Developmental Disorders and Reproductive Technologies

Table of Contents

Overview

Embryonic development in animals and humans is a finely tuned sequence of cell divisions, migrations, and differentiations. Even small disturbances in this process may lead to developmental disorders. Modern reproductive technologies can help some couples have children, but they also introduce new biological and ethical questions, and may influence which developmental disorders are more or less likely to occur or be detected.

In this chapter, we focus on:

Typical types and causes of developmental disorders in animals and humans.
How disturbances at different stages of development manifest.
What modern reproductive technologies do biologically.
How these technologies intersect with developmental biology (risks, prevention, diagnosis).
Basic ethical and societal aspects relevant for biology teaching.

The mechanics of normal embryonic development in animals and humans are treated in the corresponding chapters and are presumed here.

Types and Levels of Developmental Disorders

Developmental disorders can be grouped according to:

The level of biological organization at which the disturbance arises:

Genetic level (genes, chromosomes).
Cellular and tissue level (cell division, migration, differentiation).
Organismal and environmental level (maternal health, teratogens).

The time point in development at which the disturbance occurs:

Pre-implantation (zygote, early cleavage).
Embryonic period (organogenesis).
Fetal period (growth and maturation).

Genetic and Chromosomal Origin

Many developmental disorders begin with changes in the genetic material at conception or shortly thereafter.

Gene Mutations

Point mutations or small insertions/deletions in single genes can lead to:

Missing or non-functional proteins.
Abnormal signaling pathways during development.

Outcomes:

Some are lethal very early (pre-implantation loss).
Others manifest as congenital malformations or metabolic diseases after birth.

Examples (without going into full medical detail):

Disturbances in genes controlling limb patterning can lead to shortened or missing limbs.
Mutations in genes guiding neuronal migration can cause severe brain malformations and intellectual disability.

Details of mutation mechanisms and inheritance patterns belong to the genetics chapters; here we focus on their developmental consequences.

Chromosomal Abnormalities

Changes in chromosome number or structure often have strong effects on development:

Aneuploidies (extra or missing chromosomes):

Often lead to early embryonic death and spontaneous abortion.
Some combinations are compatible with life but cause characteristic syndromes (e.g., certain trisomies).

Structural changes (deletions, duplications, translocations):

May remove or duplicate developmental genes.
Can disturb gene dosage or gene regulation.

In animals:

Many chromosomal aberrations are incompatible with implantation or normal development.
Selective breeding sometimes inadvertently increases the frequency of certain defects (e.g., skeletal malformations in dog breeds) due to linked chromosomal regions.

Non‑Genetic and Multifactorial Causes

Not all developmental disorders are strictly genetic. Many result from interactions between genes and environment.

Teratogens

Teratogens are environmental influences that cause malformations during embryonic or fetal development. Typical categories:

Chemical teratogens:

Certain medications (e.g., some antiepileptic drugs if not properly managed).
Alcohol (can cause characteristic growth and brain abnormalities).
Industrial chemicals and environmental toxins (e.g., some pesticides, heavy metals).

Physical teratogens:

Ionizing radiation.
Extreme heat in early pregnancy.

Biological teratogens:

Some viruses, bacteria, and protozoa that cross the placenta or egg membranes.
Maternal metabolic diseases (e.g., poorly controlled diabetes) that alter the intrauterine milieu.

Key principle:

Timing is critical. The same teratogen may have:

No effect if exposure is before implantation (but can cause loss of the embryo).
Massive structural malformations during organogenesis (embryonic period).
Mainly growth restriction or functional impairment in the late fetal period.

Mechanical and Nutritional Influences

Nutritional deficiencies:

Lack of specific vitamins and micronutrients can alter developmental programs (e.g., folate deficiency is strongly associated with neural tube closure defects).

Mechanical factors:

Restricted uterine space in some animals or abnormal amniotic fluid volume can affect limb positioning and joint formation.

Placental dysfunction:

Reduced nutrient and oxygen supply can impair brain and organ development and cause low birth weight.

Multifactorial Disorders

Many developmental disorders arise from:

Several genes with small effects (polygenic inheritance).
Combined with particular environmental conditions.

These do not follow simple Mendelian patterns and often show variable severity among individuals.

Stage‑Specific Consequences of Disturbances

The same cause can have very different outcomes depending on the stage of development:

Pre‑implantation Stage

Severe genetic abnormalities or early cleavage errors frequently trigger developmental arrest and loss of the conceptus before pregnancy is clinically recognized.
Many early miscarriages are due to chromosomal anomalies and never become visible malformations.

Embryonic Period (Organogenesis)

Disruptions in this stage are most likely to cause major structural malformations, such as:

Neural tube defects.
Heart defects.
Limb malformations.
Facial clefts.

Because organ primordia are just forming, signaling gradients, cell migrations, and patterning processes are extremely sensitive.

Fetal Period

Once major organs are formed:

Disturbances more often cause growth restriction, functional impairments, or milder structural anomalies:

Brain growth reduction leading to smaller brain size.
Disturbances in lung maturation.
Changes in endocrine systems affecting metabolism after birth.

Detecting Developmental Disorders Before Birth

Modern reproductive medicine offers numerous methods to detect or predict developmental disorders during pregnancy (prenatal diagnosis) or even before pregnancy is fully established (preimplantation diagnosis).

Non‑Invasive Prenatal Diagnosis (NIPD / NIPT)

Based on material from the pregnant individual without penetrating the uterus:

Ultrasound examinations:

Visualize fetal anatomy and growth.
Can detect many structural malformations (e.g., heart defects, limb abnormalities).

Biochemical screening tests:

Measure maternal blood parameters that correlate with certain anomalies or placental dysfunction.

Analysis of free fetal DNA in maternal blood:

Small fragments of fetal DNA circulate in maternal blood.
Can be used to screen for some chromosomal aberrations.
Typically considered a screening test, not definitive diagnosis.

These methods carry low risk to the embryo/fetus but can generate uncertain or probabilistic results.

Invasive Prenatal Diagnosis

Here, samples containing fetal cells or tissues are taken from the uterus:

Chorionic villus sampling (CVS):

Sampling of placental tissue early in pregnancy.
Allows chromosomal and sometimes molecular genetic analyses.

Amniocentesis:

Sampling of amniotic fluid, which contains fetal cells and soluble substances.
Chromosome analysis, DNA testing, and biochemical tests are possible.

Risks:

Small but real risk of pregnancy loss.
Therefore usually offered only when there is increased risk for a developmental disorder (e.g., abnormal screening results, family history, known parental chromosomal rearrangements, advanced maternal age).

Preimplantation Genetic Testing (PGT)

Preimplantation genetic testing is closely linked to assisted reproduction technologies and is described further below. Biologically, it is a form of very early prenatal diagnosis:

Embryos created in vitro are biopsied at the cleavage or blastocyst stage.
Single or few cells are analyzed genetically.
Only embryos without specific detected defects are selected for transfer into the uterus.

This procedure does not change the embryo’s genes; it selects among existing embryos. It raises specific ethical questions because the selection occurs before implantation.

Reproductive Technologies: Basics and Variants

Reproductive technologies intervene in the processes of gamete production, fertilization, and early development. Here we focus on those that directly connect to developmental disorders.

Assisted Reproductive Technologies (ART)

The central idea in ART is to support or replace steps that naturally occur in the body.

Controlled Ovarian Stimulation

To retrieve multiple mature oocytes:

Hormonal stimulation is used to cause growth of several follicles in the ovaries.
This increases the number of available oocytes per cycle, enabling:

Generation of multiple embryos for selection.
Cryopreservation (freezing) of surplus gametes or embryos.

Biological implications:

Higher hormone levels than in a natural cycle.
Potential for retrieving oocytes that might differ in quality.
Oocyte quality and age remain key determinants of genetic stability.

In Vitro Fertilization (IVF)

In classical IVF:

Oocytes are collected from the ovary.
Sperm cells are processed and added to the oocytes in culture.
Fertilization occurs in a controlled medium outside the body.
Embryos develop in vitro to a specific stage (e.g., 2–8 cells or blastocyst).
One or a few embryos are transferred into the uterus.

Biologically important aspects:

Embryos develop in an artificial environment, but culture media attempt to mimic oviduct and uterine fluids.
The early developmental sequence (cleavage, compaction, blastocyst formation) follows the same basic pattern as in vivo, but may be sensitive to culture conditions.

Intracytoplasmic Sperm Injection (ICSI)

ICSI is a specialized form of IVF:

A single sperm is injected directly into the oocyte cytoplasm using a fine micropipette.
Particularly useful when:

Sperm count or motility is very low.
Sperm cannot effectively penetrate the zona pellucida.

Biological consequences:

The natural selection steps that normally occur (competition among sperm, interaction with zona pellucida) are largely bypassed.
Sperm that might not achieve fertilization naturally can still pass on their genes, including possible genetic causes of male infertility.

Intrauterine Insemination (IUI)

Less invasive:

Prepared sperm are introduced into the uterus close to the time of ovulation.
Fertilization still occurs in vivo.

Developmental relevance is minimal beyond slightly altered sperm selection; embryonic development proceeds in the natural environment.

Gamete and Embryo Cryopreservation

Biological principle:

Cells are cooled to very low temperatures (usually in liquid nitrogen, about $-196^\circ\text{C}$) with cryoprotective agents to prevent ice crystal formation.

Applications:

Sperm and oocyte banking before:

Gonadotoxic treatments (e.g., chemotherapy).
Age-related decline in fertility.

Embryo freezing:

Surplus embryos from IVF cycles can be stored for later use.

Developmental aspects:

Frozen–thawed embryos can resume development upon warming.
Modern methods (e.g., vitrification) have greatly improved survival rates.
Long-term follow-up studies are ongoing to assess subtle developmental or epigenetic effects, but current data suggest largely comparable outcomes to fresh transfers for many parameters.

Use of Donor Gametes and Surrogacy

Some reproductive technologies change the genetic or gestational relationships among participants.

Donor Sperm and Donor Oocytes

When one partner cannot produce functional gametes, cells from donors can be used.
Biological consequences:

The resulting child is genetically unrelated to one parent (or both, if donor oocyte and sperm plus gestational carrier are used).
Genetic risk profile is that of the donor; donors are typically screened for certain heritable diseases.

Developmental issues:

Donor selection aims to reduce risk of severe genetic disorders.
Still, de novo mutations or undetected carrier status mean that developmental disorders cannot be entirely excluded.

Surrogacy / Gestational Carriers

Embryos (often from the commissioning couple’s gametes) are transferred into another person’s uterus.
Developmental biology:

Genetic contribution comes from the gamete providers, but:

The intrauterine environment (placental interactions, maternal metabolism, stress hormones, nutrition) comes from the gestational carrier.

This environment can influence:

Birth weight.
Epigenetic modifications.
Some aspects of long-term health (as suggested by the developmental origins of health and disease concept).

Interactions Between ART and Developmental Disorders

Reproductive technologies can affect developmental disorders in three main ways:

Changing who can reproduce (parents with genetic risks or infertility).
Modifying pre- and peri-conceptional conditions (culture media, hormonal milieu).
Allowing selection and diagnosis (screening/diagnosis before implantation or birth).

Potential Risks Associated with ART

Most children conceived via ART are healthy, but research has identified some tendencies:

Slightly increased rates in some studies of:

Preterm birth and low birth weight.
Certain imprinting disorders (which involve epigenetic regulation) in rare cases.

Possible contributing factors:

Underlying infertility itself (parental biology).
Hormonal stimulation.
In vitro culture conditions influencing early gene expression and epigenetic marks.

It is important to distinguish:

Disorders directly caused by the technology itself (likely rare).
Disorders associated with the parental conditions that made ART necessary.

Prevention and Reduction of Developmental Disorders Using ART

On the other hand, ART makes new preventive strategies possible:

Preimplantation Genetic Testing for Monogenic Diseases (PGT‑M)

Used when parents carry known mutations that cause severe inherited diseases.
Procedure:

IVF/ICSI is performed to obtain embryos.
At a certain stage, 1–several cells are removed from each embryo.
DNA analysis detects whether the embryo carries the harmful mutation.
Only embryos free of the disease-causing genotype are transferred.

Biological effect:

Does not alter any genome but selects among embryos with different genotypes.
Can drastically reduce the probability that a child will be born with that specific hereditary disease in the family.

Preimplantation Genetic Testing for Aneuploidies (PGT‑A)

Screens embryos for chromosomal number abnormalities.
Intended to:

Reduce miscarriage rates.
Increase the chance of successful implantation.
Potentially reduce the birth of children with certain chromosomal syndromes.

Limitations:

Mosaicism: different cells in the same embryo may carry different karyotypes, making interpretation complex.
Technical and biological variability can lead to false‑positive or false‑negative diagnoses.

Carrier Screening and Gamete Selection

Before ART, prospective parents (or donors) may be genetically screened.
Donors are often excluded if they carry certain recessive disease alleles at high risk of expression.
This can lower the incidence of some profound developmental disorders in offspring.

Ethical and Societal Considerations (Biological Perspective)

While this course focuses on biology, developmental disorders and reproductive technologies raise interlinked ethical and societal issues that influence research, regulation, and clinical practice.

Selection and “Reproductive Autonomy”

Biological facts:

Many more embryos are produced in ART than are eventually implanted.
With preimplantation testing, embryos are evaluated and selected based on genetic information.

Questions with biological relevance:

How do we define “serious” developmental disorders vs. acceptable variation?
Could widespread selection against certain genetic traits reduce genetic diversity in the population?
How might this influence the future spectrum of hereditary diseases?

Boundary Between Therapy and Enhancement

Current practice:

ART and genetic testing are predominantly used to overcome infertility and avoid severe disease.
However, in principle, genetic information could be used to select for non‑medical traits (e.g., predicted height polygenic scores).

From a biological standpoint:

The more traits are understood genetically, the more technically possible selection becomes.
Many such traits are polygenic and strongly environment‑dependent, so predictive power is limited and may be misinterpreted.

Long‑Term Effects and Epigenetics

Early embryonic development is accompanied by extensive epigenetic reprogramming:

DNA methylation patterns and chromatin states are reset and re‑established.
Culture conditions, oxygen levels, and media components can influence these processes.

Biologically important:

Some subtle effects on imprinting and long‑term metabolic regulation may appear only later in life.
Longitudinal follow-up of individuals conceived via ART is crucial to understand long-term outcomes.

Developmental Disorders in Animal Breeding and Research

Although much public attention focuses on human ART, similar principles apply in animals.

Assisted Reproduction in Animals

Frequently used methods:

Artificial insemination in livestock and pets.
Embryo transfer and in vitro fertilization in valuable breeding animals or endangered species.
Cloning (somatic cell nuclear transfer) in research and agriculture.