The development of a human embryo is a complex and highly regulated biological process beginning with the fertilization of an egg by a sperm. An embryo is the developing organism from conception until the end of the eighth week of gestation, after which it is termed a fetus. An “abnormal” embryo has developmental issues that prevent successful implantation, result in spontaneous miscarriage, or lead to a severe birth defect. The occurrence of such abnormalities is common, with estimates suggesting that 30% to 40% of all fertilized eggs may miscarry, often before a pregnancy is recognized. Most of these early developmental failures are due to random, spontaneous errors in the genetic material, largely outside of parental control.
The Primary Cause Chromosomal Errors
The most frequent underlying reason for an abnormal embryo is a numerical chromosomal error known as aneuploidy, which accounts for over half of all first-trimester miscarriages. Aneuploidy refers to a cell having an incorrect number of chromosomes, possessing either extra copies (trisomy) or missing a copy (monosomy). Humans should have 46 chromosomes (23 pairs), and any deviation severely disrupts the embryo’s development.
These numerical errors predominantly originate during meiosis, the specialized cell division process that creates the egg and sperm cells (gametes). A failure of precise chromosome separation, called non-disjunction, results in a gamete with 22 or 24 chromosomes instead of the correct 23. Upon fertilization, this creates a zygote with 45 or 47 chromosomes, an imbalance typically incompatible with life.
The most common aneuploidy observed in miscarriages is Trisomy 16, which is always lethal in utero. Monosomy X (45, X), resulting in Turner syndrome, is the second most frequent error. Trisomy 21 (Down syndrome) and Trisomy 18 (Edwards syndrome) are other examples resulting from the failure of proper chromosome segregation.
Structural Genetic Defects and Single-Gene Mutations
Genetic abnormalities causing embryonic failure include defects affecting the structure or function of specific genes. Structural defects involve the rearrangement of large segments of chromosomes, often passed down from a parent who is a healthy carrier. For example, a translocation occurs when a piece of one chromosome breaks off and attaches to another.
A parent with a balanced translocation may be unaffected, but the embryo often receives an unbalanced set, causing gene duplication or deletion. Other structural errors include deletions (a missing segment) or inversions (a flipped segment). These changes disrupt the genetic code and can lead to conditions like Cri-du-chat syndrome, caused by a deletion on chromosome 5.
Single-Gene Mutations
Single-gene mutations, or monogenic disorders, are caused by a defect in just one specific gene. These mutations follow standard inheritance patterns, such as autosomal dominant or recessive, and can cause embryonic lethality in severe forms. If parents are recessive carriers, the embryo may inherit two copies of the defective gene, leading to developmental failure due to the inability to produce a necessary protein.
Parental and Environmental Risk Factors
The likelihood of genetic errors is strongly influenced by parental biological factors and external environmental exposures. Advanced maternal age is the most documented risk factor for aneuploidy, with the risk rising exponentially after age 35.
Advanced Maternal Age
The mechanism involves the decades-long arrest of the oocyte (egg cell) in prophase I of meiosis. This leads to the gradual degradation of cohesin proteins that hold chromosomes together. This loss of cohesion increases the probability of meiotic non-disjunction, resulting in an egg with an incorrect chromosome count.
Advanced Paternal Age
Advanced paternal age (generally over 40) contributes to embryonic abnormality through issues with sperm DNA quality. As men age, continuous sperm production ( spermatogenesis) is associated with a higher rate of DNA fragmentation and an accumulation of de novo point mutations. These errors increase the risk of single-gene disorders and structural abnormalities in the resulting embryo.
Environmental Factors (Teratogens)
External environmental agents, known as teratogens, can directly disrupt embryonic development and organ formation. Uncontrolled maternal diabetes, for instance, causes hyperglycemia, leading to oxidative stress and hypoxia in the early embryo. This hostile environment alters gene expression, increasing the risk of congenital heart defects and neural tube defects. Exposure to substances like alcohol, tobacco, or industrial chemicals can interfere with cell migration and differentiation during the first trimester.
Errors in Post-Fertilization Cell Division
While most abnormalities originate in the gametes, some defects arise after fertilization during the embryo’s initial, rapid cell divisions. This post-fertilization error is typically a mitotic failure, where replicated chromosomes do not separate correctly in one of the first few cell divisions. The result is mosaicism, where the embryo contains a mixture of both chromosomally normal and abnormal cells.
The outcome depends on the percentage and type of abnormal cells, and which tissues are affected. If the error occurs early, a large proportion of cells may be abnormal, increasing the chance of developmental failure. In some cases, the embryo may self-correct by eliminating abnormal cell lines, or the abnormal cells may be confined to the placenta, allowing a healthy pregnancy to continue.