Early Pregnancy Loss: Causes and a Rational Approach to Management.

There is nothing more stressful to patients and to caring physicians than dealing with recurrent early pregnancy losses (RPL). There is also no greater imperative in such cases than to carefully identify the underlying cause that without which successful treatment is far less likely.

In about 80% of cases, early pregnancy loss (whether due to miscarriage or chemical pregnancy) is due to embryo abnormalities which are usually (but not invariably) related to chromosomal irregularities (aneuploidy) originating in the egg (rather than the sperm). In the remaining 20% of cases, the cause is implantation dysfunction which can result from anatomical (lining), immunologic implantation dysfunction (IID) or molecular biochemical abnormalities.

Since egg and embryo aneuploidy occur so frequently as a variant of normal reproductive performance, it follows that early pregnancy loss is likewise normal to the human condition. Moreover, since egg chromosomal irregularities increase with age advancement beyond 34y, starting at about 1:2 eggs/embryos ty about19; 20 (5%) by age 45y. the incidence of embryo aneuploidy will likewise increase as the woman gets older.

Depending upon how early the pregnancy loss occurs, it might manifest as a positive pregnancy test, prior to the emergence of clinical or ultrasound evidence of a pregnancy (a chemical pregnancy) or later after clinical or ultrasound evidence of an established pregnancy has become evident.

The incidence of early pregnancy loss rises dramatically as the women age beyond 40 years such that by the mid 40’s it is greater than 50%. This is largely due to the age-related increase in egg aneuploidy. Such chromosomal early pregnancy losses occur randomly and sporadically so that a woman might have a baby, lose one or two and then have another healthy pregnancy. In other words, they rarely occur repeatedly (>2 in a row). In contrast, early pregnancy losses that are due to implantation dysfunction (i.e. attributable to surface lesions in the uterine cavity, a thin uterine lining or due to IID) tend to be recurrent in nature. In summary, while miscarriages most commonly occur as a result of chromosomal egg-related embryo abnormalities, these rarely present as recurrent losses and thus when recurrent pregnancy loss (RPL) occurs, it is important to consider and rule out implantation dysfunction problems as the primary cause, before proceeding to another IVF attempt.

Women who have repeated IVF failures thus need to be evaluated thoroughly for both embryo competency and implantation dysfunction before and/or in the course of their next IVF attempt. Implantation problems should be evaluated before proceeding to the next IVF cycle. The tests needed include:

  1. Evaluation of the anatomical integrity of the uterus. This necessitates performance of a sonohysterogram (saline sonogram), a hysteroscopy or a pelvic MRI (rarely is it necessary to go this far). A hysterosalpingogram (HSG), also known as a dye x-ray, is inadequate because it involves injecting a radio-opaque substance into the uterine cavity which can obscure small lesions due to scarring, polyps or fibroids protruding into the uterine cavity.
  2. Assessment of endometrial thickness. This can be determined by ultrasound examination around the time of normal ovulation or can be determined based on endometrial thickness as measured in the previous cycle. A lining of > 9 mm in thickness is ideal. Less than 8 mm is poor and between 8 – 9 mm in thickness is “intermediate”. In my opinion, embryos should not be transferred into a uterus where the lining measures < 8 mm. The administration of vaginal Viagra (sildenafil) suppositories for at least 72 hours prior to the hCG trigger will often dramatically improve a “thin lining”.
  3. Autoimmune and alloimmune causes of immunologic implantation dysfunction should be assessed. Since both allo-and autoimmune implantation dysfunction ultimately are linked to Natural Killer Cell activation, you can start by doing a Natural Killer Cell activity (NKa) test using the K562 target cell test and/or endometrial cytokine analysis, and only proceed to more detailed evaluations if this turns out to be abnormal. Numerous blog articles on this site provide more details on IID and the use of immunotherapy that address/reverse such problems.
  4. Testing molecular and biochemical factors in the endometrium. There has been a growing interest in the measurement of various endometrial factors as a method to assess implantation potential, including the endometrial receptivity assay (ERA) and other molecular assessments. Frankly, I personally do not share enthusiasm for most such tests which by and large lack concrete evidence of efficacy.

Recent advances in egg and embryo karyotyping using Preimplantation Genetic Testing (PGT)- technologies have improved our ability to identify “competent” chromosomally normal embryos for transfer. This requires biopsying the advanced embryo (blastocyst) and testing its DNA for aneuploidy. When the so tested, embryo transfer must be deferred until a subsequent hormone replacement cycle (staggered IVF) so as to allow enough time for the results of the testing to become available. In such cases, the embryos can be vitrified (ultra-rapidly frozen) and stored for subsequent dispensation without prejudice.

Aside from the above, there are other less common causes of embryo incompetency (e.g., unbalanced embryo chromosomal translocations) and implantation dysfunction (bacterial and parasitic infections, etc.).

2 Comments

JILL S

Hi Dr Sher,
My history is ttc hard core for 7yrs. I am 40. I have a 16yo son I naturally instantly conceived, due to getting pregnant the first time not using condoms. Got married in 2011. In 2013, while visiting my husband’s hometown in Mexico, we decided to look into medical intervention. We had some blood tests run, I did a vaginal ultrasound. We were told it was due to my husband’s low count of 9mil. I was told my uterus looked perfect. Since we were at the right time in my cycle & it was cheap we performed a double IUI, resulting in no pregnancy, i don’t recall testing avidly, plus did the trigger so if I did get any faint positives I attributed to the trigger. Fast forward to 2015 did an HSG, in MX. On the films you can see the outlines of my fallopian tubes, the Dr said (not an RE) you should be pregnant soon. In 2016 did a mini-stim IVF, in GDL, MX; had 5 follicles, I was awake for the retrieval, 2 of the follicles were empty, because I was awake I watched them try multiple times and they asked when I did my trigger etc. We desperately want a girl, used Microsort & PGS to know for sure the gender, they told us on day 3 they were starting to degrade, I was naively confident they would make it to day 5. I was wrong, all died, no transfer.
In 2016 did another double IUI because we were in MX again during the right part of my cycle, it’s cheap, why not? Again failure.
2017, got good insurance that covers IVF thought why not use it. I did an SIS, the doctor said due to none of the fluid not entering behind the uterus I had a blockage, 3rd doctor saying my uterus looked perfect, just blocked tubes. No fibroids, no endometriosis, nothing abnormal. Did a high dose, IVF cycle here in Utah, maxed out on Menopur & gonal-f. 9 retrieved, 5 mature, 3 made it to blast. No gender sorting available, did PGS, 1 normal, all 3 boy. No transfer.
In 2018 did another IVF, this one, a different clinic, in PV, Mexico. Used Pergoveris & Gonal-f. Used Microsort. 14 follicles, 11 retrieved, 5 embryos, 3 were starting to degrade on day 3, due to not having any transfers thus far instead of discarding I wanted to be the “trashcan” my lining this time was not optimal, it was 18.5mm & irregular shaped, we did the 3day fresh transfer. I started spotting not long after. Was using vaginal 1000mg progesterone per day. Did get a faint HPT BFP around day 9-10, by Beta got a less than 1.
Dec 2018 transferred the remaining 2, the very stern-like doctor was very excited as one of the embryos was expanding upon thaw & my lining was “perfect”. We used embryo glue & HCG wash. Estradiol, Vaginal Progesterone, occasionally Cuerpo Amarillo Fuerte 100mg if experiencing cramps, 20mg of prednisone, Again by day 9-10 got a faint positive, mentally chalked it up to the HCG wash. By beta same results, less than 1.
In 2019 changed clinics to one in Tijuana that everyone raved about & has a high success rate especially those with difficult cases. I did a duo-stim, with Ericsson, & hubby used Licorice Root, clomid, 7 day abstinence, had a 40mil count. She retrieved 9 first half, 5 mature, allowed all to go to day 5, for PGS, only 1 made it to blast; girl, PGS abnormal (46, XX, -21, +22). 2nd half retrieved 11, 9 mature, we requested the 5 best to go to blast to test & freeze the other 4 in pairs on day 3. Unfortunately the allowed the 5 worst to grow to day 5, none made it to blast. Did Hysteroscopy with scratch in Nov, everything normal. My Dr agreed to allow the transfer of the pgs abnormal girl to be transferred with a pair of the others, just needed to grow them to day 5, 1 of the pair ended in blast, the other was an expanding morula by transfer on day 5 as well as the PGT abnormal embryo was expanding, this doctor too was excited & expected a pregnancy. Used PIO & 8mg of estradiol. I got a faint positive HPT on day 7-8 but beta too ended in less than 1.
We started doing LIT(Lymphocyte Infusion Therapy) 3 rounds, final done 4 days prior to FET. Did an infusion of Intralipids 10days before FET. Transferred the final two 3wks 4 days ago. This time using 50mg of PIO daily, occasional oral or vaginal progesterone if feeling cramps, 8mg of estradiol & 60mg of Clexane (Lovenox), 5mg of Prednisone, 12mg of Astaxanthin, Baby Aspirin, 500mg Metformin, Flax Oil Max & Ultimate Omega + CoQ10, Triple Strength Cranberry (recurrent UTI), vitamin D3 200iu, 450mg Vitamin E. Got faint positives again on day 9-10. By beta…again less than 1. Did another round of Intralipids 4 days prior to beta due.

So to conclude…I don’t seem to have uterine abnormalities. In hindsight I seem to get faint positives (chemical pregnancy) about a week after transfer but nothing by day of beta. I also passed a complete endometrial cast the 2nd transfer in PV & a partial endometrial cast upon this last transfer. Could that be due to using 2 different types of Progesterone?

Basically my question is…how can I get past the first 7 days where my faint BFP turns instantly to a BFN to get pregnant? I presume I have IID? What can I do? Both my husband and I have different MTHFR mutations. I am a cystic fibrosis carrier. My husband has managed type 2 diabetes. He was a preemie & has no biological children. His siblings each have 3+ children.

I have also been told: I have high total values of my NK cells (254.1 and 3,753.5) as well as High Sensitivity C Reactive Protein (8.7), the other parameters are within normal limits. Cholesterol is elevated.

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Dr. Geoffrey Sher

Hi Jill!

This is a complex situation that cannot be resolved here. We really should talk.

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about 15y ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.

4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:

a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
e. Ureaplasma Urealyticum (UU) Infection of cervical mucous and the endometrial lining of the uterus, can sometimes present as unexplained early pregnancy loss or unexplained failure following intrauterine insemination or IVF. The infection can also occur in the man, (prostatitis) and thus can go back and forth between partners, with sexual intercourse. This is the reason why both partners must be tested and if positive, should be treated contemporaneously.
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF?
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ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

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