Conception,also known as fertilization, occurs when a sperm nucleus enters the nucleus of the oocyte (Fig. 3-8).
■ Fertilization normally occurs in the outer third of the fallopian tube.
■ The fertilized oocyte is called a zygote and contains the diploid number of chromosomes (46).
Cell Division
■ The single-cell zygote undergoes mitotic cell division known as cleavage.
■ Three days after fertilization, the zygote forms into a 16-cell, solid sphere that is called a morula.
■ Mitosis continues, and around day 5 the developing human is known as the blastocyst and enters the uterus.
■ The blastocystis composed of an inner cell mass known as the embryoblast,which will develop into the embryo, and an outer cell mass known as the trophoblast,which will assist in implantation and become part of the placenta.
■ Multiple gestationrefers to more than one developing embryo such as twins and triplets.
■ Twins can be either monozygotic or dizygotic.
■ Monozygotic twins, also referred to as identical twins, are the result of one fertilized ovum splitting during the early stages of cell division and forming two identical embryos.
These developing fetuses are genetically the same.
■ Dizygotic twins, also referred to as fraternal twins, are the result of two separate ova being fertilized by two separate sperm. These developing fetuses are not geneti- cally the same.
Implantation
■ Implantation,the embedding of the blastocyst into the endometrium of the uterus, begins around day 5 or 6.
■ Progesterone stimulates the endometrium of the uterus, which becomes thicker and more vascular in preparation for implantation.
■ Enzymes secreted by the trophoblast, now referred to as the chorion, digest the surface of the endometrium in preparation for implantation of the blastocyst.
■ Implantation normally occurs in the upper part of the posterior wall of the uterus.
E
MBRYO AND FETAL DEVELOPMENT EmbryoThe developing human is referred to as an embryofrom the time of implantation through 8 weeks of gestation. Organogenesis, the formation and development of body organs, occurs during this critical time of human development.
■ Primary germ layers begin to develop around day 14 (Table 3-3).
■ These germ layers, known as the ectoderm, mesoderm, and endoderm, form the different organs, tissues, and body structure of the developing human.
■ Theectoderm is the outer germ layer.
■ Themesoderm is the middle germ layer.
■ Theendoderm is the inner germ layer.
■ The heart forms during the 3rd gestational week and begins to beat and circulate blood during the 4th gestational week.
■ By the end of the 8th gestational week the developing human has transformed from the primary germ layers to
Fertilization
2 cell stage (36 hours)
4 cell stage (48 hours)
Morula
Blastocyst Inner cell mass Blastocoele Trophoblast
Implantation (7–8 days) Embryonic disc
Endometrium of uterus
Primary follicles Maturing follicles
Ovary Ovulation
Ovum Corpus luteum
Corpus
albicans Artery Fallopian tube Vein
Sperm
Ovum (enlarged for greater clarity)
Corona radiata Zona pellucida
Figure 3–8 Ovulation, fertilization, and early embryonic development.
Fertilization takes place in the fallopian tube, and the embryo has reached the blastocyst stage when it becomes implanted in the endometrium of the uterus.
C H A P T E R 3 ■ Genetics, Conception, Fetal Development, and Reproductive Technology 35
a clearly defined human that is 3 cm in length with all organ systems formed (Fig. 3-9).
Fetus
The developing human is referred to as a fetusfrom week 9 to birth. During this stage of development, organ systems are growing and maturing (Table 3-4).
Fetal Circulation
■ The cardiovascular system begins to develop within the first few weeks of gestation.
■ The heart begins to beat during the 4th gestational week.
■ Unique features of fetal circulation are (Fig. 3-10):
■ High levels of oxygenated blood enter the fetal circulatory system from the placenta via the umbilical vein.
■ The ductus venosus connects the umbilical vein to the inferior vena cava. This allows the majority of the high levels of oxygenated blood to enter the right atrium.
■ The foramen ovale is an opening between the right and left atria. Blood high in oxygen is shunted to the left atrium via the foramen ovale. After delivery, the fora- men ovale closes in response to increased blood returning to the left atrium. It may take up to 3 months for full closure.
TABLE 3–3 STRUCTURES DERIVED FROM THE PRIMARY GERM LAYERS
LAYER STRUCTURES DERIVED*
ECTODERM
MESODERM
ENDODERM
*These are representative lists, not all-inclusive ones. Most organs are combinations of tissues from each of the three germ layers. Scanlon &
Sanders (2007).
Epidermis; hair and nail follicles; sweat glands
Nervous system; pituitary gland; adrenal medulla
Lens and cornea; internal ear Mucosa of oral and nasal cavities;
salivary glands
Dermis; bone and cartilage
Skeletal muscles; cardiac muscles; most smooth muscles
Kidneys; adrenal cortex
Bone marrow and blood; lymphatic tissue; lining of blood vessels Mucosa of esophagus, stomach, and
intestines
Epithelium of respiratory tract, including lungs
Liver and mucosa of gallbladder Thyroid gland; pancreas
■ The ductus arteriosus connects the pulmonary artery with the descending aorta. The majority of the oxygenated blood is shunted to the aorta via the ductus arteriosus with smaller amounts going to the lungs. After delivery, the ductus arteriosus constricts in response to the higher blood oxygen levels and prostaglandins.
P
LACENTA, MEMBRANES, AMNIOTIC FLUID, AND UMBILICAL CORDPlacenta
■ The placenta is formed from both fetal and maternal tissue (Fig. 3-11).
■ The chorionic membrane that develops from the trophoblast along with the chorionic villi form the fetal side of the pla- centa. The chorionic villi are projections from the chorion that embed into the decidua basalis and later form the fetal blood vessels of the placenta.
■ The endometrium is referred to as the decidua and consists of three layers: decidua basalis, decidua capsularis, and decidua vera. The decidua basalis, the portion directly beneath the blastocyst, forms the maternal portion of the placenta.
■ The maternal side of the placenta is divided into com- partments or lobes known as cotyledons.
■ The placental membrane separates the maternal and fetal blood and prevents fetal blood mixing with maternal blood, but allows for the exchange of gases, nutrients, and electrolytes.
Function of the Placenta
■ Metabolic and gas exchange: In the placenta, fetal waste products and CO2are transferred from the fetal blood into the maternal blood sinuses by diffusion.
Nutrients, such as glucose and amino acids, and O2are transferred from the maternal blood sinuses to the fetal blood through the mechanisms of diffuse and active transport.
■ Hormone production: The major hormones the placenta produces are progesterone, estrogen, human chorionic gonadotropin (hCG), and human placental lactogen (hPL), also known as human chorionic somatomam- motropin.
■ Progesterone facilitates implantation and decreases uterine contractility.
■ Estrogen stimulates the enlargement of the breasts and uterus.
■ hCG stimulates the corpus luteum so that it will continue to secrete estrogen and progesterone until the placenta is mature enough to secrete these hormones. This is the hor- mone assessed in pregnancy tests. hCG rises rapidly during the first trimester and then has a rapid decline.
■ hPL:
■ Promotes fetal growth by regulating glucose available to the developing human.
■ Stimulates breast development in preparation for lactation.
Endometrium Trophoblast Amnion Yolk sac Embryo Placenta Chorion
Approximately 20 days
Approximately 14 days Approximately 12 days
Approximately 4–5 weeks
Umbilical cord
Chorionic villi Head of
embryo
Head of embryo
Limb buds Embryonic disc Embryonic
disc
Figure 3–9 Embryonic development at 12 days (after fertilization), 14 days, 20 days, and 4–5 weeks. By 5 weeks, the embryo has distinct parts but does not yet look definitely human.
TABLE 3–4 SUMMARY OF FETAL DEVELOPMENT
GESTATIONAL WEEK LENGTH* AND WEIGHT FETAL DEVELOPMENT/CHARACTERISTICS 12
16
20
8 cm 45 grams
14 cm 200 grams
19 cm 450 grams
Red blood cells are produced in the liver.
Fusion of the palate is completed.
External genitalia are developed to the point that sex of fetus can be noted with ultrasound.
Eyelids are closed.
Fetal heart tone can be heard by Doppler device.
Lanugo is present on head.
Meconium is formed in the intestines.
Teeth begin to form.
Sucking motions are made with the mouth.
Skin is transparent.
Lanugo covers the entire body.
Vernix caseosa covers the body.
Nails are formed.
Brown fat begins to develop.
C H A P T E R 3 ■ Genetics, Conception, Fetal Development, and Reproductive Technology 37
■ Viruses, such as rubella and cytomegalovirus, can cross the placental membrane and enter the fetal system and cause fetal death or defects.
■ Drugs can cross the placental membrane. Women should consult with their health care provider before taking any medication/drugs. Drugs with an FDA
pregnancy category C, D, or X should be avoided during pregnancy or when attempting pregnancy.
■ The placenta becomes fully functional between the 8th and 10th weeks of gestation.
■ By the 9th month, the placenta is between 15 and 25 cm in diameter, 3 cm thick, and weighs approximately 600 grams.
TABLE 3–4 SUMMARY OF FETAL DEVELOPMENT—cont’d
GESTATIONAL WEEK LENGTH* AND WEIGHT FETAL DEVELOPMENT/CHARACTERISTICS 24
28
32
36
40
*Length is measured from the crown (top of head) to the rump (buttock). This is referred to as the CRL.
Sources:Sadler (2004); Scanlon & Sanders (2007).
23 cm 820 grams
27 cm 1,300 grams 30 cm 2,100 grams 34 cm 2,900 grams 36 cm 3,400 grams
Eyes are developed. Alveoli form in the lungs and begin to produce surfactant.
Footprints and fingerprints are forming.
Respiratory movement can be detected.
Eyelids are open. Adipose tissue develops rapidly.
The respiratory system has developed to a point that gas exchange is possible, but lungs are not fully mature.
Bones are fully developed. Lungs are maturing.
Increased amounts of adipose tissue are present.
Lanugo begins to disappear. Labia majora and minora are equally prominent.
Testes in upper portion of scrotum
Fetus is considered full term at 38 weeks. All organs/systems are fully developed.
Aortic arch
Ductus arteriosus Pulmonary artery
Left atrium
Foramen ovale
Right atrium Inferior vena cava
Aorta
Ductus venosus Umbilical cord
Navel of fetus
Umbilical arteries Umbilical vein
Placenta
Internal iliac arteries
Maternal blood vessels
Figure 3–10 Fetal circulation. Fetal heart and blood vessels are shown on the left. Arrows depict direction of blood flow. The placenta and umbilical vessels are shown on the right.
Embryonic Membranes
■ Two membranes (amnion and chorion) form the amniotic sac (also referred to as the bag of waters).
■ The chorionic membrane (outer membrane) develops from the trophoblast.
■ The amniotic membrane (inner membrane) develops from the embryoblast.
■ The embryo and amniotic fluid are contained within the amniotic sac.
■ The membranes stretch to accommodate the growth of the developing fetus and the increase of amniotic fluid.
Amniotic Fluid
■ Amniotic fluid is the fluid contained within the amniotic sac (Fig. 3-12).
■ Amniotic fluid is clear and is mainly composed of water.
It also contains proteins, carbohydrates, lipids, elec- trolytes, fetal cells, lanugo, and vernix caseosa.
■ Amniotic fluid during the first trimester is produced from the amniotic membrane. During the second and
third trimesters, the fluid is produced by the fetal kidneys.
■ Amniotic fluid increases during pregnancy and peaks around 34 weeks at 800–1,000 mL and then decreases to 500–600 mL at term.
Maternal arteriole
Maternal venule
Chorionic villus
Maternal blood sinus
Fetal arteriole and venule
Umbilical vein Umbilical cord
Umbilical arteries
Chorion
(fetal part of placenta) (maternal
part of placenta) Myometrium
Endometrium
Figure 3–11 Placenta and umbilical cord. The fetal capillaries in the chorionic villi are within the maternal blood sinuses.
Arrows indicate the direction of blood flow in the maternal and fetal vessels.
CRITICAL COMPONENT Medications
Women who are pregnant or attempting pregnancy should consult with their health care provider before taking any pre- scribed or over-the-counter medications, as medications can cross the placental membrane.
Amniotic sac Amniotic fluid
Placenta
Umbilical cord
Urinary bladder
Symphysis pubis
Vagina
Mucus plug Cervix
Anus Rectum Spine
Figure 3–12 Fetus, placenta, umbilical cord, and amniotic fluid.
C H A P T E R 3 ■ Genetics, Conception, Fetal Development, and Reproductive Technology 39
Function of Amniotic Fluid
■ Acts as a cushion for the fetus when there are sudden maternal movements
■ Prevents adherence of the developing human to the amniotic membranes
■ Allows freedom of fetal movement, which aids in symmetrical musculoskeletal development
■ Provides a consistent thermal environment Abnormalities
■ Polyhydramniosor hydramnios refers to excess amount of amniotic fluid (1,500–2,000 mL). Newborns of mothers who experienced polyhydramnios have an increased inci- dence of chromosomal disorders and gastrointestinal, car- diac, and/or neural tube disorders.
■ Oligohydramniosrefers to a decreased amount of amni- otic fluid (<500 mL at term or 50% reduction of normal amount), which is generally related to a decrease in placental function. Newborns of mothers who experi- enced oligohydramnios have an increased incidence of congenital renal problems.
Umbilical Cord
■ Connects the fetus to the placenta
■ Consist of two umbilical arteries and one umbilical vein
■ Arteries carry deoxygenated blood.
■ The vein carries oxygenated blood.
■ The vessels are surrounded by Wharton’s jelly,a collagenous substance, which protects the vessels from compression.
■ Usually inserted in the center of the placenta.
■ Average length of the cord is 55 cm.
Causes
One third of the causes are related to female factors alone, one third to male factors alone, and one third to a combina- tion of male and female factors (Frey & Patel, 2004).
■ Male causative factors are classified into five categories:
endocrine, spermatogenesis, sperm antibodies, sperm transport, and disorders of intercourse (Porche, 2006).
■ Endocrine: Pituitary diseases, pituitary tumors, and hypo- thalamic diseases may interfere with male fertility. Low levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), or testosterone can also decrease sperm production.
■ Spermatogenesis is the process in which mature functional sperm are formed. Several factors can affect the develop- ment of mature sperm. These factors are referred to as gonadotoxins and include:
■ Drugs (e.g., chemotherapeutics, calcium channel block- ers, heroin, alcohol, and nicotine)
■ Infections (e.g., prostatitis, sexually transmitted illnesses, and contracting mumps after puberty)
■ Systemic illness
■ Heat exposure: Prolonged heat exposure to the testicles (e.g., use of hot tubs, wearing tight underwear, and fre- quent bicycle riding)
■ Pesticides
■ Radiation to the pelvic region
■ Sperm antibodiesare an immunological reaction against the sperm that causes a decrease in sperm motility. This is seen mainly in men who have had either a vasectomy reversal or experienced testicular trauma.
■ Sperm transport factor addresses the structures related to the male reproductive anatomy that might be missing or blocked, thus interfering with the transportation of sperm.
These causes can include vasectomy, prostatectomy, inguinal hernia, and congenital absence of the vas deferens.
■ Disorders of intercourse include erectile dysfunction (inability to achieve and/or maintain an erection), ejac- ulatory dysfunctions (retrograde ejaculation), anatomi- cal abnormalities (hypospadias), and psychosocial factors that can interfere with fertility.
■ Female causative factors are classified into three major categories: ovulatory dysfunction, tubal and pelvic pathol- ogy, and cervical mucus factor (Frey & Patel, 2004).
■ Ovulatory dysfunction includes anovulation or inconsistent ovulation. These factors affect 15%–25% of couples experi- encing infertility and have a very high success rate with appropriate treatment (Storment, 2006).
■ Tubal and pelvic pathology include (1) damage to the fallopi- an tubes most commonly related to previous pelvic inflamma- tory disease or endometriosis and (2) uterine fibroids, benign growths of the muscular wall of the uterus, which can cause a narrowing of the uterine cavity and interfere with embryonic and fetal development, causing a spontaneous abortion.
■ Cervical mucus factors include (1) cervical surgeries such as cryotherapy, a medical intervention used to treat cervical dysplasia, and (2) infection. These may interfere with the ability of sperm to survive or enter the uterus.
CRITICAL COMPONENT Umbilical Vessels
■ After delivery of the newborn, assess the number of vessels in the cord.
■ Newborns with two vessels (one artery and one vein) have a 20% chance of having a cardiac or other vascular defect.
■ Document the number of vessels present in the newborn.
Record and report abnormalities to the pediatrician or pediatric nurse practitioner.
I
NFERTILITY AND REPRODUCTIVE TECHNOLOGYInfertilityis defined as the inability to conceive and maintain a pregnancy after 12 months (6 months for woman older than 35 years old age) of unprotected sexual intercourse. More than 5 million couples experience difficulties in conceiving (Storment, 2006). In approximately 80% of these couples, a cause can be identified. Infertility affects the physical, social, psychological, sexual, and economic dimensions of the cou- ple’s lives.
Diagnosis of Infertility
When a couple is experiencing difficulty in conceiving, both the man and the woman need to be evaluated. Initial screen- ing for the female partner can be provided by her gynecologist (history, physical examination, and pelvic examination) (Table 3-5). Initial screening for the male partner should be performed by a urologist and includes history and physical (Table 3-6). The couple may be referred to a reproductive specialist after this initial screening.
Common Diagnostic Tests
■ Screening for sexually transmitted illnesses (STIs)
■ Laboratory test to assess hormonal levels (TSH, FSH, LH, and testosterone)
■ Semen analysis
■ The male partner abstains for 2–3 days before providing a masturbated sample of his semen.
■ Specimens are either collected at the site of testing or brought to the site within an hour of collection.
■ The semen analysis includes volume, sperm concentration, motility, morphology, white blood cell count, immunobead, and mixed agglutination reaction test.
■ Several semen analyses may be required because sperm pro- duction normally fluctuates.
■ Assessing for ovulatory dysfunction
■ Basal body temperature (BBT): The female partner takes her temperature each morning before rising using a basal thermometer and records her daily temperature. Ovulation has occurred if there is a rise in the temperature by 0.4°F for 3 consecutive days.
■ Ovarian reserve testing: On day 3 of the menstrual cycle a serum FSH and estradiol test is performed. Further evalu- ation is needed by a reproductive specialist when the FSH is greater than 10 IU/L (Frey & Patel, 2004).
CRITICAL COMPONENT Risk Factors for Infertility Women:
Autoimmune disorders Diabetes
Eating disorders or poor nutrition Excessive alcohol drinking Excessive exercising Obesity
Older age
Sexually transmitted infections Men:
Environmental pollutants
Heavy use of alcohol, marijuana, or cocaine Impotence
Older age
Sexually transmitted infections Smoking
PubMed Health, 2011
TABLE 3–5 AREAS OF FOCUS FOR THE MEDICAL HISTORY OF THE FEMALE PARTNER
HISTORY
COMPONENTS FOCUS OF ASSESSMENT MEDICAL
HISTORY AND REVIEW OF SYSTEMS
SURGICAL HISTORY
MENSTRUAL CYCLE AND DEVELOPMENTAL HISTORY
SEXUAL HISTORY
INFERTILITY HISTORY
SOCIAL HISTORY
FAMILY HISTORY OF GENETIC DISEASES
Frey & Patel (2004).
Abnormal hair growth Weight gain
Breast discharge
Hypothyroid or hyperthyroid symptoms
History of diabetes mellitus or current symptoms of DM Current medical problems and
medications Vaccination history Allergies
Fallopian tube surgery Ectopic pregnancy Appendectomy Other pelvic surgeries Age of menarche Breast development Dysmenorrhea
History of sexually transmitted illnesses
Use of prior contraception History of diethylstilbestrol (DES)
exposure
History of abnormal results from Papanicolaou smear and subse- quent treatment
Frequency of sexual intercourse Timing of intercourse with basal
body temperature charting or ovulation predictor kits
Dyspareunia (painful intercourse) Use of lubrications
Previous births
History of infertility treatment in pregnancy
Duration of current infertility Use of alcohol, tobacco, caffeine,
recreational drugs
Exposure to chemotherapy or radiation
Excessive stress
Ancestry-based genetic diseases, i.e., cystic fibrosis, sickle cell disease, and thalassemia
C H A P T E R 3 ■ Genetics, Conception, Fetal Development, and Reproductive Technology 41
■ Detecting LH surge: There is a rapid increase in LH 36 hours before ovulation that is referred to as the LH surge and can be tested with urine or serum. The urine test can be performed at home and be used to assist in identifying the ideal time for intercourse when pregnancy is desired.
■ Endometrial biopsyis performed to assess the response of the uterus to hormonal signals that occur during the cycle. The biopsy is performed at the end of the menstru- al cycle. The procedure is performed in the clinical or medical office.
■ Hysterosalpingogramis a radiological examination that provides information about the endocervical canal, uterine cavity, and the fallopian tubes. Under fluoroscopic observa- tion, dye is slowly injected through the cervical canal into the uterus. This examination can detect tubal problems such as adhesions or occlusions; and uterine abnormalities such as fibroids, bicornate uterus, and uterine fistulas.
TABLE 3–6 AREAS OF FOCUS FOR THE MEDICAL HISTORY OF THE MALE PARTNER
HISTORY
COMPONENTS FOCUS OF ASSESSMENT MEDICAL HISTORY
AND REVIEW OF SYSTEMS
SURGICAL HISTORY SEXUAL HISTORY
FAMILY HISTORY OF GENETIC DISEASES
Frey & Patel (2004).
General health Erectile function Degree of virilization
History of sexually transmitted illnesses
Testicular infections (mumps), genital trauma, or undescended testicle
Pubertal development
History of exposure to high tem- peratures (hot tubs) or recent fever
Current medical problems and medications such as calcium channel blockers
Vaccination history Allergies
History of hernia or testicular or varicocele surgery
Previously fathered a pregnancy History of contraception use History of infertility in a previous
relationship
Excessive use of lubricants Ancestry-based genetic diseases,
i.e., cystic fibrosis, sickle cell disease, and thalassemia Family history of male infertility
■ Laparoscopy is performed with a laparoscope that is used to visualize and inspect the ovaries, fallopian tubes, and the uterus for abnormalities such as endometriosis and scarring.
Treatment
■ Treatment for the male partner ranges from lifestyle changes to surgery.
■ Treatment for endocrine factors may include hormonal therapy.
■ Treatment for abnormal sperm count may focus on lifestyle changes such as stress reduction, improved nutrition, elimi- nation of tobacco, and elimination of drugs known to have an adverse effect on fertility.
■ Treatment for sperm antibodies is corticosteroids to decrease the production of antibodies.
■ Treatment for infections of the genitourinary tract may include antibiotics.
■ Treatment for sperm transport factor may include repair of varicocele or inguinal hernia.
■ Treatment for disorders related to intercourse may include surgery such as transurethral resection of ejaculatory ducts.
■ Treatment for the female partner also ranges from lifestyle changes to surgery.
■ Treatment for anovulation can focus on lifestyle changes such as stress reduction, improved nutrition, elimination of tobacco, and elimination of drugs known to have an adverse effect on fertility. Treatment also includes the use of a variety of medications that stimulate egg production. The most common medication used is clomiphene citrate.
■ Treatment for tubal abnormalities may include surgery to open the tubes.
■ Treatment for uterine fibroids may include surgical removal of the fibroids known as a myomectomy.
■ Treatment for cervical factor related to infection is antibiotics.
Medication Clomiphene Citrate
■ Indication: Anovulatory infertility
■ Action: Stimulates release of FSH and LH, which stimulates ovulation
■ Common side effects: Hot flashes, breast discomfort, headaches, insomnia
■ Route and dose: PO; 50–200 mg/day from cycle day 3–7.
(Data from Vallerand & Sanoski, 2013)
Common Methods of Assisted Fertility
When the previously mentioned treatments are not successful, the couple is usually referred to an infertility expert. This is an obstetrician who has specialized in infertility. Additional test- ing is done, and based on the outcome there are a variety of procedures that can be used to assist in fertility (Table 3-7).