Lack of embryos in the IVF protocol – who is to blame and what to do?

Causes

The causes of anembryonia are still being studied. It is believed that the embryo dies due to its inferiority. This occurs with genetic pathologies that are incompatible with life. Gene defects can be inherited or caused by damaging factors.

In addition to a genetic abnormality, the cause of embryo death can be:

• exposure and radiation;
• exposure to harmful chemicals;
• acute infections in the short term;
• bad habits (smoking, alcoholism and drug addiction);
• inflammatory processes of the genital organs;
• stress;
• taking certain medications;
• a sharp change in hormonal levels.

Therefore, to avoid such a situation, pregnancy should be planned.

Diagnostics

Anembryonia can be suspected if the size of the uterus does not correspond to the gestational age and if there is no fetal heartbeat. If a dynamic determination of the hCG level is carried out, then its insufficient growth is observed. Diagnosis of anembryonia using ultrasound is the main informative method. It is usually detected during a routine examination (week 5-7). An ultrasound detects a fertilized sac in which there is no embryo. If the pregnancy is short, the doctor may prescribe a repeat ultrasound in a week to make sure the embryo has died.

When pregnancy does not develop

Obstetricians and gynecologists are witnesses not only of immense human happiness, but also of concentrated grief. When a happy woman looks with hope at the ultrasound monitor screen, the gloomy faces of the doctors and tense voices do not immediately penetrate her consciousness. “Your pregnancy is not progressing” is a terrible sentence for those who were already inspired by hope.

Undeveloped pregnancies, alas, are a common occurrence. In recent years, we have been making this diagnosis more and more often. Of course, I really want to explain the failures by “bad ecology”, junk food, GMOs, radiation from space and the evil eye. But scientists who study the problems of miscarriage believe that all this has nothing to do with it.

What are the chances?

In an ideal menstrual cycle, the maximum probability of pregnancy does not exceed 40%. And the majority (60%) of fertilized eggs do not develop into an embryo. Some eggs stop developing at the very early stages of fragmentation, others do not make it through the long journey to find the uterus, and others cannot attach well to the endometrium. All these lost in very early stages of pregnancy, as a rule, are not noticed or taken into account.

If you take pregnancy tests every day (like the participants in a clinical study in 19881), you may find that the test may become weakly positive on some days and then negative again. Doctors call this phenomenon “biochemical pregnancy” and do not classify it as a painful condition. In fact, this is one of the very first steps of natural selection that a future person will have to go through in order to come into this world.

When an early pregnancy enters the clinical stage (a slight delay in menstruation and a confidently positive test), the chances of a successful outcome increase: 80% of pregnancies progress, and 20% either end in miscarriage or “freeze” - stop developing. In general, too often.

The less you know the better you sleep?

The main reason for the modern “epidemic” of undeveloped diseases, in fact, is the rapid progression of diagnostic techniques. When I was studying at the institute, dozens of male frogs, kept for diagnosing early pregnancy (Galli-Mainini reaction), croaked in the basement of the cathedral maternity hospital. The woman's urine was injected into the lymphatic sac of the amphibians. If the patient was pregnant, the males inflated their throat sac, croaked loudly and respectably, and sperm were found in their cloaca.

Compare this circus of 25 years ago with modern possibilities: pregnancy tests with “results in words”, ultrasound under every bush, blood tests for hCG with results in numbers. We have learned to diagnose pregnancy not just too early - too early. Long before the future man can confidently declare his viability.

Literally 15–20 years ago, we simply did not notice most of these problems: menstruation was delayed, breasts hurt, and then menstruation came and the breasts stopped hurting. The meaningless term “hormonal imbalance” comes from that period of medical development.

Treatment

Although anembryonia can result in spontaneous miscarriage, if it is detected, it is necessary to remove the fertilized egg. In the early stages, a medical abortion is possible; it is carried out under the mandatory supervision of a doctor. At later stages, curettage of the uterus is performed (more details here). The woman is prescribed antibacterial drugs and uterine contractions. You can get pregnant again after 3-6 months. During this time, the body will recover. It is advisable to plan and prepare for conception. If the next pregnancy also ends unsuccessfully, you need to establish the cause and undergo comprehensive treatment for anembryonia. Both spouses undergo the examination, since the cause of the anomaly may be a genetic defect in the man.

Specialists at the AltraVita clinic provide pregnancy care from an early stage. If anembryonia is detected, we carry out comprehensive treatment. In the future, you can be examined and prepared for pregnancy with us. There is no need to despair even if there is another missed abortion, since in the case of genetic disorders in one of the spouses, IVF can be done with donor material.

Lack of embryos in the IVF protocol – who is to blame and what to do?

On June 4-6, 2021, the next conference “Cornerstone Aspects of Reproductive Medicine” (CARM) was held in Moscow. As always, our doctors took part in it. At the embryology section, Yulia Alekseevna Koloda, a reproductive doctor, candidate of medical sciences, medical director of our reproduction center, spoke to her colleagues.

The topic of Yulia Alekseevna’s report is “Adverse embryological outcomes: Who is to blame and what to do?” These questions, of course, concern not only specialists. Therefore, we will briefly and, as simply as possible, retell the doctor’s report to future parents.

What are adverse embryological outcomes?

This is about the sad situation when the ART program does not reach the point of transfer, because there is nothing to transfer. The reasons may be different:

• poor response to stimulation – few mature, high-quality oocytes were obtained;
• few eggs were fertilized;
• blastocysts have not formed from fertilized eggs (blastocyst is the stage of embryo development that is considered optimal for transfer into the body of the expectant mother);
• blastocysts were formed, but of poor quality.

What is the reason?

The older the woman, the more difficult it is to obtain a sufficient number of high-quality eggs as a result of stimulation. Age is an obvious culprit in adverse embryological outcomes. But not the only one.

There is evidence of the negative effects of oxidative stress (the process of cell damage as a result of oxidation), obesity, and psychological stress[1]. Of course, this list also includes alcohol and smoking. The issue may be a genetic disorder in one of the partners or problems with sperm.

A separate story is the retrieval of immature oocytes and empty follicle syndrome. This happens if follicles that have not reached 14 mm are punctured, if LH and hCG do not work as expected. Empty follicle syndrome (EFS) can be associated both with disorders of folliculogenesis and with other reasons: errors during puncture, use of low-quality drugs, incorrect introduction of a trigger (at the wrong time, not completely), etc. EFF is more common with low ovarian reserve, in late reproductive age, with obesity, PCOS.

What can you do before your next attempt?

In preparation for the next ART program, both partners need to give up alcohol and smoking and normalize body weight. The expectant mother should take folic acid supplements in dosages recommended by the attending physician. Normalizing sleep and rest patterns can play a positive role (according to a recent systematic review[2], lack of sleep negatively affects ART outcomes, but more research is required).

Research is actively underway in the direction of adjuvant (additional) therapy. A recently published review[3] showed that adjuvant therapy with DHEA, testosterone, coenzyme Q10 and growth hormone is effective in patients with poor response: with a lower dose of stimulation drugs, the number of embryos and clinical pregnancy rates increased. But large studies are needed to confirm the findings.

In addition, after an unsuccessful program, patients are advised to:

• genetics,
• andrologist,
• psychologist.

What can you do during your next stimulation?

How to stimulate the ovaries in the new protocol to increase the chances of success? There are different approaches. The fertility specialist may use a different stimulation protocol, change the type of ovarian stimulation drugs or their dosage. Another trigger for the final maturation of eggs or the use of a double trigger may be effective when a combination of drugs is used [4] (ovulation triggers are drugs that ensure the final maturation of eggs), increasing the time between the introduction of the trigger and puncture of the follicles. It all depends on the specific situation.

IVF or ICSI?

A solution to the problem may be to use another method of fertilization - for example, ICSI or PIXI instead of IVF. However, in the absence of male factor infertility or low fertilization rates, routine use of ICSI or PICSI for all oocytes is not recommended[5]. The role of PIXI and other sperm selection methods continues to be studied and requires large studies on this issue.

If again there are no quality blastocysts

What if patients have had multiple ART programs in the past resulting in poor quality embryos? Maybe in this case we can simply transfer those embryos that we are able to obtain? Several studies have been conducted to answer this question. Thus, in 2020, the results of a retrospective study of 2585 cryotransfers of category BB blastocysts (good quality embryos) and 102 cryotransfers of category CC blastocysts (usually such embryos are not transferred or cryopreserved) were published [6]. It showed that transfer of CC blastocysts leads to pregnancies and the birth of healthy children. Although clinical pregnancy and live birth rates were lower in the CC blastocyst group compared with BB blastocysts (21.6% vs. 51.3% and 16.7% vs. 41.4%, respectively), assessment of neonatal outcomes did not demonstrate significant differences in body weight of newborns, the frequency of low birth weight children, early neonatal mortality and congenital malformations.

However, there are also studies that have demonstrated an increased risk of chromosomal abnormalities and malformations when poor quality embryos are transferred.

Transfer of low-quality blastocysts or embryos that have not reached the blastocyst stage (days 5-6 of development) can be used in patients with a history of receiving multiple poor-quality embryos after being informed of the possible risks.

In situations where no additional approaches allow achieving the desired goal - the birth of a healthy baby, donor biomaterial is used: donor oocytes or donor sperm, or both (so-called “cross-fertilization”).

Conclusion

Canceling a transfer in an IVF program, even in several programs in a row, is not a reason to give up. Specialists may use different approaches depending on the specific case:

• Change preparation for stimulation.
• Change the type of protocol, dosage, type of drugs for stimulation.
• Apply another trigger.
• Schedule an additional examination with your partner and prepare for the next ART program.
• Use another fertilization method.
• Change your migration strategy.
• Use donor biomaterial.

Continue to move towards success by trusting your doctor and strictly following his instructions. In this case, the experience of a reproductive specialist and his professionalism when performing stimulation and puncture of follicles are very important.

Make an appointment with a “Life Line” fertility specialist by phone or send a request using the form below. You and I will succeed! [1] Meldrum DR, Casper RF, Diez-Juan A, Simon C, Domar AD, Frydman R Aging and the environment affect gamete and embryo potential: can we intervene? Fertil Steril. 2021 Mar;105(3):548-59. doi: 10.1016/j.fertnstert.2016.01.013. Epub 2021 Jan 23. [2] Gabriela Caetano, Ines Bozinovic, Charlotte Dupont, Damien Leger, Rachel Levy, Nathalie Sermondade. Impact of sleep on female and male reproductive functions: a systematic review Fertil Steril. volume 115, issue 3, P715-731, March 01, 2021. [3] Yu Zhang, Chao Zhang, Jing Shu, Jing Guo, Hsun-Ming Chang, Peter C. K. Leung, Jian-Zhong Sheng, Hefeng Huang. Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis. Hum Reprod Update. 2020 Feb 28;26(2):247-263. [4] Chi-Huang Chen, Chii-Ruey Tzeng, Peng-Hui Wang, Wei-Min Liu, Heng-Yu Chang, Huang-Hui Chen & Ching-Hui Chen. Dual triggering with GnRH agonist plus hCG versus triggering with hCG alone for IVF/ICSI outcome in GnRH antagonist cycles: a systematic review and meta-analysis Arch Gynecol Obstet. 2018 Jul;298(1):17-26. [5] Intracytoplasmic sperm injection (ICSI) for non-male factor indications: a committee opinion. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020 Aug;114(2):239-245. doi: 10.1016/j.fertnstert.2020.05.032. Epub 2021 Jul 9. [6] Li, M., Yin, M., Wu, L. et al. Pregnancy and neonatal outcomes of morphologically grade CC blastocysts: are they of clinical value?. Arch Gynecol Obstet 302, 1511–1521 (2020).