IVF success : the importance of characterizing optimal embryo transfer technique

Live birth rate following embryo transfer is significantly influenced by the physician performing the transfer: data from 2707 euploid blastocyst transfers by 11 physicians

Pregnancy and live birth rates obtained after in vitro fertilization (IVF) are highly variable depending on the practitioner who performs the embryo transfer, regardless of the number of transfers performed per practitioner and years of practice, according to a US study presented in 2016 at the American Society for Reproductive Medicine (ASRM) conference in Salt Lake City.

2016 Study Abstract

Objective
Multiple prior studies have demonstrated variation in IVF success rates according the provider performing the embryo transfer procedure. However, these studies were limited by lack of control for embryonic aneuploidy and evaluation of cleavage stage transfers only. Thus, our objective was to isolate the contribution of physician variability on the chance of embryo transfer (ET) success in contemporary ART by evaluating euploid blastocyst transfers in a single practice setting.

Design
Retrospective cohort.

Materials and Methods
All euploid blastocyst transfers from 2011 to 2015 were evaluated. The physician performing the ET, maternal age, blastocyst grade, and information regarding fresh versus frozen transfer were recorded. During the study period, 11 physicians were randomly assigned to be “ET physician of the day” in a rotating fashion. To avoid selection bias, all transfers not performed by the assigned “physician of the day” were excluded to assure that the randomness provided by the rotating schedule remained intact. Analysis was performed using chi-squared tests.

Results
There were 2707 euploid ETs performed that met inclusion criteria. The mean number of transfers per physician was 246. There was no difference in maternal age, blastocyst grade, or proportion of fresh vs. frozen transfers among the physicians. The implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR) differed significantly between worst performing and best performing physicians. When compared to worst performer, an additional live birth could be expected for every 6 ETs performed by the best performer. There was no association between success rates and number of ETs performed by provider during the study period or number of years elapsed since completion of training.

Conclusions
When controlling for embryonic factors by utilizing euploid blastocyst transfers, live birth rate is still strongly influenced by the physician performing the transfer procedure. Given that these data only include ETs in which patients were randomly assigned to a given provider, the impact of the physician factor on success rates is truly isolated. These findings highlight the importance of characterizing optimal ET technique and present an opportunity for improving success rates through remediation of experienced providers and formalized instruction of trainees.

Reference.

Can in vitro fertilisation increase the risk for preeclampsia ?

Embryo cryopreservation and preeclampsia risk

Pre-eclampsia is a disorder of pregnancy that increases the risk of poor outcomes for both the mother and the baby.

2017 Study Abstract

Objective
To determine whether assisted reproductive technology (ART) cycles involving cryopreserved-warmed embryos are associated with the development of preeclampsia.

Design
Retrospective cohort study.

Setting
IVF clinics and hospitals.

Patient(s)
A total of 15,937 births from ART: 9,417 singleton and 6,520 twin.

Intervention(s)
We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data, considering resident singleton and twin births from autologous or donor eggs from 2005–2010.

Main Outcome Measure(s)
We compared the frequency of preeclampsia diagnosis for cryopreserved-warmed versus fresh ET and used multivariable logistic regression to adjust for confounders.

Result(s)
Among pregnancies conceived with autologous eggs resulting in singletons, preeclampsia was greater after cryopreserved-warmed versus fresh ET (7.51% vs. 4.29%, adjusted odds ratio = 2.17 [95% CI 1.67–2.82]). Preeclampsia without and with severe features, preeclampsia with preterm delivery, and chronic hypertension with superimposed preeclampsia were more frequent after cryopreserved-warmed versus fresh ET (3.99% vs. 2.55%; 2.95% vs. 1.41%; 2.76 vs. 1.48%; and 0.95% vs. 0.43%, respectively). Among pregnancies from autologous eggs resulting in twins, the frequency of preeclampsia with severe features (9.26% vs. 5.70%) and preeclampsia with preterm delivery (14.81% vs. 11.74%) was higher after cryopreserved versus fresh transfers. Among donor egg pregnancies, rates of preeclampsia did not differ significantly between cryopreserved-warmed and fresh ET (10.78% vs. 12.13% for singletons and 28.0% vs. 25.15% for twins).

Conclusion(s)
Among ART pregnancies conceived using autologous eggs resulting in live births, those involving transfer of cryopreserved-warmed embryos, as compared with fresh ETs, had increased risk for preeclampsia with severe features and preeclampsia with preterm delivery.

Sources

IVF treatment : a healthy singleton delivery is best achieved by SET

Single-embryo transfer point – it is the way forward

In vitro fertilization (IVF) treatment in the United States is complicated by a high rate of multiple-gestation pregnancies. In 2014, the Society for Assisted Reproductive Technology reported that 23% of women <38 years of age with a pregnancy from their IVF treatment had a twin-gestation pregnancy. Although this is an improvement over past years, it remains an unacceptably high rate of twins, considering the medical risks and financial burdens associated with such pregnancies.

In this issue of Fertility and Sterility, Mersereau et al. have added strong support to the conclusion that single-embryo transfer (SET) is highly effective at reducing multiple-gestation birth rates: a 47% decrease with the use of SET compared with double-embryo transfer (DET). Furthermore, using data from their study and others, Mersereau’s team has led a revision of American Society for Reproductive Medicine committee opinion guidelines to unambiguously call for SET for women under the age of 38 years with a favorable prognosis for pregnancy. With the increasing weight of evidence and explicit professional guidelines, why is DET still so common in the United States?

In their article, Mersereau et al. report a comprehensive analysis of 10 years of national SET data, finding a 10%–15% reduction in live birth rate (LBR) with the use of SET. This reduction is not attractive to either physicians or patients, for whom IVF pregnancy rates matter a great deal. Indeed, we have shown that, despite education about the risks of twins after DET, most patients would still choose this option over SET, even with as little as a 10% drop in the LBR.

Yet we think that the 10%–15% difference in LBR may be an overestimate of the negative effect of SET on LBR, considering trends in current clinical IVF care. As reported, blastocyst transfers are becoming increasingly common, and SET live birth rates are higher with blastocysts than with cleavage-stage embryo. In fact, the LBR differences between DET and SET were still reduced, but only in the 6%–8% range, when looking at fresh blastocyst transfers in a first or second cycle. Even this may be an overestimate of the true difference between DET and SET, because higher pregnancy rates are seen when the single transferred embryo comes from a larger cohort of available embryos.

Thus, it is likely a false comparison to judge the success of SET with one or more embryos cryopreserved (at least two embryos in the cohort) against DET with one or more embryos cryopreserved (at least 3 embryos in the cohort). In a recent analysis of national IVF outcomes data, we strictly controlled for the size of the available cohort and found very similar pregnancy rates in younger good-prognosis patients undergoing elective SET versus DET on day 5–6.

We think that this trend of increasing blastocyst transfers combined with improvements in embryo selection techniques (such as preimplantation genetic screening) will result in further increases in SET pregnancy rates and allow clinics to more confidently offer SET with little to no impact on their clinic-specific pregnancy outcome. Despite continuing technical advances, however, it is likely that small but potentially significant LBR differences will persist between SET and DET if as a field we continue to report and emphasize pregnancy rates per transfer instead of cumulative pregnancy rates per fresh IVF cycle. As mentioned in Mersereau et al.’s paper, predictive models suggest that cumulative LBRs with the use of sequential SET are equal or superior to DET.

Further studies confirming this prediction will help to convince physicians, patients, and insurance providers of the benefits and feasibility of SET, even if this strategy requires additional transfers and a slightly longer time to pregnancy. A healthy singleton delivery should be the goal of all IVF cycles, and this is best achieved by SET.

Do we need to choose between improved sperm selection or efficacy ?

The latest attempt to improve the sperm’s path

Our goal in the in vitro fertilization laboratory is to maximize the ratio between the number of oocytes retrieved and the production of highly viable embryos. We receive the raw material from our patients (oocytes and sperm cells) and, with our knowledge and the available technologies; we try to improve our success rates day by day. One of our endpoints should be the objective application of validated, repeatable, and non-biased therapies and technologies. Few options remain available for oocytes as all the oocytes will be treated to achieve fertilization. In the case of sperm, millions of cells are available to us, but only a few of them will be used. Is there room to improve the sperm’s path? We must move away from the classical methods of sperm selection (swim up or gradients) and pursue any kind of technology that may take into consideration their molecular characteristics, which are related to successful fertilization, embryo development, and live birth.”…

…continue reading What else can we do? The latest attempt to improve the sperm’s path on Fertility and Sterility, Volume 108, Issue 3, Pages 444–445, September 2017.

Sex Hormones and Related Compounds, Including Hormonal Contraceptives

ResearchGate, Side Effects of Drugs Annual, July 2017

Abstract

This is a review of publications from January 2016 to December 2016 on sex hormones and related compounds. This chapter covers estrogens (diethylstilbestrol, estradiol and derivatives), progestins (drospirenone, levonorgestrel, medroxyprogesterone, ulipristal), hormone replacement therapy (combination estrogen and progestin, estrogen only, tibolone, oral preparations and topical preparations), hormonal contraceptives (oral, non-oral, combination and progestin only), in vitro fertilization agents, triptorelin (gonadotropin-releasing hormone agonist), anastrozole (aromatase inhibitor) testosterone, anabolic steroids and androgen deprivation therapy.

Request the full-text on ResearchGate.

DES DiEthylStilbestrol Resources

The Diethylstilbestrol Legacy

A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016 Report Abstract

Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.

In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy,
Pediatrics, November 2016, VOLUME 138 / ISSUE Supplement 1, Supplement_1/S42.abstract, November 2016.

Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for “routine prophylaxis in ALL pregnancies” and administered to women with otherwise healthy pregnancies.

By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. Several months later, the Food and Drug Administration issued a bulletin indicating that the use of DES was contraindicated in pregnancy. By then, however, millions of women, along with their sons and daughters, had been needlessly exposed.

In addition to the increased risk of CCA of the vagina and cervix, daughters exposed in utero to DES also suffered from an increased occurrence of reproductive tract abnormalities, infertility, and pregnancy complications; earlier menopause; twice the incidence of cervical dysplasia; and a possible elevated risk of breast cancer and continued increased risk of CCA in middle age. Recent preliminary data indicate the possibility of an increased risk of cardiovascular disease and diabetes in the prenatally exposed women. Mothers administered DES during pregnancy have an increased risk of breast cancer incidence and mortality. Sons who were exposed in utero have an increased risk of genitourinary defects and a possible increase in testicular cancer. The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation. Preliminary findings showed increased menstrual irregularity and a possible excess of ovarian cancer in very young women.

The link between prenatal DES exposure and subsequent adverse health outcomes, most of which are fairly common, may easily have escaped detection. The investigation of DES outcomes was initiated solely because a rare tumor occurred in a cluster of cases at an unusually young age, decades before the usual age of presentation. This historical example underscores the necessity of carefully weighing the risks and benefits of interventions in pregnancy and long-term monitoring of the health outcomes in mothers and offspring.

Whether and/or when to use pharmaceutical intervention in pregnancy continues to pose special challenges. At the present time, progesterone used to prevent pregnancy loss appears to be effective, although more data are needed. Thus far, there is little evidence of short-term adverse consequences for the offspring, but continued monitoring of mothers and offspring is warranted to identify any short- or long-term adverse effects. The use of progestins for luteal phase and early pregnancy support after in vitro fertilization is routine, and there are even fewer data on potential short- and long-term risks of this therapy. The tragic legacy of DES supports a cautious approach to the use of pregnancy interventions and assiduous appraisal of their effects.

Rebecca Troisi, Elizabeth E. Hatch, Linda Titus,
Reviewed by Dr Robert Hoover,

Click to download the full paper.

More DES DiEthylStilbestrol Resources

Preconception exposures to phthalates effect in fathers on reproductive success via embryo quality

Dad’s exposure to phthalates in plastics may affect embryonic development

Abstract

STUDY QUESTION
Are preconception urinary concentrations of phthalates and phthalate alternatives associated with diminished early stage embryo quality in couples undergoing IVF?

SUMMARY ANSWER
Male, but not female, urinary concentrations of select metabolites of phthalates and phthalate alternatives are associated with diminished blastocyst quality.

WHAT IS KNOWN ALREADY
Although phthalates are endocrine disrupting compounds associated with adverse reproductive health, they are in widespread use across the world. Male and female preconception exposures to select phthalates have been previously associated with adverse reproductive outcomes in both the general population and in those undergoing IVF.

Parental contributions to early embryo development: influences of urinary phthalate and phthalate alternatives among couples undergoing IVF treatment, Oxford Journals, Medicine & Health, Human Reproduction, Advance Access10.1093/humrep/dew301, October 28, 2016.

“Odd ducks Bob, Squish, and Slim. The Boon company seems very proud that their ducks are “BpA-free, Phthalate-free, and PVC-free” I bet they are also Gluten-free, Fat-free, and Sugar-free. So go ahead and eat one!” said Jamie – Image © all rights reserved.

STUDY DESIGN, SIZE, DURATION
This prospective cohort included 50 subfertile couples undergoing IVF in western Massachusetts.

PARTICIPANTS/MATERIALS, SETTING, METHODS
This study includes the first 50 couples recruited from the Baystate Medical Center’s Fertility Center in Springfield, MA, as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Relevant data from both partners, including embryo quality at the cleavage (Day 3) and blastocyst (Day 5) stages, were collected by clinic personnel during the normal course of an IVF cycle. A spot urine sample was collected from both male and female partners on the same day as semen sample procurement and oocyte retrieval. Concentrations of 17 urinary metabolite were quantified by liquid chromatography mass spectrometry and normalized via specific gravity. Generalized estimating equations were used to estimate odds ratios (OR) and 95% CI, with urinary phthalates and phthalate alternatives fitted as continuous variables and embryo quality as a binary variable.

MAIN RESULTS AND THE ROLE OF CHANCE
The 50 couples contributed 761 oocytes, of which 423 progressed to the cleavage stage, 261 were high-quality cleavage stage embryos, 137 were transferrable quality blastocysts and 47 were high-quality blastocysts. At the cleavage stage, male urinary monoethyl phthalate concentrations were positively associated with high-quality cleavage stage embryos (OR = 1.20, 95% CI 1.01–1.43, P = 0.04); no other significant associations were observed at this stage. At the blastocyst stage, male urinary concentrations of monobenzyl phthalate (OR = 0.55, 95% CI 0.36–0.84, P = 0.01), mono-3-hydroxybutyl phthalate (OR = 0.37, 95% CI 0.18–0.76, P = 0.01), mono-n-butyl phthalate (OR = 0.55, 95% CI 0.42–0.73, P < 0.01) and monomethyl phthalate (OR = 0.39, 95% CI 0.26–0.60, P < 0.01) were inversely associated with high-quality blastocysts. A borderline statistically significant relationship was observed for male concentrations of mono(2-ethylhexyl) phthalate (OR = 0.52, 95% CI 0.27–1.00, P = 0.05) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (OR = 0.21, 95% CI 0.04–1.03, P = 0.05) at the blastocyst stage. Similar inverse associations were observed between male urinary phthalate metabolite concentrations and likelihood of transferrable quality blastocysts. For female partners, select metabolites were positively associated with odds of high or transferrable blastocyst quality, but the observed associations were not consistent across blastocyst quality measures or between sex-specific and couples-level models. All models were adjusted for age of both partners, urinary metabolite concentrations of female partners and male infertility status, while models of blastocysts were additionally adjusted for embryo quality at cleavage stage.

LIMITATIONS, REASONS FOR CAUTION
Our modest sample included only 50 couples contributing one cycle each. In addition, non-differential misclassification of exposure remains a concern given the single-spot urine collection and the short half-life of phthalates.

WIDER IMPLICATIONS OF THE FINDINGS
Our results suggest an inverse association between male preconception concentrations of select phthalate metabolites and blastocyst quality, likely occurring after genomic activation. If corroborated with other studies, such findings will have public health and clinical significance for both the general population and those undergoing IVF.

STUDY FUNDING/COMPETING INTERESTS
This work was generously supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.

Online calculator that tries to predict IVF success released

A woman’s age is the most important factor in her chances of having a baby

Abstract

Objective
To develop a prediction model to estimate the chances of a live birth over multiple complete cycles of in vitro fertilisation (IVF) based on a couple’s specific characteristics and treatment information.

Design
Population based cohort study.

Setting
All licensed IVF clinics in the UK. National data from the Human Fertilisation and Embryology Authority register.

Predicting the chances of a live birth after one or more complete cycles of in vitro fertilisation: population based study of linked cycle data from 113 873 women, The BMJ 2016;355:i5735, 16 November 2016.

Participants
All 253 417 women who started IVF (including intracytoplasmic sperm injection) treatment in the UK from 1999 to 2008 using their own eggs and partner’s sperm.

Main outcome measure
Two clinical prediction models were developed to estimate the individualised cumulative chance of a first live birth over a maximum of six complete cycles of IVF—one model using information available before starting treatment and the other based on additional information collected during the first IVF attempt. A complete cycle is defined as all fresh and frozen-thawed embryo transfers arising from one episode of ovarian stimulation.

Results
After exclusions, 113 873 women with 184 269 complete cycles were included, of whom 33 154 (29.1%) had a live birth after their first complete cycle and 48 925 (43.0%) after six complete cycles. Key pretreatment predictors of live birth were the woman’s age (31 v 37 years; adjusted odds ratio 1.66, 95% confidence interval 1.62 to 1.71) and duration of infertility (3 v 6 years; 1.09, 1.08 to 1.10). Post-treatment predictors included number of eggs collected (13 v 5 eggs; 1.29, 1.27 to 1.32), cryopreservation of embryos (1.91, 1.86 to 1.96), the woman’s age (1.53, 1.49 to 1.58), and stage of embryos transferred (eg, double blastocyst v double cleavage; 1.79, 1.67 to 1.91). Pretreatment, a 30 year old woman with two years of unexplained primary infertility has a 46% chance of having a live birth from the first complete cycle of IVF and a 79% chance over three complete cycles. If she then has five eggs collected in her first complete cycle followed by a single cleavage stage embryo transfer (with no embryos left for freezing) her chances change to 28% and 56%, respectively.

Conclusions
This study provides an individualised estimate of a couple’s cumulative chances of having a baby over a complete package of IVF both before treatment and after the first fresh embryo transfer. This novel resource may help couples plan their treatment and prepare emotionally and financially for their IVF journey.

In vitro fertilization success rate for older women is consistently low

The Misleading Promise of I.V.F. for Women Over 40

” Many young women were understandably seduced by the once widely publicized message that if they chose to delay pregnancy and were then unable to conceive, they could still have babies through in vitro fertilization, also known as I.V.F.

Miriam Zoll was one of them. Married at age 35, she thought she had plenty of time to start a family. After all, she said, “My mother had me at 40, and since 1978, the fertility industry has been celebrating its ability to help women have children at older ages.”

When at 39 she and her husband decided to start a family, they discovered that nature refused to cooperate. Four emotionally and physically exhausting I.V.F. cycles (and two attempted donor egg cycles) later, they remained childless. ” …

… continue reading The Misleading Promise of I.V.F. for Women Over 40NY Times, OCT. 17, 2016.

How women are being misled about the success rates of IVF and fertility treatments

Some people are getting IVF who shouldn’t be getting it

The Baby Business – Four Corners, May 31, 2016.

An Australian documentary has claimed that women over 40 are being misled about their chances of conceiving via IVF treatment when using their own eggs.

An investigation by the current affairs documentary Four Corners, on ABC, explained that chances of having a live birth per cycle following IVF treatment using their own fresh eggs were:

  • almost 6% for women aged 41-42 years old,
  • reduced to just under 3% for women aged 43–44 years old,
  • limited to a mere 1% for women over the age of 45.

More Information