations include the small number of frozen low birthweight neonates. Our study suggests that changes in IVF practice, with the exception of fresh or frozen embryo transfer, have little impact on mean live birthweight. No funding was received for this study. The authors have no conflicting interests. Not applicable.

Association of the very early rise of human chorionic gonadotropin with adverse outcomes in singleton pregnancies after in vitro fertilization

To determine if very early serum hCG, a marker of trophoblast differentiation, is associated with adverse perinatal outcomes in singleton pregnancies. Retrospective cohort study. University fertility program. A total of 360 singleton IVF live births. Serial hCG measurements were used to determine the within-woman slope for hCG (hCG rise). Primary outcomes included birth weight and gestational age at delivery. Statistical comparisons used t test, chi-square test, and linear and logistic regressions as appropriate. hCG rise was positively associated with birth weight but not gestational age at delivery. Infant sex, gestational age, and type of embryo transfer (fresh vs. frozen/thawed) were significantly associated with birth weight and confounded the associations of interest. hCG rise was slower among subjects delivering an infant with low birth weight (slope 0.386 ± 0.05 vs. 0.407 ± 0.06) or small for gestational age (slope 0.371 ± 0.07 vs. 0.406 ± 0.06). Analysis of hCG rise by quartile showed that, compared with the first quartile (slowest), subjects with a rate of hCG rise in the fourth quartile (fastest) had a significantly decreased risk of delivering an infant of low birth weight. No relationship was noted between hCG rise and hypertensive disorders of pregnancy. Slower very early first-trimester hCG rise is associated with low birth weight but not gestational age at delivery among singleton IVF conceptions. The rate of increase in serum hCG may reflect early trophoblast differentiation and placentation and, possibly, may predict subsequent development.

Do We Pay Enough Attention to Culture Conditions in Context of Perinatal Outcome after In Vitro Fertilization? Up-to-Date Literature Review.

Adverse perinatal outcomes in singleton IVF pregnancies have been most often explained by parental underlying diseases and so far laboratory conditions during embryo culture are still not explored well. The following review discusses the current state of knowledge on the influence of IVF laboratory procedures on the possible perinatal outcome. The role of improved media for human embryo culture is unquestionable. Addition of certain components to culture media and their effect on embryo survival and implantation rates have been taken into consideration recently and studied on animal model. Impact of media on perinatal outcome in IVF offspring has also been studied. It has been discovered that epigenetic changes and neonatal birth weight are probably associated with the use of specific culture media, as is the relation between placental size and its influence on perinatal outcome. There are still questions in the discussion about duration of embryo culture (cleavage stage versus blastocyst transfer). Some of the IVF methods, such as in vitro maturation of oocytes and freezing/thawing procedures, also require well-powered randomized controlled trials in order to define their exact impact on perinatal outcome. Constant further research is needed to assess the impact of laboratory environment on fetal and postnatal development.

Early fetal growth in progesterone-treated IVF pregnancies.

The aim of this study was to compare fetal growth in the first and second trimesters of pregnancy and final birth weights between two groups of women: (a) spontaneous conceptions with reliable menstrual dates and (b) IVF pregnancies on progesterone supplementation during the first trimester. We included in the study 73 singleton IVF pregnancies and 138 singleton spontaneous pregnancies. Exclusion criteria were: medications or presence of medical conditions affecting fetal growth. Fetal crown-rump length (CRL) at 10+1 to 13+6weeks of gestation, and head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL) at 18-24weeks, were measured prospectively. The birth weights of the babies born were collected and compared. Independent sample t test was applied for comparing quantitative variables with normal distribution, and Wilcoxon-Mann-Whitney test was used for comparison of quantitative variables without normal distribution. IVF fetuses on progesterone supplementation had larger CRL measurements when compared to their counterparts from spontaneous pregnancies (p value=0.045). Similarly, in the second trimester, the BPD was significantly larger but HC, AC and FL, although larger, did not reach statistical significance. The birthweights of babies between the two groups showed no statistically significant difference, although some IVF babies were born prematurely. Enhanced fetal growth during the first trimester has been observed with progesterone supplementation in IVF pregnancies. Aspects of enhanced fetal growth were observed in the second trimester but not at birth. The effect of progesterone supplementation on fetal growth needs further investigation.

Perinatal outcomes among IVF singletons are reassuring after comprehensive chromosomal screening and frozen blastocyst transfer

Perinatal outcomes among IVF singletons are reassuring after comprehensive chromosomal screening and frozen blastocyst transfer

Birth weight in IVF singleton births is not associated with blastocyst quality

Birth weight in IVF singleton births is not associated with blastocyst quality

The effect of mode of conception on obstetrical outcomes differs by body mass index

This study compared the odds of adverse obstetrical outcomes of pregnancies in women who conceived from IVF (n = 464) versus spontaneous conception (n = 1171) after stratification into three body mass index (BMI) groups: normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (>30 kg/m2). With increasing BMI, incidences of complications between IVF and spontaneously conceived groups narrowed. Among women with normal BMI, IVF pregnancies were associated with increased odds of placental ischaemic disorders (11.3% versus 7.0%, adjusted odds ratio [aOR] = 2.24; 95% confidence interval [CI] = 1.25–4.04) and low birthweight <2500 g (10.6% versus 8.0%, aOR = 2.08; 95% CI = 1.12–3.88). Among overweight women, only low birthweight (<2500 g) was significantly increased (15.6% versus 6.2%, aOR = 4.33; 95%, CI = 1.61–11.63). For obese women, there were no differences between IVF and spontaneously conceived pregnancies for either placental ischaemic disorders (12.5 versus 20.2%, OR = 0.43, 95% CI = 0.17–1.1) or low birthweight (10.0% versus 11.0%, aOR = 0.7, 95% CI = 0.24–2.08). Overall, the odds of adverse obstetrical outcomes were not significantly greater in IVF singleton pregnancies compared with those conceived spontaneously as BMI increased.

Early luteal serum levels of biomarkers are predictive of preterm delivery (PTD) in singleton IVF pregnancies

ObjectiveA variety of mediators interact with the fetus and endometrium to influence implantation and embryo survival. We investigated serum concentrations of 13 biomarkers in IVF patients to determine their possible association with PTD in singleton IVF pregnancies.DesignWe evaluated a retrospective cohort (matched by age, prior pregnancy history, BMI, IVF response and number of embryos replaced) of 103 singleton pregnancies after IVF, utilizing sera from days 28 (initial pregnancy test) and 35 (1 week after the initial pregnancy test). There were 35 (34 %) with PTD (< 37 WGA) and there were 68 (66.0%) with term deliveries.Materials and MethodsSerum levels of 13 different compounds were determined by quantitative ELISAs by investigators blinded to pregnancy outcome. Data was analyzed by Fisher’s exact test for categorical variables and non-parametric tests for continuous variables.ResultsOn day 28, the following compounds independently predicted PTD of a singleton IVF pregnancy – Interleukin (IL)-13, Human Epididymis Protein 4 (HE4), IGF-2 and Secretory Leukocyte Protease Inhibitor (SLPI). On day 35, the following biomarkers independently predicted PTD of a singleton IVF pregnancy – IL-6, IGF-1, IL-13 and IGF-2. There were no associations between levels of these biomarkers and cause of infertility. Given that IGF-2 was significant over both time periods, we evaluated the change of IGF-2 as a predictor of PTD. When IGF-2 was stable over the 2 time frames, there was significantly more likely to be a full term delivery (p = 0.02).ConclusionCirculating biomarker levels as early as the day of the pregnancy test (CD#28) are highly predictive of PTD of a singleton IVF pregnancy. ObjectiveA variety of mediators interact with the fetus and endometrium to influence implantation and embryo survival. We investigated serum concentrations of 13 biomarkers in IVF patients to determine their possible association with PTD in singleton IVF pregnancies. A variety of mediators interact with the fetus and endometrium to influence implantation and embryo survival. We investigated serum concentrations of 13 biomarkers in IVF patients to determine their possible association with PTD in singleton IVF pregnancies. DesignWe evaluated a retrospective cohort (matched by age, prior pregnancy history, BMI, IVF response and number of embryos replaced) of 103 singleton pregnancies after IVF, utilizing sera from days 28 (initial pregnancy test) and 35 (1 week after the initial pregnancy test). There were 35 (34 %) with PTD (< 37 WGA) and there were 68 (66.0%) with term deliveries. We evaluated a retrospective cohort (matched by age, prior pregnancy history, BMI, IVF response and number of embryos replaced) of 103 singleton pregnancies after IVF, utilizing sera from days 28 (initial pregnancy test) and 35 (1 week after the initial pregnancy test). There were 35 (34 %) with PTD (< 37 WGA) and there were 68 (66.0%) with term deliveries. Materials and MethodsSerum levels of 13 different compounds were determined by quantitative ELISAs by investigators blinded to pregnancy outcome. Data was analyzed by Fisher’s exact test for categorical variables and non-parametric tests for continuous variables. Serum levels of 13 different compounds were determined by quantitative ELISAs by investigators blinded to pregnancy outcome. Data was analyzed by Fisher’s exact test for categorical variables and non-parametric tests for continuous variables. ResultsOn day 28, the following compounds independently predicted PTD of a singleton IVF pregnancy – Interleukin (IL)-13, Human Epididymis Protein 4 (HE4), IGF-2 and Secretory Leukocyte Protease Inhibitor (SLPI). On day 35, the following biomarkers independently predicted PTD of a singleton IVF pregnancy – IL-6, IGF-1, IL-13 and IGF-2. There were no associations between levels of these biomarkers and cause of infertility. Given that IGF-2 was significant over both time periods, we evaluated the change of IGF-2 as a predictor of PTD. When IGF-2 was stable over the 2 time frames, there was significantly more likely to be a full term delivery (p = 0.02). On day 28, the following compounds independently predicted PTD of a singleton IVF pregnancy – Interleukin (IL)-13, Human Epididymis Protein 4 (HE4), IGF-2 and Secretory Leukocyte Protease Inhibitor (SLPI). On day 35, the following biomarkers independently predicted PTD of a singleton IVF pregnancy – IL-6, IGF-1, IL-13 and IGF-2. There were no associations between levels of these biomarkers and cause of infertility. Given that IGF-2 was significant over both time periods, we evaluated the change of IGF-2 as a predictor of PTD. When IGF-2 was stable over the 2 time frames, there was significantly more likely to be a full term delivery (p = 0.02). ConclusionCirculating biomarker levels as early as the day of the pregnancy test (CD#28) are highly predictive of PTD of a singleton IVF pregnancy. Circulating biomarker levels as early as the day of the pregnancy test (CD#28) are highly predictive of PTD of a singleton IVF pregnancy.

Neonatal outcomes among singleton births after blastocyst versus cleavage stage embryo transfer: a systematic review and meta-analysis

Several studies have evaluated outcomes of singleton pregnancies after blastocyst versus cleavage stage embryo transfer. Higher incidences of preterm birth (PTB), very preterm birth (VPTB), low birthweight (LBW) and congenital malformations were identified in a few of them. The objective of our study was to systematically review and meta-analyze pregnancy and neonatal outcomes among singleton births following blastocyst versus cleavage stage embryo transfer. METHODS EMBASE, MEDLINE, EBM Reviews and bibliographies of included studies were searched from their inception until March 2013. Observational studies or clinical trials comparing blastocyst with cleavage stage embryo transfer and reporting on outcomes of PTB (<37 weeks), VPTB (<32 weeks), LBW (<2500 g), very low birthweight (VLBW) (<1500 g) and/or congenital anomalies in singleton neonates were included. Data on the outcomes were extracted by two reviewers. Statistical heterogeneity among studies was evaluated by calculating I(2) values and χ(2) statistics. Meta-analyses were conducted to estimate the pooled unadjusted odds ratio (OR) and the adjusted OR (AOR) with a 95% confidence interval (CI) using the random effect model. RESULTS Six observational studies, of low to moderate risk of bias, were included in this review. There were significantly higher odds of PTB (four studies, 54 792 cleavage stage and 20 724 blastocyst stage births; AOR 1.32, 95% CI 1.19-1.46) and congenital anomalies (two studies, 22 068 cleavage stage and 4517 blastocyst stage births; AOR 1.29, 95% CI 1.03-1.62) among births after blastocyst transfer compared with cleavage stage transfer. There was no difference in the adjusted odds of VPTB (four studies, 54 792 cleavage stage and 20 724 blastocyst stage births; AOR 1.18, 95% CI 0.93-1.49), LBW (four studies, 54 109 cleavage stage and 20 392 blastocyst stage births; AOR 1.06, 95% CI 0.99-1.15) or VLBW (three studies, 22 088 cleavage stage and 5772 blastocyst stage births; AOR 1.01, 95% CI 0.73-1.38). CONCLUSIONS Risk of PTB in IVF singleton pregnancies is significantly higher following blastocyst transfer compared with cleavage stage transfer. Risk of congenital anomalies may also be higher but further studies are needed to confirm this finding and to identify reasons for such outcomes.