Polyploidy as a Cause of Early Pregnancy Loss
Monday, August 31, 2009
Kenneth F. Trofatter, Jr., MD, PhD
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
Labels: aneuploidy, chromosomal abnormalities, nondisjunction, polyploidy, recurrent pregnancy loss, tetraploidy, triploidy
22 Comments:
At Tue Sep 01, 01:42:00 PM 2009,
Anonymous said…
Hello Dr. as a teenager I had quite a few abortions about 6 or 7 to be exact because I was afraid to tell my mom and what my family would think about me and I also was not ready for a child either and about to 2 or 3 yrs ago I had 2 miscarriages back to back I wanted to know if the abortions were the reason why I had the 2 miscarriages, since then I had been on birth control and I want a child now but I don't want to go thru another miscarriage again can you please tell me what you think...
Thanks
At Tue Sep 01, 09:47:00 PM 2009,
Anonymous said…
So glad that you are back! Have missed your blogging!!
At Wed Sep 02, 02:51:00 PM 2009,
Anonymous said…
Dr T. My wife, 37, is pregnat with twins via IVF. Her midtrimester screen and NT were normal with 1/2700 odds of a having a baby with DS. during a 20 week US an EIF was observed on twin 1 (boy) and a CPC on twin 2 (girl). No other abnormalities were observed and the babys growth and weight is normal. The doctor indicated that given the midtrimeter test result and the presence of just one isolated marker (for T21 on Twin 1 nad T18 on twin 2)on each baby he does not recommend an amnio in those cases. We are concern about the fact that both babies present soft markers for different chromosom abnormalities and want to have a second opinion about whether amnio is recommended in this case.
At Wed Sep 02, 04:13:00 PM 2009,
Anonymous said…
Hello, Dr. My wife is 22 weeks pregnant at age 31. The last ultrasound has shown anhydramnios, attributed to the placenta being aligned with a large fibroid. Kidney development appears normal, however. I've searched the usual haunts (Google/google scholar/Google books/medline) for literature on fibroids as a cause of anhydramnios/oligohydramnios and have come empty handed, at least until I can sneak into a college library and access ScienceDirect. The OB at present is not prescribing any intervention beyond rest. Can you tell us anything about the frequency of such pregnancies or probabilities of their outcomes?
Many thanks.
At Thu Sep 03, 07:18:00 AM 2009,
amylynn said…
I have recently experienced my 7th miscarriage. This pregnancy I was treated empircally with Lovenox 30mg/twice a day and Prometrium 200mg 2x a day. The pregnancy ended at 9wks 1day gestation after confirmed heartbeat at 6wks4days. 4 of my pregnancies ended after confirmed heartbeats. I had a septum resection done in 2007 and have since had 3 miscarriages. I have not been tested for any immunologic factors. My clinic does not see value in that or the treatment. With the lovenox this pregnancy was much more developed than any of my previous pregnancies even though it ended in the same time frame. My questions are,
1. What are your opinions on immunologic testing?
2. Since this pregnancy was further developed would there be value in starting lovenox sooner or at a higher dosage? (I started lovenox after my second beta at 20dpo)
3. This pregnancy was spontaneous but we did three cycles of Femara before this cycle we were taking off and got pregnant. Would there be benefit in trying Femara again with timed intercourse and possibly an HCG trigger shot?
4. Or is it time to look at other options for parenthood?
Thank you so much for your time, I know it is valuable.
At Fri Sep 04, 10:18:00 AM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Sep 1: I imagine many of your abortions and even the miscarriages were managed by D&C procedures. These can damage the lining of the uterus and cause scarring that might lead to 'infertility.' When this occurs, it is called Asherman's syndrome and if you go through my posts over the past several years, you can find some information related to that. I would recommend that you find a specialist in Reproductive Endocrinology and Infertility who can perform a sonohysterogram and/or hysteroscopy to look for evidence of scarring inside the uterus. Best wishes and thanks for writing.
Dr T
At Sat Sep 05, 10:58:00 PM 2009,
Anonymous said…
Dear Dr. T,
I have read through your past posts from the beginning and have not found any that address my question. But...I have learned alot!! I am 25 1/2 and have had one healthy pregnancy (Pregnancy #2) and baby boy, now 15 months old. I have had 3 early miscarriages in the last 2 years, 6.4. 5.2 and 6.6 weeks. I have recently had testing done by an RE and the only unusual thing is TSH 3.99, and normal T4. I have been started on Levoxyl 50mcg/day. Don't know if that is the cause or not. I have not read what you think about where the TSH level should be.
But the question that is most disconcerting to me is about my FSH and LH levels. They came back as FSH 9.6 and LH 9.3 drawn on CD3. My husband and I have wanted to have several more children and are now concerned that my ovaries are apparently aging fast! This has been VERY distressing! My DR said that we should try and be finished by age 30 with our family. With my m/c history I am even concerned that I may not have any more! I wonder what you have found in your experience with elevated FSH and LH at my young age? We are actively TTC!!!
I know you are so very busy, and I appreciate any time and wisdom you could give to me!
Thank you so very much!
At Wed Sep 09, 07:59:00 PM 2009,
gpw said…
Dr T,
A friend on mine went for her 20 week ultrasound, just looking to determine the sex of her baby. Her 11 week US was normal. The tec told her they saw several problems. the tec got a Dr and after reviewing the US informed her that the fetus had a hole in its heart, clenched hands and a nuchal sac and thickened neck. They sent her to a counselor and was informed that the pregnancy would more than likely terminate. They then performed an amino and received the initial tests done on 5 chromosomes. The test came back negative, but told her not to get her hopes up because this could be worse than they had anticipated. She is now awaiting the final tests. The baby is very active. Can you shed some light on these findings. what could cause this, if not chromosome abnomolies?
At Sun Sep 27, 03:24:00 AM 2009,
longingforthird said…
Dear Dr. T.
My last pregnancy ended in a D&C at 5 weeks as the fetus had stopped growing at 6 weeks. The chromosome study showed the pregnancy to be triploidy. I have to talk to the doctor but I am worried, as this was my 3rd miscarriage, that my low ovarian reserve (AMH 4.3 pmol/l) means my oocytes are "allowing"2 sperm in instead of shutting the gate, so to speak. I am now 35 and have 2 live Children, a son of 11 and a daughter of 7. I had my first m/c in Feb 2006, then no pregnancies until early this year after being treated for a non visible micro prolactinoma that stopped me ovulating for at least 3 years. My ovaries are still the normal size. also, is it possible that poor pituitary function could have numbed my ovaries and given an unduly low AMH reading they may increase with tie, or am I wishful thinking. I come from a long line of older mothers and am having a hard time dealing with my secondary infertility. I have researched triploidy and understandthe 3 variations. It also occurs to me that maybe my husband or myself have diploid gametes and have just been lucky in the past. Kind Regards, Longing for a Third.
At Mon Sep 28, 06:23:00 PM 2009,
gpw said…
Wed Sept 9th regarding friend: Amnio came back negative, but at the last level II ultra sound they found the following: sepatated, av canal defect,cystic hygroma, choroid plexus cysts, large VSD, 2 vessel cord and consistently clenched hands. She is a full 6 months at this point. They are awaiting an array CGH findings. What could this be?
At Wed Sep 30, 11:05:00 AM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Sep 5: If you are undergoing premature ovarian failure, it is not too soon to be discussing some form of assisted reproductive technology with your REI doctor. Good luck and thank for writing.
Dr T
At Wed Sep 30, 11:09:00 AM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To GPW: The baby could have a chromosomal mosaicism, however, I am more concerned that this is a syndromic (genetic) problem where the overall chromosomal number is normal but there is some inborn error. There are many different genetic syndromes that can cause the features you have described so all I can recommend is to continue open communication with the Genetics people and if a diagnosis cannot be made before birth, perhaps it can be after the baby is born. This will be important even if the baby dies for proper counseling and future prospects of diagnosis. Thank you for writing and I am sorry I cannot be of more help at this time.
Dr T
At Wed Sep 30, 11:11:00 AM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To longingfor third: It is VERY unlikely that you or your husband have a chromosomal abnormality and, as pointed out in this post, spontaneous triploidy events are not infrequent. If you are in a panic, however, about another successful pregnancy, I would suggest you see a specialist in Reproductive Endocrinology and Infertility sooner than later! Best wishes and thank you for writing.
Dr T
At Thu Oct 08, 02:32:00 PM 2009,
gpw said…
Dr T, thank you for your feedback. We heard back today from the geneticist with the following news: 1 or the 2 chromosome 10s detached and then reattached to chromosome 20. Chromosome 20 has 3 sets of 20, they referred to this as mosaicism and the problem with 10 as translocation. They said they had never seen this particular problem before and could not shed any definite light on the problem. Is this truly as uncommon as they say? Please refer back to the symptoms from my previous post on Sept 9th.
At Thu Oct 15, 06:31:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To gpw Oct 8: do they think the translocation is "balanced"? I suspect it is not in view of the multiple abnormalities of the baby. I am afraid there will probably not be a very good outcome to this pregnancy. I am so sorry, but please let me know.
Dr T
At Thu Oct 29, 06:30:00 AM 2009,
Anonymous said…
Dear Dr.T, i had a miscarriage in early 07 at 11 wks and a D&C was done to remove remaining tissue. It was tested and results showed endometrial glands showing Arias-Stella reaction. What does this mean? I had another miscarriage after which I was put on Duphaston. At 6 months it was discovered that the fetus had dilated cardiomyopathy. C'd the progesterone hv caused this? It also hd a nuchal cord and ended into a stillbirth. I hv since gone on to hv 4 Chemical pregnancies that come out before 5 wks. I hv done tests like thyroid hormones,toxo,brucella agglutination, coombs and they hv all come out normal. What c'd be wrong with me?
At Wed Nov 11, 11:04:00 AM 2009,
Ty said…
Hello Dr,
I have questions and concerns and hope you can help me. My LMP was October 3, 2009 and I am now confirmed pregnant. My cycles are usually 31 to 32 days long and sometimes 34 days long. When I went in to confirm my pregnancy, I had not even missed a period yet, and my HCG on October 30, 2009 was 67. On November 2, 2009 it went up to 467. The next HCG I had was on November 6, 2009 in the ER. They did it at 8 pm and it was 3100. They also did an ultrasound and saw nothing in the uterus and told me it is probably ectopic because with levels that high, they should see something. I had coplaints of abdominal pressure due to the fact I had not had a bowel movement in 4 days. They never addressed that issue by the way. They admitted into the hospital and told me no food or water just in case they have to do surgery in the morning. They also saw some free fluid in the abdomen and 2 cysts on my left ovary measuring 2cm and 3cm. They tested HCG again and white blood cell count was normal. HCG at 8 am in the morning came back at 4100. I had a followup appt on November 10, 2009 to check HCG and repeat the ultrasound. This time they saw the same thing as before but also saw 2 small sacs each measuring about 4 weeks. They would not call them gestational sacs just yet and told me I still could have an ectopic pregnancy. They checked hcg levels again and scheduled another ultrasound for 1 week. They also saw a mass in my abdomin that they had no clue what it was - ectopic or maybe bowel? They said they were not sure. I got my levels back and they were 15,564. The doctor told me that with twins, you do not see as much early on in the pregnancy as you would with a single baby. By next week, they will see if there is a yolk sac or sac growth. I am confused as to why they keep talking about ectopic pregnancy and surgery and why they won't say that the 2 sacs are gestational sacs for sure. She said it could be fluid or blood or twins. What is your advice? Should i get a second opinion and I am concerned about the 2 cysts on the left ovary, the free fluid and the unknown mass. I took 100 mg of Clomid and got this pregnancy. What should i do. No pain just twinges on my left side in the ovary area sometimes - feels like ovulating pain and just pressure in the lower abdomin, but no tenderness or bleeding.
At Thu Nov 12, 01:36:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 29: The Arias-Stella is the name given to the proliferative changes in the glands of the lining of the uterus seen during normal pregnancy. As far as I know, the synthetic progestational agent Duphaston has had no deleterious effects described during pregnancy. It would also have been unlikely to lose the baby at 6 months from a nuchal cord unless there was a very thin or abnormal cord. If you have not been screened for the more common autoimmune or severe genetic thrombophilias, I recommend that be done. I would also suggest you find a specialist in Reproductive Endocrinology and Infertility to help systematically evaluate and treat you for recurrent early pregnancy loss. Best wishes!
Dr T
At Thu Nov 12, 01:43:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
Ty: Since this is a 'clomid pregnancy', based on all that you have told me so far, I am betting you have twins that came from separate eggs. The two simple cysts on the left ovary are probably the ovulatory sites for the eggs that became these babies (corpus luteal cysts). If you had been constipated at the time of the previous ultrasound, the "mass" in your abdomen may well have been stool in the bowel, but that is not something I can tell you for certain - my crystal ball only works so far! The small amount of fluid in the abdomen is unlikely to be blood if you are not having pain. My suggestion is to be patient for another week or so and you will have your answer. Wishing you the best of luck! Let me know how things turn out.
Dr T
At Mon Nov 16, 01:46:00 PM 2009,
Lisa said…
Dr. Trofatter,
I am a 42 year old who has tried late in life to have a baby. So far, I have had 5 miscarriages. One confirmed trisomy 22. I have also been diagnosed with antiphospholipid antibody syndrome and need to take Lovenox during pregnancy. I am currently 6 weeks pregnant with my first ultrasound tomorrow. Though we have guarded optimism, what are the statisitics for a person with my risks that I will have a child with Trisomy 21, 13,18? Thank you.
At Mon Nov 16, 10:12:00 PM 2009,
Anonymous said…
Dear Dr. T, this is anonymous Oct 29. I did not lose the baby at 6 months, i was induced at 41 wks. My worry right now is that i believe i conceived around Oct 30 and even started getting pregnancy signs. The signs then disappeared at 12 dpo apart from the discharge. I am now 18 dpo but no Af as yet. I am too scared to do the pregnancy test coz i hv a feeling my pregnancy is not growing anymore. Is it possible to have a chemical and not pass the tissue by this time?
At Mon Nov 16, 10:30:00 PM 2009,
Anonymous said…
Dear Dr.T, is it possible that hormones like duphaston can make one carry a pregnancy with chromosomal abnormalities to term when otherwise it would have been miscarried?
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