Why Do Miscarriages Happen?

So what is the reason behind the high percentage of human pregnancy loss? On an evolutionary, teleological level, human pregnancy loss rates, which are high compared to other species on the planet, may be due to the fact that raising a human infant/child to the level of independence is a very labor-intensive job for human parents. Perhaps miscarriage is one of the means, albeit a sad one, of not having too many successful pregnancies in a row and for a mother to recover fully from one pregnancy before having the next. This theory is, of course, speculative on my part and I will never be able to prove it. However, it seems to me there must be some reason why humans are built to abort almost 1 out of every 3 conceptions.

Speculative reasons aside, what is the underlying mechanism for miscarriages? There are two major areas involved: fetal reasons and maternal reasons. The evidence suggests that, in the overwhelming majority of cases, there is something wrong with the fetus.

Embryo and fetal abnormalities can include abnormalities in chromosome number – i.e. having an extra or a missing chromosome, also known as aneuploidy – or can be a sporadic, non-chromosomal abnormality that makes further development incompatible with life, for example, a major heart defect. Aneuploidy (having an incorrect number of chromosomes) is exceedingly common in human pregnancies, especially as a woman ages. Aneuploidy accounts for over half of all sporadic, spontaneous pregnancy losses2. It is also a common cause of failure of early embryos to implant in the uterus. The maternal age-related incidence of aneuploidy of human embryos can be seen in this table of data from Gene Security Network, a laboratory that performs genetic analysis on human embryos using DNA micro-array technology:

This data shows that even in women less than 30 years of age, almost 60% of embryos at 5 days of life are abnormal. However, aneuploidy does not explain the entire picture with regards to implantation success or miscarriage. One recent study found that that using newer DNA analysis techniques, some aborted fetuses showed gene abnormalities that would not be identified using the common genetic methods currently used to evaluate fetal DNA3. These studies suggest that there are sub-chromosomal level abnormalities that also contribute to human fetal wastage. One interesting area of research has involved performance of embryoscopy, (using a lighted scope to visualize an intact fetus) prior to performing a dilation and evacuation procedure (D&C, D&E), a procedure which may render the tissues unrecognizable. These video images have shown us that a substantial number of non-viable human fetuses have recognizable abnormalities, even recognizable in the first trimester, and that not all of these anatomic anomalies are associated with chromosome abnormalities 4-5,

Implantation and the successful early-stage development of an embryo is an exceedingly complex process. On the maternal side, there are a large number of growth factors and other molecules that must be expressed on cells as well as complex anatomic and physiologic processes that must occur for the process to result in a successful live birth6. There is little doubt that some uterine abnormalities can cause a normal embryo to fail to survive. These include congenital abnormalities such as a uterine septum (abnormal shape of the uterine cavity) or acquired abnormalities such as uterine fibroids that distort the endometrial cavity. The majority of these abnormalities can be surgically repaired with good results. Other identified maternal causes of fetal loss are rare but include an auto-immune abnormality, anti-phospholipid antibody syndrome, which is mainly associated with second-trimester fetal loss and poor obstetric outcomes. Endocrine abnormalities such as sub-clinical or clinical hypothyroidism (low thyroid hormone levels with or without symptoms) can cause an increase in fetal loss. There is some limited data suggesting women with thrombophilias (tendency for increased blood clotting) may have a higher risk of miscarriage. More difficult to study and substantiate are possible associations between abnormalities in progesterone levels, infection, alcohol and caffeine use.

On the paternal side, there is a growing body of evidence that increasing paternal age may lead to increasing pregnancy losses in their partners7. This effect has been noted in men older than 50 years of age.

In approximately 40% of all pregnancy losses, there is no identifiable cause. This lack of causation may lead to frustration, especially if a couple experiences two or more miscarriages. It is important to realize that miscarriages are common, even in couples with no fertility problems. Miscarriage appears to be a natural phenomenon built into our evolution and in most cases, an occurrence we are not likely to change the odds of happening, unless couples consciously try to have children at a younger age. It is also important to realize that the risks of experiencing a miscarriage do not increase until three or more miscarriages occur. That means, in a woman with one or two miscarriages, her odds of having a second or third miscarriage are the same as for a woman her age that have never had a miscarriage. Only after the third consecutive miscarriage do the odds of having another increase over the age-related background rates.

References:

1. Incidence of Early Loss of Pregnancy, Wilcox, AJ, et al. NEJM Jul 28, 1988, (319) 189-194.
2. Cytogenetic analyses of culture failures by comparative genomic hybridization (CGH) – re-evaluation of chromosome aberration rates in early spontaneous abortions. Fritz B et al, Eur J Hum Genet 2001, 9; 539.
3. Identification of Copy Number Variants in Miscarriages from Couples with Idiopathic Recurrent Pregnancy Loss. Rajcan-Separovic E, et al. Hum Reprod. 2010 Nov;25(11):2913-22. Epub 2010 Sep 16.
4. Transcervical embryoscopy: images of first trimester missed abortion. Abdala LT et al, J Minim Invasive Gynecol Jan-Feb 2010 17(1):12-13.
5. Abnormal embryonic development diagnosed embryoscopically in early intrauterine deaths after in vitro fertilization: a preliminary report of 23 cases. Fertil Steril Nov 2004 82(5): 1337-42.
6. Implantation and the Survival of Early Pregnancy, Norwitz ER et al. NEJM Nov 8, 2001, 345 (19) 1400-8.
7. The effect of paternal age on assisted reproductive outcome. Dain, L, et al. Fertil Steril Jan 2011, 95(1) 1-8.

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