ISAR Flash e-News

POSSIBLE ASSOCIATION BETWEEN IVF OFFSPRINGS & NEOPLASMS.

1,583 IVF & 5,874 spontaneous offsprings were followed up for 18yrs.The incidences of offspring benign neoplasm were 14 (0.9%) versus 21 (0.4%), & of malignancies were 17 (1.1%) versus 29 (0.5%), respectively.

IS NECK CIRCUMFERENCE (NC) THE NEW PARAMETER FOR INSULIN RESISTANCE (IR) IN PCOS ?

A recent study showed NC was associated significantly with increased risk of IR, additionally, NC was able to identify IR in women with PCOS; the optimal cut-off points was 34.3 cm (Youden index 1/4 0.586).

BLOOD GLUCOSE & FECUNDABILITY.

Women attempting spontaneous pregnancy were studied for 12 months.
After adjusting for age, ethnicity, education, body mass index, and cycle regularity , Increasing preconception plasma glucose was associated with reduced fecundability, even within the normal range of glucose concentrations.

RATE OF TRUE RECURRENT IMPLANTATION FAILURE

In 4,429 women with anatomically normal uterus, three consecutive frozen euploid single blastocyst transfers, shows a cumulative implantation rate of 95.2%.

Suggesting that “true” recurrent implantation failure is rare , < 5%.

Best Sperm selection based on high DNA integrity !

A device using Automated, acoustic based continuous-flow method , translates larger sperm and guides highly motile sperm across the channel width. The result is the selection of sperm with over 50% and 60% improvement in vitality and progressive motility and more than 38% improvement in DNA integrity.

RISK OF BIRTH DEFECTS IN CONCEPTION BY ART.

In a huge population based analysis of 135 051 ART children, 23 647 naturally conceived ART siblings and 9396 with OI/IUI and 1 067 922 naturally conceived children……

Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively.

Couple’s pre pregnancy BMI linked to Time to pregnancy.
In a huge database (2,301,782 ) of eligible couples it was shown that Underweight, overweight,or obese status in women and underweight status in men were associated with couples’ prolonged TTP.
The worse combination was obese female & underweight male.

Premature follicular phase P4 rise.
Another theory in the never ending effort to understand origins of PCOS !
It is proposed that PCOS begins with a triggering event when, in an otherwise healthy and highly fertile woman, gonadotropin surge takes place prematurely because of P elevation above the triggering threshold between days 6 and 8 of the follicular phase.

The search for a single biomarker for male fertility may be over !!
High sperm mitochondrial DNA copy number (mtDNAcn) had as much as 50% lower odds of cycle-specific pregnancy, and 18% lower probability of pregnancy within 12 months.
Sperm mtDNAcn has utility as a biomarker of male reproductive health and probability of pregnancy.

An unexpected fallout of Covid19 pandemic….
Women rush to freeze eggs !!
Fertility clinics have seen a sharp rise in the number of women inquiring about egg freezing – up to 50 percent – at least in the UK.
This may be triggered by the uncertainties of the future !

Should an IUI cycle be cancelled for a thin endometrium ?

This big study of 2459 IUI cycle compared GnTr/CC/ Letrozol for endometrial thickness(EMT) & LBR.
In IUI for unexplained infertility, higher LBR are observed with increasing EMT; however, EMT is not significantly associated with LBR when adjusted for OS treatment type. Appreciable LBR are seen at all EMT, even those of ≤5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium.

In a large study of 8627 donor/recipient cycles it was shown that total FSH dose was negatively associated with LBR. For every 500-unit increase in FSH dose, there was a 3% reduction in the odds of a live birth (odds ratio [OR] 0.97; 95% confidence interval 0.95, 0.99).

The results highlight that excessive stimulation of donors for maximum oocytes may not be a good strategy.

Endometrial regeneration

Human plasma from umbilical cord blood and adult blood platelet-rich plasma (PRP), was compared for regeneration of endometrial damage in a mice model.
Human umbilical cord blood had a stronger effect than adult PRP in endometrial regeneration.

Jacques Donnez et al, in a first reported use of linzagolix (oral GnRH antagonist) showed significant (On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3), reduction in lesion size in patient with severe adenomyosis, who was previously nonresponsive to treatment.

In the largest study to date evaluating the freeze-all strategy in normal responders showed in general, there were a higher implantation (25.5% versus 19.3%, p=0.002) and ongoing pregnancy rate (41% versus 32%, p=0.004) in freeze-all group. The results of this study show that although the freeze-all policy may be related to better IVF outcomes in normal responders, these potential advantages decrease with worsening ovarian response.

Patients with poorer ovarian response don’t have benefit from the freeze-all strategy.

Early ovarian ageing associated with early overall ageing !

Reports a large Danish study of 20 000 IVF cases over 20 years study period. Women with DOR had higher risk of long term morbidly & even mortality.
This study strongly supported the hypothesis that low ovarian reserve may be a useful marker of later health problems.

Another random association shows increased risk of “ectopic pregnancy”.
In a cohort analysis of 1691366 pregnancies, benzodiazepine use for anxiety & insomnia before conception was associated with a 50% higher risk of ectopic pregnancy.

An excess of 80 ectopic pregnancies per 10,000 pregnancies was noted with IPT- weighted risk of ectopic was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception.

Septum resection is second nature to reproductive surgeons. Evidence does not support it !

This study from HR reported LBR, OGPR, Pregnancy loss rate, and PTL comparable between those who underwent resection vs expectant management.
Concluded no improvement in reproductive outcome following septum resection !!

A new Sperm imaging technology likely better than IMSI

A new three-dimensional (3D) imaging method from Israel, can identify sperm moving at high speed and may help select the best sperm for use in assisted conception.
Using harmless light instead of x-rays the teams were able to create high-resolution, accurate 3D reconstructions of individual Sperm.

A study low in science but high on reassurance!!

7000 IVF VS 12000 non IVF primary school Children, performed similarly in reading and math assessments. They found consistent racial and ethnic differences, gender differences, and beneficial effects of older maternal age & concluded that there is no negative effect of IVF conception on academic achievement .

In a study of 34 adult males, diagnosed with COVID-19 through confirmatory qRT-PCR.

SARS-CoV-2 was not detected in the semen. ACE2-mediated viral entry of SARS-CoV-2 into target host cells is unlikely to occur within the human testicle based on ACE2 and TMPRSS2 expression. The long-term effects of SARS-CoV-2 on male reproductive function remain unknown.

IS THERE AN ASSOCIATION BETWEEN DIMINISHED OVARIAN RESERVE (DOR) & UNEXPLAINED RPL?

A question long unanswered …

An extensive systematic review and meta-analysis suggests that women with DOR are at increased risk of developing RPL (odds ratio 2.77, 95% confidence interval 1.41–5.46).DOR is significantly associated with unexplained cases of RPL (odds ratio 3.23, 95% confidence interval 1.81–5.76).

These data indirectly suggest that ovarian reserve markers could be used to predict the risk of pregnancy loss.

ISAR/ASRM/ESHRE:ART Recommendations during Covid19 outbreak.

1. Do not initiate new cycles, OI/IUI/IVF/FET/NON URGENT GAMETE PRESERVATION.
2. Strongly consider cancellation of all embryo transfers, whether fresh or frozen.
3. Continue cycle already started, in IVF recommend freezing all.
4. Fertility preservation for cancer should be done.
5. Suspend elective diagnostic/therapeutic surgeries.
6. Explore telemedicine options.

These recommendations are for 2 wks and may continue to evolve.
(Starting 30th March to 13th April)

THE DR WHO PERFORMED THE FIRST GENE EDITED BABY IS IN JAIL !

Dr He Jiankui, of China, who claimed that the world’s first babies had been born with edited genomes, has been sentenced to three years in prison and fined millions for performing ‘illegal medical practices’.

LETROZOLE FOR ECTOPIC PREGNANCY !

In a small study, first time reported in literature, presented at ASRM 2019, letrozole showed promise as medical treatment for ectopic pregnancy.

Advantages compared to methotrexate are better safety and hypothetically better long term ovarian reserve.

What is the Evidence supporting these TEN add-ons in IVF ??

10 add-ons used to improve IVF success rates : Screening Hysteroscopy, DHEA , Testosterone, GH , Aspirin, Heparin, Antioxidants for male/female, Seminal Plasma, & PRP

This exhaustive review found no high-quality evidence to support the use of these in routine IVF practice.

Retrospective comparison of a large (14491) cohort of live borns after fresh vs frozen ETs, showed that compared with fresh ET, those born by FET have higher birth weight but increased odds of infectious disease, hematologic, respiratory and neurologic abnormalities.

These risks should be considered when making decisions on fresh versus FET.

NON INVASIVE METABOLIC IMAGING APPEARS LIKE A HIGHLY PROMISING TOOL FOR PREDICTING EMBRYO & OOCYTES QUALITY IN THE NEAR FUTURE.

Early studies show that, the combined use of fluorescence lifetime imaging microscopy (FLIM)-based metabolic imaging and second harmonic generation (SHG) spindle imaging may be a feasible and safe approach for noninvasive embryo assessment !!

ART OUTCOMES AFTER OVARIAN TISSUE TRANSPLANT (OTT).

Total 360 cases of OTT with 130 live births reported worldwide. Current evidence clearly shows that ART outcomes in women undergoing OTT are poor compared with the general IVF population, corresponding to those of poor ovarian reserve patients.
Consensus is lacking regarding the timing of ART in women undergoing OTT and the type of ART protocol.

These findings are interesting because they disrupt the patterns between health and wealth established in other Westernized societies.

F & S PUBLISHED INDIAN STUDY OF 711 PCOS WOMEN SHOWED MORE SEVERE PHENOTYPE WITH CONSUMPTION OF WESTERN STYLE DIET (WSD). THEY REPORT A SIGNIFICANT INCREASE IN BMI, HIRSUTISM, INSULIN RESISTANCE AND AMH IN URBAN AFFLUENT WOMEN ON WSD COMPARED TO POORER RURAL VEGETARIANS.

These findings are interesting because they disrupt the patterns between health and wealth established in other Westernized societies.

LARGEST PUBLISHED STUDY OF AGONIST ONLY TRIGGER SHOWS SR LH LEVEL ON STARTING DAY OF OVARIAN STIMULATION, CAN PREDICT SUBOPTIMAL OOCYTE YIELD.

A GnRH agonist trigger may result in an inadequate oocyte yield in a small subset of patients. This failure can range from empty follicle syndrome to the retrieval of much fewer oocytes than expected.

LH levels at the initiation of ovarian stimulation remained an independent predictor of suboptimal response (adjusted OR 0.920, 95% CI 0.871–0.971). Patients with immeasurable LH levels at the start of stimulation (<0.1 IU/l) had a 45.2% risk of suboptimal response, while the risk decreased with increasing basal LH levels; baseline circulating LH <0.5 IU/L, <2 IU/L and <5 IU/L were associated with a 39.1%, 25.2% and 13.6% risk, respectively.

ZHENG ET AL. IN “NATURE” REPORT THE CREATION OF AN ADVANCED MODEL OF HUMAN EMBRYO DEVELOPMENT THAT RECAPITULATES MANY OF THE KEY EVENTS THAT HAPPEN AROUND THE TIME OF IMPLANTATION.

The model involves the generation of synthetic structures resembling the embryonic sac — which, later in development, becomes a fluid-filled bag and the embryo. This is a great advancement in trying to understand implantation & EPL.

SEPTUAGENARIAN & CHILD !! WHERE DOES REPRODUCTIVE RIGHTS END ?

A different point of view, do read !
This does start to look more like selfishness. The urge to be a parent has little to do with the wellbeing of the child. Not just in the case of this particular couple, but for any person who longs for a child. Of course, most people hope and assume that their own child will thrive. But no-one reproduces for the sake of the child.

ENDOMETRIAL COMPACTION

is the decrease in endometrial thickness between the end of only estrogen administration and starting of progesterone, up to day of embryo transfer.
In a recent study involving FETs, ongoing pregnancy rate was significantly increased at all levels of compaction compared with no compaction.

In a large study of 2664 PCOS women undergoing FET, it was shown that endometrial preparation using letrozole was associated with higher LBR and lower miscarriage rate, compared with hormone replacement cycle albeit after statistical adjustment for confounding factors.

17% women, who failed with IVF had a spontaneous live birth (95% CI, 15–19%) within a 5 yr follow up !!

Reported a retrospective study from UK.

Also, amongst those who were successful with IVF, 15% (95% CI, 12–17%) had spontaneous live births.
Factors associated were, shorter duration of infertility, younger female age and IVF as compared to ICSI.

IN A HUGE RETROSPECTIVE ANALYSIS OF FETS (105234 CYCLES) IT WAS SHOWN THAT ENDOMETRIAL PREPARATION MATTERED !!.

Hormone replacement cycles had increased risks of hypertensive disorders of pregnancy and placenta accreta and a reduced risk of GDM compared to natural cycle FETs. Increased Odds of HDP [OR 1.43; 95% (CI), 1.14–1.80] and placenta accreta [OR 6.91; 95% (CI),2.87–16.66].

LARGE META ANALYSIS SHOWS STRONG ASSOCIATION BETWEEN RPL AND SPERM DNA FRAGMENTATION.

Male partners of women with RPL had a significantly higher rate of sperm DNA fragmentation than those of fertile control women: MD 10.7, 95% CI 5.82—15.58

POOR SLEEP & DELAYED TIME TO PREGNANCY : A WAKE UP CALL FOR PHYSICIANS?

Fascinating first look at the association between sleep health in women and time to pregnancy. This large prospective study shows a fairly robust association between troubled sleeping and lowered fecundability. Now we have another, in a long list of lifestyle factors, to counsel our patients !!

CRISPR-CAS9 IS A GENE EDITING TOOL THAT HAS BEEN TOUTED AS BREAKTHROUGH TECHNOLOGY THAT CAN HELP SCIENTISTS TREAT OR MAYBE EVEN CURE GENETIC DISEASES.

However gene editing the “germ line” is banned.

But can the scientific community control their members…..as a third child edited with the CCR5 gene (to prevent them from potentially becoming infected with HIV in the future) is due to be born in China.

MATERNAL, INFANT AND CHILDHOOD RISKS ASSOCIATED WITH ADVANCED PATERNAL AGE.

The new study reviewed 40 years of research looking at pregnancies involving older men and noted a higher risk of premature birth, stillbirth, low birth weight, newborn seizures, and birth defects, such as congenital heart disease and cleft palate. These children, also had a higher risk of childhood cancers, mental health problems, cognitive disorders, and autism.
There is no clear definition of exactly when in life “advanced paternal age” begins !

THERMOCHEMILUMINESCENCE (TCL) ANALYZER.

An embryo assessment algorithm combining morphology, morphokinetics and the embryo’s culture medium oxidative status appears to be in the horizon.
The assessment algorithm resulted in a hierarchical classification with six embryo quality categories (A to F), associated with implantation rates of between 76.5% and 29.2%.

THE DELPHI CONSENSUS

Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over-treatment or under-treatment.
Twelve consensus statements developed by a global group. Worth a read

Rare genetic variants for OHSS with agonist trigger !
We now know that SEVERE OHSS can occur with agonist trigger, although extremely rare.Defining a genetic predisposition for OHSS is essential in view of prevention. In this study, a potential link between the FLT4 gene and OHSS has been suggested.

A large database of infertile (64345) Vs non infertile (3128345) women were compared to answer the study question:
Is female infertility associated with higher risk of cancer ?
The answer was “YES”!
Although the absolute risks are low.

FINALLY AN ORALLY ACTIVE ANTAGONIST !
The US FDA has approved an orally active GnRH antagonist. This may have great impact on clinical practice to treat estrogen dependant diseases like “endometriosis “. Further endless possibilities…..scheduling ART cycles, AUB, dysmenorrhea, contraception, and male contraception!

PATERNAL MITOCHONDRIAL TRANSMISSION ?
Mitochondria are usually passed from one generation to the next via the egg cell, and so they are inherited from the mother only. In a ground of breaking discovery researchers found three families with paternal mitochondrial DNA transmitted to off springs.
It could open up an entirely new field for causes of genetic diseases. Authors suggest involvement of a nuclear gene which allows males to pass on mtDNA through sperm.

A fresh look at pre IVF Endometrial Scratch
A multi-centric RCT from France concluded that Endometrial scratch (ES) in women undergoing their first or second IVF/ICSI attempt does not enhance the CPR .In fact a tendency towards lower pregnancy rates in ES group prompted earlier stoppage of the trial before reaching sample size !!

A large retrospective study (937,848 patients) from Japan based on Single Embryo Transfer cycles, showed a prevalence of multiple pregnancy due to ZYGOTE SPLITTING of 1.36%.
There was a strong association with Blastocyst manipulation.

BIG MUSCLES COME AT THE PRICE OF SPERM QUALITY !
Bulging biceps might make men more likely to appeal to the opposite sex, but extra muscle may take its toll on their sperm count.
REPORTS A CURIOUS STUDY

CAUSE OF PCOS DISCOVERED ATLAST ?
Reports the viral article in Nature!
“Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood.” by Tata et al published in Nature Medicine, June 2018.

World’s first baby born to a 45year old woman after autologous bone marrow-derived Stem Cell therapy (ABMDSCT) into the ovary, reported from India.

An artificial ovary for fertility preservation without the risk of reintroducing malignancy !
Researchers from the Rigshospitalet in Copenhagen, Denmark, report that they have for the first time isolated and grown human follicles to a point of “biofunctionality” on a bioengineered ovarian scaffold made of “decellularised” ovarian tissue.

LIVE BIRTH FOLLOWING WORLD’S FIRST “IN UTERO” STEM CELL TRANSPLANT !!
This opens up the possibility of Fetal therapy as a viable new option for alpha thalassemia (ATM).