Reference
Salustiano, R. (2024). Fertilization and Fetal Development. In Dr. RPS Maternal & Newborn Care: A Comprehensive Review Guide and Source Book for Teaching and Learning (2nd ed., pp. 64-79). C&E Publishing, Inc.
Fertilization (conception, fecundation, impregnation) is the union of a mature egg cell (ovum) and sperm cell in the ampulla (outer third) of the fallopian tube. The resulting fertilized egg is called the zygote.
Sperm move within the female reproductive system through flagellar action. Each sperm often reach the ampulla within 5 minutes, up to 4 to 6 hours after ejaculation. From 400 million or more sperm, only ~200 actually reach the ampulla. Sperm often remain for 4 to 6 hours before being able to fertilize an egg, as this period is when sperm capacitation and acrosomal reaction occurs:
- Sperm Capacitation: the sperm becomes hypermobile, and the acrosomal membrane/covering of the sperm head becomes exposed, allowing it to bind with the zona pellucida of the ovum.
- Acrosomal Reaction: the deposition of minute amounts of hyaluronidase in the corona radiata, allowing the sperm to penetrate the ovum.
As soon as the sperm penetrates the zona pellucida and makes contact with the vitelline membrane of the ovum, a cellular change occurs in the ovum that inhibits other sperm cells from entering. This process is mediated by the release of materials from cortical granules (organelles) just under the egg surface.
Fertilization occurs when the male pronucleus units with the female pronucleus; thus, the chromosome diploid number (46) is restored and a new cell, the zygote, is created with a new combination of genetic material, which creates a unique individual different from the parents and anyone else.
The zygote undergoes cleavage/mitosis, in sequential order:
- Zygote: the cell that results from fertilization of the ovum by a spermatozoa. This cell undergoes mitosis, which is the process of cell replication where each chromosome splits longitudinally to form a double-stranded structure.
- Cleavage: a series of mitotic cell divisions by the zygote
- Blastomere: daughter cells arising from the mitotic cell division of the zygote (2-cell, 4-cell, and 8-cell blastomeres).
- Morula: a solid ball of cells produced by 16 or so blastomeres; called the “traveling” form because it is in this form when it migrates through the fallopian tube (oviduct) and reaches the uterine cavity about 3 to 4 days after fertilization.
- Blastocyst: a fluid-filled cavity that reaches the uterine cavity.
Morula Reformation
The morula reforms to become the blastocyst; the cavity within the morula is the blastocoele. This cavity expands, and the outer cells of the morula become the trophoblast. It is after this reformation that energy becomes necessary, and the blastocyst implants into the uterine wall for further development.
Implantation, also known as nidation, occurs within 6 to 9 days (average 7 days) after fertilization. In a normal implantation, the site is in the upper fundal portion or upper one-third of the uterus, either anteriorly or posteriorly. Abnormal implantation sites are the fallopian tubes (ectopic pregnancy) and the lower uterine segment (placenta previa).
Blastocyst
While the blastocyst is in the stage of implantation, its outer layer, the trophoblast, is responsible for actual implantation (nidation). The trophoblast gives rise to the placenta.
The Placenta
The placenta is a discoid (15 to 20 cm in diameter by 2 to 3 cm thick) product of conception in the uterus, positioned anteriorly or posteriorly near the fundus. Its base is always where the site of implantation occurs. It consists of two sides, the fetal side and the maternal side:
- Fetal Side: covered with amnion; under which fetal vessels course with the arteries passing over the veins. An amnion is 0.02 to 0.5 mm in thickness, a sac that engulfs the growing fetus. The clear fluid that accumulates within the amniotic cavity is the amniotic fluid.
- Maternal Side: irregular lobes consisting of fibrous tissue with sparse vessels confined mainly to the base.
By the time the pregnancy reaches term, the placenta is, on average, 500 grams in weight. The weight-ratio at term in an average fetus and placenta (feto-placental weight ratio) is 6:1 (3,000 grams to 500 grams).
The placenta forms with the union of the chorionic villi and the desidua basalis. The Decidua is the endometrium during pregnancy; thickening to 5 to 10 mm. It consists of multiple layers and sublayers:
- Decidua Basalis: the base layer, under the embedded ovum, directly under the site of implantation.
- Decidua Capsularis: the portion overlying the developing ovum; separates the ovum from the rest of the uterine cavity; most prominent by the second month.
- Decidua Vera/Desidua Perietalis: lines the remainder of the uterus.
- Layers of the Decidua Basalis and Vera:
- Zona Compacta: uppermost/surface layer made up on compact cells.
- Zona Spongiosum: the middle, spongy layer; with glands and small blood vessels. Along with zona basalis, it is the functional layer (zona functionales) as it is to this layer that implantation occurs.
- Zona Basalis: lowermost/basal layer. This is regenerated into a new endometrium after placenta separation.
- Decidual Aging: Nitabuch’s Layer, a zone of fibrinoid degeneration, is where the invading trophoblast meets the decidua. This layer is usually absent whenever the decidua is defective.
Placental Maturity
The placenta begins developing within the second month of pregnancy, and becomes completely functional on the third month of gestation. It functions most effectively through 40 to 41 weeks, and may be dysfunctional beyond 42 weeks.
Placental functions vary, and play vital roles in nutritive, respiratory, excretory, protective, and endocrine systems:
- Nutritive: transports nutrients and water-soluble vitamins to the fetus via fluid/gas transport.
- Respiratory: serves as the fetal organ of respiration.
- Excretory: the amniotic fluid is the medium of excretion.
- Protective: the placental barrier defends against organisms and substances like heparin and bacteria. It is ineffective against viruses, alcohol, nicotine, antibiotics, depressants, and stimulants.
- Endocrine: production of estrogen, progesterone, human chorionic gonadotropins (hCG), and human placental lactogen (hPL), also called chorionic somatomammotropin (hCS).
- The major source of estrogen and progesterone after the first two months.
- hCG: secreted as early as 8 to 10 days after fertilization, detected in serum as early as the time of implantation by the most sensitive pregnancy test, radioimmunoassay (RIA). Detected in urine by 10 days (2 weeks) after the first amenorrheic period. It prolongs the lifespan of the corpus luteum, and serves as the basis of pregnancy tests. It is found to be elevated in cases of excessive vomiting. Normally, its value is 50,000 to 400,000 IU/24 hours.
- hCS/hPL: secreted by the third week after ovulation, influencing somatic cellular growth (resembling growth hormone). It is the principal diabetogenic factor, being a major insulin antagonist/glucose sparing hormone. It prepares the breasts of the mother for lactation.
Placental/Cord Abnormalities
- Placenta Succenturiata
- Placental Infarcts
- Placenta bipartita
- Placenta tripartita
- Placenta circumvallata
- Battledore placenta
- Velamentous insertion of the cord
- Cord loops
- Cord torsion
- Cord knots
The Umbilical Cord
Also known as the funis, it is a 30 to 100 cm (average 55 cm) cord with a diameter of 0.8 to 2.0 cm at term. It extends from the fetal surface to the placenta to the fetal umbilicus, serving to transport oxygen and nutrients, and returning metabolic wastes from the fetus to the placenta. It contains three umbilical vessels (mn. AVA): one vein and two arteries. These cords spiral in a dextral or sinistral manner, believed to prevent clamping.
- Umbilical Vein: carries oxygenated blood to the fetus.
- Umbilical arteries: carries deoxygenated blood from the fetus to the placenta.
Protective Covering of the Funis
The cord is covered by Wharton’s Jelly, a specialized gelatinous connective tissue, an extension of the amnion that prevents cord compression.
The Amniotic Fluid
A clear, straw-colored fluid in which the fetus floats. It appears from both the fetal and maternal placenta, amniotic epithelium, maternal serum, and in the latter part (10th week), fetal urine. It is continuously replaced to prevent “dry labor” in a premature rupture of the bag of water. It reaches 500 to 1,000 mL. More than this results in polyhydramnios (1,000 to 1,500 mL), and less results in oligohydramnios (300 to 500 mL). Its pH is normally neutral to alkaline (pH 7.00 to 7.25).
It functions as a protective cushion/shock absorber. It separates the fetus from membranes, allowing symmetrical growth and free movement. As previously mentioned, it is the medium by which wastes are excreted from the fetus. It also serves as a fetal drink.
- The amniotic fluid can be used as a specimen for periodic diagnostic exams (amniocentesis) to determine fetal well-being or its absence.
- Fetal temperature is also maintained by amniotic fluid.
- The liquid prevents marked interference with placental circulation during labor.
Abnormalities
- Polyhydramnios: an elevation in amniotic fluid volume, over 1,000 mL.
- One of the causes of polyhydramnios is when the fetus is unable to drink; if an abnormality in the deglutition center of the brain or if there is esophageal atresia that the fetus cannot swallow.
- Oligohydramnios: a decrease in amniotic fluid volume, under 500 mL.
- Meconium-stained amniotic fluid, especially if the fetus is non-breech, is a sign of fetal distress.
- Golden-colored amniotic fluid may be found in hemolytic disease.
Intrauterine Growth and Development
| Age | Development (RPS) | Short Ver. (Sir V.) |
|---|---|---|
| 4 weeks | All systems in rudimentary form: beginning formation of eyes, nose, and GIT Partitioning of the primitive heart begins; heart chambers are formed; the heart beats (14 days); the heart is completely formed by the end of 6 weeks With arm and leg buds By the end of the 4th week after ovulation, the chorionic sac is 2 to 3 cm in diameters, and the embryo is about 4 to 5 mm in length | - Dizziness due to nervous system development of the fetus. For this, glucose is the foremost requirement. This results in the slight hypoglycemia of the mother that results in dizziness. - Fetal Heart Beat begins 16 days after conception. |
| 8 weeks | Head size is large in proportion to the body, neuromuscular development, and some movements. Rapid brain development External genitalia appear | - Sex Differentiation (6th week) - Fetal Heart Tone auscultation with a doppler, unheard with a stethoscope. - Placental development (not fully functional) |
| 12 weeks | Placenta fully formed Functioning kidneys develop, secrete urine Centers of ossification in most bones With sucking and swallowing Gender distinguishable FHT detected by ultrasound (10 to 12 weeks) Crown-rump fetal length is 6 to 7 cm. Uterus is palpable just above the symphysis pubis | - Placenta is fully functional - Renal system becomes functional. This is when the fetus begins to urinate in-utero. |
| 16 weeks | More human appearance Quickening felt by the multigravida Meconium in the bowels External genitalia are obvious; gender correctly determined by experienced observers by inspection of the external genitalia at 14 weeks (Cunningham et al., 2022) Scalp hair develops Formed eyes, nose, and ears FHT detected by fetoscope By the end of 16 weeks, crown-rump length is 12 cm, and fetal weight is 110 g | - Sex Differentiation is complete, but the external genitals remain small, which may lead to false determination. - Fetal Heart Tone auscultation with a fetoscope. - Lanugo: fine downy hair on the shoulder, nape, arms, etc. - Quickening: first fetal movement felt by multiparous women. - IgG transfer from mother to fetus |
| 20 weeks | Skin is less transparent With vernix caseosa and downy lanugo covering the entire body Quickening is stronger, felt by the primigravida FHT is audible using a stethoscope Bones are hardening Weight is more than 300 g | - The best period for sex determination through ultrasound. - Vernix caseosa appears: the cheese-like substance for lubrication during delivery. - Fetal Heart Tone auscultation with a stethoscope. - Quickening: first fetal movement felt by primiparous women. |
| 24 weeks | Weight is about 630 g Body is well-proportioned Skin is red and wrinkled; fat deposition begins Hearing established Eyebrows and eyelashes are recognizable Canalicular period of lung development. When born, some may breathe, but most will die because the terminal sacs required for gas exchange have not yet formed | - Surfactant Production for alveolar lubrication. - Hearing ability develops: the best time to start singing or talking to the fetus. |
| 28 weeks | Weight is 1,100 g. The crown-rump length is about 25 cm Viable; immature if born at this time; surfactant production begins Thin skin, red, covered with vernix caseosa Body less wrinkled With iron storage Nails appear The pupillary membrane has just disappeared from the eyes | - Bone Ossification: fetal bone development. Calcium demand increases. This results in leg cramps for the mother. Premature occurrence of leg cramps indicate inadequate calcium intake. (Vitamin D increases Calcium absorption; Vitamin C increases Iron absorption). |
| 32 weeks | Weight is 1,800 g. The crown-rump length is about 28 cm Subcutaneous fats begin to deposit; the skin is smooth and pink More reflexes (moro) are present With iron and calcium storage Good chance of survival if delivered at this stage | - Iron is transferred to the fetus. - Ultrasound at this period shows high presence of calcium in the base of the placenta. Calcium may be visualized (placental grading) due to the clumping of calcium with each other. - Lanugo disappears. |
| 36 weeks | Weight is 2,500 g. The crown-rump length is about 32 cm Lecithin/sphingomyelin (L/S) ratio is 2:1. Nails firm With a definite sleep/wake pattern More rotund body because of subcutaneous fat deposition Lanugo disappearing Excellence chance of survival with proper care; survival is the same as term | - Vernix caseosa disappears. |
| 40 weeks | Weight: approximately 3,400 g. Crown-rump length is 36 cm Full-term, fully developed, with good muscle tone and reflexes Little lanugo If male, testes in the scrotum The age at the time of EDC counts from first day of LMP With other characteristic features of the newborn | |
| This occurs in three stages of prenatal development: the germinal (first two weeks after conception); the embryonic (third through eighth week); and the fetal (ninth week until birth) stages. Cell division begins approximately 24 to 36 hours after conception. |
- Germinal Stage: from fertilization to two weeks; the period of pre-differentiation of organs. When the ovum is exposed to a teratogen, the “all or none” law applies, meaning the ovum is either damaged and becomes aborted, or is not damaged and continues normally.
- Embryonic Stage: from two weeks to eight weeks; the period of organ differentiation (organogenesis). It is the most dangerous period, as the introduction of a teratogen during this period may result in severe organ malformation and dysfunction.
- Fetal Stage: from eight weeks to birth; the period of post-differentiation for organs. When exposed to a teratogen, a malformation is least likely to occur. Even if the fetus is affected, the effects will most likely be an alteration in size or function but not in form.
Teratology
The study of the etiology and defects of birth. Teratogenesis is the dysgenesis of fetal organs as evidenced either structurally or functionally. Any agent that produces permanent alterations of form or function during embryonic or fetal development is a teratogen. These can cause premature birth, stillbirth, or other pregnancy complications. Teratogens vary; drugs, medicine, chemicals, alcohol, toxic substances, and certain infections.
- Cigarette smoking is associated with fetal growth retardation (intrauterine growth restriction; IUGR), premature birth, and miscarriage. It also affects fetal lung tissue and brain.
The typical manifestations of teratogenesis is restricted growth or death of the fetus, carcinogenesis, and malformations. These vary in severity, and major malformation may be life-threatening, or may have cosmetic functional effects and require major surgery.
Pharmacology
Because any medication can present risks in pregnancy and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. Each drug should be assessed, and its risks and benefits should be weighed.
Take only prescribed drugs, do not self-medicate, do not take over-the-counter drugs, including vitamins and minerals, and avoid hot tubs, saunas, and anything that raises internal body temperature.
Alcohol
Do not take alcohol, no matter how slight.
| Known Teratogenic Drugs | Teratogenic Effect |
|---|---|
| Anticholinergic Drugs | Neonatal meconium ileus |
| Antithyroid Drugs (Prophylthiouracil, methimazole) | Fetal and neonatal goiter, hypothyroidism |
| Cyclophosphamide | CNS malformation, secondary cancer |
| Diethylstilbestrol | Vaginal cancer, other genitourinary defects in male or female offspring |
| Hypoglycemic Drugs | Neonatal hypoglycemia |
| Methotrexate | CNS and limb malformations |
| NSAIDs | Constriction of ductus arteriosus, necrotizing enterocolitis |
| Phenytoin | Growth retardation, CNS defects |
| Psychoactive Drugs (Barbiturates, opioids, benzodiazepines) | Neonatal withdrawal syndrome when given in late pregnancy |
| Tetracycline | Teeth staining and bone defects |
| Thalidomide | Limb defects/shortening, internal organ defects |
| Warfarin (Coumadin) | Skeleton and CNS effects. Heparin is the drug of choice as an anticoagulant, as it does not cross the placental barrier. |
The drug, substance, or toxin asserts varying severities depending on length of exposure, amount of exposure, gestational age during exposure, and hereditary factors that could increase fetal risk.