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Genetic Causes Of Early Pregnancy Loss

Probably one of the most popular series I have written over the past few years is the one on recurrent early pregnancy loss. There is not a week that goes by that I still don’t get inquiries related to that subject, most accompanied by the pain, frustration, sense of loss, and feelings of hopelessness for future fertility. There are several points I always remind readers and patients about whenever I have the opportunity to discuss their concerns: 1) In most cases, the tincture of time alone offers the answer to their prayers; 2) If specific reasons for their losses are found or suspected, these can often be addressed medically and/or surgically; 3) If specific reasons cannot be identified, there are reasonable approaches to ‘empiric therapy’; and, 4) If these approaches fail, the science of assisted reproductive technology (ART) has advanced to the point that it can often overcome most obstacles that stand in the way of fertility.

The other points I always mention in response to the questions of “Why did this happen to me?”, “What did I do wrong to cause this?”, “What can I do to assure that it never happens to me again?, particularly to couples who have had their first or second miscarriage, or a sporadic miscarriage after successful pregnancies, are the following: 1) Miscarriages occur in 15-20% of all conceptions; 2) The MOST COMMON cause of early pregnancy losses are chromosomal abnormalities that occur by chance (except in the case of parental chromosomal rearrangements) and are not under any controllable influences; 3) It is unlikely that anything was “done” to cause the loss, although if there are such potential factors identified, the loss may provide an incentive to modify lifestyle prior to another pregnancy attempt to minimize their risks.

Recently, I received the query below from a woman who has had early pregnancy losses related to documented chromosomal abnormalities. Despite the other problems that have been identified which might contribute to reduced fertility in her case, these probably had no influence on her babies’ chromosomal abnormalities. But, they do give us the opportunity to briefly discuss the well-known observations that certain seemingly “unusual” chromosomal abnormalities (“unusual” in that they rarely or never result in a live born baby) actually contribute to a relatively high percentage of early pregnancy losses.

At Fri Aug 07, 03:17:00 PM 2009, Anonymous said…
I’ve experienced my 2nd miscarriage in 4 months – my husband and I had undergone intrauterine insemination after over a year of unsuccessful pregnancy attempts. These were my first two pregnancies. I had a D&C both times to test the products of conception, and both times, the result was tetraploidy, 92, XXXX. After the first loss, I was tested for many of the miscarriage factors, and was found to have elevated anticardiolipins, so was on 2x daily heparin shots and baby aspirin for the second pregnancy. I’m 35, almost 36, and have been diagnosed with PCOS in the past year. I’ve been on 1500 mg metformin as well as my prenatals, folic acid supplement (and Vitamin D when I was on the Heparin). It looks like tetraploidy is a pretty unusual outcome; what could cause this, and what would be the next recommended steps for us? Is a normal pregnancy *ever* possible?

Thanks for your response.

To anonymous Aug 7:

Humans normally have 46 chromosomes (23 from each of their parents) in each of their cells, except in eggs and sperm (which end up with just 23). When we think of fetal chromosomal abnormalities, the ones that usually come to mind are those associated with one extra chromosome (trisomy) as in the case of Down syndrome (an extra chromosome 21 – or 47 +21) or one less chromosome (monosomy) as in the case of Turner syndrome (one less sex chromosome – 45XO). The most common factor leading to one extra or one less chromosome is an event called nondisjunction that results when a single chromosomal pair (not all 23 pairs) fails to separate during the formation of a gamete (egg or sperm). When a gamete with an abnormal chromosomal complement resulting from nondisjunction then gets together with a normal gamete containing 23 chromosomes, the resulting baby will end up with either 47 or 45 chromosomes and in the vast number of instances (even with Down and Turner syndromes) such pregnancies will not develop past an early stage and be lost as a ‘”blighted ovum” or “spontaneous abortion” (miscarriage) before the end of the first trimester. One of the most common trisomies found in 1 of every 12 to 15 first trimester losses, trisomy 16, never results in a live born baby.

Polyploidy on the other hand describes conditions in which there are additional whole sets of chromosomes. Triploidy has three complete sets (69 chromosomes) and tetraploidy has four complete sets (92 chromosomes). Triploidy occurs in 1 of every 12-15 early losses and teraploidy can actually be found in about 1 out of every 30 early miscarriages, so they are NOT that uncommon! Tetraploidy is believed to result when an unequal division of chromosomes in mitosis during early embryogenesis occurs and causes the cell to not complete the division into two separate cells, resulting in a single cell with 92 chromosomes rather than two cells each with 46 chromosomes.

Triploidy seems to occur by several mechanisms. At the risk of oversimplification, a triploid embryo can have either two set of chromosomes from the mother plus one set from the father or two sets from the father and one from the mother. In the former case, the mother contributes an abnormal gamete containing 46 chromosomes (rather than 23) and that gamete is fertilized by a male gamete containing the normal 23 chromosomes. This is termed digynic triploidy. When the father is the cause of the triploidy, this can result by two mechanisms: 1) fertilization of a normal egg by two sperm from the father (dispermy) or, 2) actual fertilization of a normal egg by a sperm containing two sets of chromosomes. When the father is the source of the extra set of chromosomes, this is termed diandric triploidy. The most common cause of triploidy appears to be the result of paternal dispermy. Whether of maternal or paternal origin, triploidy is associated with multiple fetal abnormalities and usually death of the baby in utero and in the few survivors to birth (usually those of maternal origin), death within the first year of life. Diandric triploidy is often associated with large placentas that have a “Swiss cheese” appearance (partial molar pregnancies) and digynic triploidy typically is accompanied by very small, noncystic, placentas and early fetal growth restriction.

With regard to the reader’s inquiry, I do not believe there is a familial tendency for tetraploidy to occur although the formation of tetraploid cells is a common intermediate found in the development of certain cancers. And yes, there is a very high likelihood you can have a successful pregnancy even with the other factors working against you! Best wishes and thanks for writing.
Dr T

This post, Genetic Causes Of Early Pregnancy Loss, was originally published on by Kenneth Trofatter, M.D., Ph.D..

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