TERATOLOGY: An abridged medical-legal survey (by Naira Matevosyan)

TERATOLOGY:An abridged medical-legal survey

06/30/2017

Naira R. Matevosyan, MD, PhD, MSJSeton Hall University School of Law

ISBN: 978-1548510381. Copyright © 2017. All Rights Reserved

Company address: http://obgynvienna.wixsite.com/panther-lawGWU profile: https://www2.gwu.edu/~rpsol/scholars/matevosyan.htm

http://obgynvienna.wixsite.com/panther-law

IN THIS ISSUE:Basics of Human Embryology - Week 1: Fertilization; Blastocyst Formation; Implantation (7)

- Week 2: The Rule of Twos; Singularities in Embryoblast v. Trophoblast Divisions (8 -9)

- Week 3: The Rule of Three; Gastrulation and Formation of the Primitive Streak; Endo-Meso-Ecto-derms; Everything or Nothing Rule (10-15)

- Week 4: The Rule of Fours; Neural Tube Closure (16 - 19)

- Weeks 5 -8: Organogenesis (20)

- Week 9 +: Fetal Period, Erythropoiesis and Circulation (20 -25)

Twinning: The 3 and 8 Days Rule (zygotic, amniotic, chorionic divisions) (26 -27)

System Outset: Cardiac (28-34), Vascular (35-36), Neural (37-39), Gastro- Intestinal (40-43), Renal (44-45), Reproductive (46-50), Head & Neck (51-60), Ear (61-63), Eye (64-65) Embryology (continued)

Teratogens (66 - 85)

- Illicit Substances; Licit Medications; Radiation; Infectious Agents; Metabolic Factors; Mechanical Factors; Paternal Factors

Inherited Anomalies (86 - 103)

- Mitochondrial Inheritance; Mendelian Chromosomal Inheritance (aneuploidy, polyploidy, nondisjunction); Triplet Repeat Expansions; Hardy-Weinberg Principle, Pedigree Punnett; Heme Synthesis Disorders; Sphingolipidoses; Histone Modification Disorders

Antenatal Fetal Assessment (104-111)

End of Medical Survey Q & A (112-113)

Malpractice; Fault; Causality (114 -140)

Court Hearings (141 - 142 )

End of Legal Survey Q & A (143 -145)

Disclaimer (146)

IN THIS ISSUE

THE OVAOögenesis starts in germinal epithelium and is staged of:

Oocytogenesis - formation of oogonium from primordial follicles through mitosis (diploid/46, two chromatides [2C]) in the 18-22 - week old female fetus

Ootidogenesis - formation of primary oocyte through meiosis I (diploid/46, 4C), secondary oocyte through meiosis II (haploid/23, 2C), ootid (meiosis II, haploid/23, 1C) at birth of the female neonate

Oogenesis proper - maturation, formation of the ovum (haploid/23, 1C) in puberty and menarche.

Folliculogenesis (age 11-51 years) starts when the immature ovum (arrested at metaphase-2 stage, haploid/23, 1C) matures through follicular phase, ovulation, and luteinization. This includes formation of the antral follicle, early tertiary, late tertiary and pre-ovulatory follicles, opening of cumulus oophorus (stigma) at 11-14th days of menstrual cycle, release of the ovum (ovulation), atresia (collapse of the follicle), radical apoptosis, and formation of corpus luteum (the steroidogenic powerhouse that maintains the endometrium by secretion of large amounts of progesterone and small amounts of estrogens (E1, E2). 4

FEMALE GAMETOGENESIS: The Oocyte CyclePRIMORDIAL OOCYTE => Interphase S (Interphase G1, 2C, 2N) (2C x 2 = 4C, 2N)

=> Interphase G2 => Prophase 1 => (Crossing Over, 4C, 2N)

=> Metaphase 1 => Anaphase 1 => (4C, 2N) (2C, N + 2C, N)

=> Telophase 1 => Prophase 2 => (2C, N +2C,N) (Polar Body, 2C, N; 2C, N)

=> Metaphase 2 => Anaphase 2 => (2C, N; 2C, N) (C, N + C, N; C, N + C, N)

=> Telophase 2 => MATURE OVA (C, N) (Haploid/23, 1C) 5

MATURATION: BATTLE FOR FERTILIZATION ● During menstruation, a cohort of primordial follicles is recruited. The

mechanism and criteria of such recruitment remains nebulous.● In proliferation phase, the FSH stimulates both mitotic division of the

granulosa cells surrounding the oocyte, and granulosa - cell aromatization from androgens to estradiol [E2] - the key hormone of follicular maturation.

● The LH stimulates theca cells' production of androstendione. The latter is taken by the granulosa cells and under the FSH is aromatized into estron (E1) and estradiol (E2). (Note, there is no estriol [E3] production in non-pregnant women).

● The follicle most efficient in E2 production is selected as “the winner ” or the dominant follicle, with other follicles undergoing atresia.

● In secretory phase, serum progesterone levels peak by day 8-9 after ovulation. The corpus luteum begins to shrink, unless - at that point - rescued by the hCG (if the ovum is fertilized).

● With an ideal duration of 28 days and the normal range of 21-35 days, the length of a menstrual cycle depends (along with non-hereditary or hereditary factors) on a woman's ethnicity, geographical region (latitude to the equator, i.e. the yearly average of solar position and altitude). The closer to the poles, the longer the menstrual cycle. 6

WEEK 1: Fertilization, Blastocyst Formation; Implantation ● DAY O: Fertilization. - The head and acrosome of the

spermatozoon(s) enter(s) the egg (usually in the ampullar fallopian tube), followed by the acrosome reaction (the sperm releases lysing enzymes to penetrate zona pellucida).

● DAYS 1 -2: Cleavage. - A single-cell zygote (formerly suspended at metaphase-2) undergoes rapid mitotic divisions into smaller cells. Each cleavage doubles the cells.

● DAY 3: Morula (“mulberry”) is formed by 16-32 cells.

● DAYS 4-5: Embryoblast & Trophoblast Formation. On day-4 there are 58 cells; on day-4.5 there are 107 cells. The Na+/K+ - ATPase pumps deliver sodium, creating an osmotic gradient to form a fluid-filled cavity inside the morula. Blastocyst is formed from the embryoblast and trophoblast. Embryoblast seats on the embryonic pole (Fig 1, page 9).

● DAY 6: Implantation. - The blastocyst implants into the endometrium (ideally, in the posterior uterine wall). 7

WEEK 2: The Rule of Two

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Cytoblasts are mononuclear. Syncytiotrophoblasts are multinucleated. At this stage, the blastocyst has already begun to make mRNA for human chorionic gonadotropin (hCG), the first hormone signal from the early embryo that in turn will make the trophoblast differentiate into placenta and umbilical cord, and the epiblast into amniotic sac and bilaminar disk (pre-embryo).

Day-8: The Rule of Twos

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The process of gastrulation starts from the formation of a primitive streak, a midline invagination (Fig. 2). The epiblast cells move through the streak: the bottom-most layer becomes endoderm, the middle layer - mesoderm, and the top layer - ectoderm. These three layers will give rise to various parts of the developing embryo and to organ-systems of the fetus, and this arrangement of “three” will remain the paradigm throughout gestation.

WEEK 3: Gastrulation, Primitive Streak Formation

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WEEK 3: THE RULE OF THREE

I. ECTODERMI. ECTODERM => =>

Surface Ectoderm

Neuroectoderm

Neural Crest Cells

II. MESODERM II. MESODERM =>=>Sclerotone

Myotome

Dermatome

III. ENDODERM III. ENDODERM =>=>

Auditory

Digestive

Endocrine

Excretory

Respiratory

(continued)

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WEEK 3: ECTODERMECTODERM SPLITS INTO THREE PARAXES CLINICAL

SIGNIFICANCE

1) SURFACE ECTODERM1) SURFACE ECTODERM => =>

Surface layer of some organs, some glands (adenohypophysis - the Rathke pouch, mammary, sweat, salivary), the skin epidermis, hair, nails, olfactory epithelium, oral and anal mucose.

2) NEUROECTODERM2) NEUROECTODERM => => CNS (brain, spinal cord), and retina

3) NEURAL CREST CELLS3) NEURAL CREST CELLS =>=>

Peripheral nervous system, melanocytes, thyroid parafollicular (C) cells, chromaffin cells of the adrenal medulla, conotruncal endocardial cushions, some structures of face (teeth, facial bones).

This explains why many congenital diseases (DiGeorge Syndrome - a thymic disorder) involve both cardiac and cranio-facial abnormalities. 12

WEEK 3: MESODERM

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MESODERM SPLITS INTO 5 PARAXES CLINICAL SIGNIFICANCE

1) SCLEROTOME1) SCLEROTOME => => Bones, cartilages, dura mater

Mesoderm differentiates via intercellular signaling and polarization, to protect beta-catenin from degradation. Mesoderm also has the capacity to induce growth of other structures, like the neural plate.

2) MYOTOME2) MYOTOME => =>

Muscles (smooth, cardiac, skeletal), occipital (the tongue) muscles, pharyngeal arch (mastication, mimicry) muscles

3) DERMATOME3) DERMATOME =>=> The skin dermis, connective tissue

4) PARENCHOTOME 4) PARENCHOTOME =>=> Gonads, kidneys, adrenal cortex, spleen. The adrenal medulla

(chromaffin cells) is from ectoderm. Part of the urethra, urinary bladder, prostate are from endoderm.

5) CUSTOPOETOME 5) CUSTOPOETOME =>=>

Mesenchyme, mesothelium, peritoneum, endothelium of the vessels, blood cells (RBC, WBC), microglia, Kupffer cells (hepatic macrophages), coelomocytes, lymph.

WEEK 3: ENDODERM

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ENDODERM SPLITS INTO 5 PARAXES CLINICAL SIGNIFICANCE

1) AUDITORY1) AUDITORY => => Epithelium of the Eustachian tube and the tympanic cavity

The epithelium and parenchyma of the GI (gut) glands are derived from endoderm. The muscular walls of the digestive tract (lamina propria, muscularis mucosae, submucosa, muscularis externa, adventitia and serosa) are derived from the splanchnic mesoderm.

2) DIGESTIVE2) DIGESTIVE => =>

Gut (liver, biliary apparatus, pancreas, superior and inferior mesenteric arteries, except spleen), the entire alimentary canal (except mouth and distal 1/3 of rectum)

3) ENDOCRINE3) ENDOCRINE =>=> Glands (thyroid, parathyroid), thymic epithelium)

4) EXCRETIVE =>4) EXCRETIVE => Urinary bladder, part of the urethra

Kidneys are formed from mesoderm.

5) RESPIRATORY =>5) RESPIRATORY => Trachea, bronchi, pulmonary alveoli

Pharynx is formed from mesoderm.

WEEK 3: Everything-or-Nothing Rule

During weeks 1-3, teratogens typically have all-or-none effect: they either do no harm at all, or entirely terminate the pregnancy (spontaneous abortion).

For a bilaterian mammal such as human being, the rule of 3 of week-3 also concerns to the formation of three body axes: cranio-caudal, medial-lateral, and dorsal-ventral.

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The embryonic period covers the days 18 - 55 after the conception. The complete 8 weeks announce the fetogenesis and the closure of the neural tube (see further).

WEEK 4: The Rule of Fourths● Week-4 also marks

the rule of fours as organogenesis starts taking place:

● Four limb buds begin to grow (Fig. 3).

● Four cardiac chambers have developed and now begin to beat. Heart starts beating at the days 22-23, when it grows to such a size that it can't get adequate nutrition by diffusion alone. 16

WEEK 4● Week-4 is a critical stage, as teratogenic exposure in this

period is deleterious (see in further chapters), contrasted to the former period (weeks 1-3) where the principal rule was “everything or nothing.”

Figure 4 presents Thalidomide exposure in the week-4 period, causing amelia (agenesia of the limb) in the upper extremities and phocomelia

(shortening) in the lower extremities. 17

WEEK 4: Neural Tube Closure● Although week-3 marks the

beginning of the neural plate development (which will give rise to the spinal cord), week-4 marks the closure of the neural tube.

● This closure can be normal and abnormal.

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● Abnormal cranial closure leads to anencephaly (Fig. 5), whereas abnormal caudal closure leads to spina bifida in one of its three main forms (Fig. 6-8):

- Spina bifida occulta

- Spina bifida meningocele

- Spina bifida myelomeningocele.● Spina bifida occurs when the neural tube does not close in the L5 -

S1 area. The opening size and related severity manifest in a wide range of clinical forms: from a completely assymptomatic course to the permanent paralysis.

Spina BifidaSpina bifida occulta (Fig 6), from Latin occulta (“hidden”), is usually asymptomatic as the incomplete closure is so minor that the spinal cord cannot protrude out of the defect. However, there can be a small tuft of hair or hyperpigmented skin over the affected area. The small vertebral fusion defect can be detected on the spine radiography.

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Spina bifida with meningocele (Fig. 7) occurs when the meninges surrounding the spinal cord protrude through the vertebral defect, but the spinal cord does not protrude. The meningeal sac may be visible at the defective site.

Spina bifida with myelomeningocele (Fig. 8) is a severe defect, where the spinal cord and meninges both protrude and are damaged. This typically leads to paralysis and sensory loss in the legs.

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WEEKS 5 + : Placentation ● The formed placenta is a feto-maternal organ (Fig.9), as part of it

(amnion, chorion) is from the blastocyst, and the other part (decidua basalis) is from the maternal endometrium.

● The umbilical cord consists of two umbilical arteries and one umbilical vein.

● The umbilical arteries will turn to the medial umbilical ligaments as they close at birth.

● Do not confuse this with the median umbilical ligament that forms at the closure of urachus.

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WEEKS 5 + : Fetal Erythropoiesis● Fetal hemoglobin (HbF, 2 2) binds oxygen with greater α γ affinity

than maternal hemoglobin (Hb). Thus, the fetal oxygen dissociation curve (partial pressure/saturation) is leftward shifted.

● In adult Hb, 2,3-DPG (diphosphoglycerate) is synthesized by the RBC during breakdown of glucose. 2.3-DPG decreases the Hb-oxygen affinity. Yet, fetal Hb cannot bind 2,3-DPG which is the reason of its higher affinity for oxygen.

● The bone marrow of the fetus does not synthesize RBC until the 28th gestation week. This lack is substituted by other sources in various stages of gestation (Fig. 10) :

- Yolk sac: weeks 3 - 8

- Liver: weeks 6 – 30

- Spleen: weeks 9 – 28

- Bone marrow: week 28 +

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Fetal Circulation● The main difference

between the fetal and adult circulation is in oxygen concentration and in presence of physicologic shunts.

● The oxygen tension is highest in the umbilical vein (Fig.11).

● The first physiologic shunt is in the liver. The ductus venosus is shunting half of the oxygenated blood away from the liver, as the fetal liver (an erythropoietic organ) doesn't need all blood to be properly oxygenated. The blood moves to the inferior vena cava, then into the right atrium. 22

Fetal Circulation Highlights

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Fetal blood is oxygenated in placenta and flows to the right heart through the umbilical vein.

The oxygen tension is highest in the umbilical vein as it is the most proximate to placenta.

Fifty percent (50%) of this oxygenated blood bypasses the liver through the ductus venosus.

Once in the right heart, there are two possible shunts bypassing the lung: the foramen ovale and the ductus arteriosus.

Fetal lungs do not oxygenate blood as they do not breathe, rather they breathe amniotic fluid.

SHUNTS

The first physiological shunt is the (1) liver. The ductus venosus is shunting away the half of the oxygenated blood from the liver to the inferior vena cava, then to the right atrium. The pulmonary circulation is bypassed through the second and third shunts: (2) foramen ovale - a passageway between the right and left atria, and (3) ductus arteriosus – a passageway between the pulmonary artery and aorta.

Nature's 'engineering tricks' and wisdomThe ductus arteriosus is distal to the aortic arch (Fig. 12), which makes the blood flow to the descending aorta and to various end organs, or back to placenta for reoxygenation.

On the other hand, the blood flowing to the left ventricle can go to the aortic arch, oxygenating the upper limbs and brain.

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Interestingly, more deoxygenated blood returning from the brain through the superior vena cava will move to the right ventricle, into the pulmonary artery, ductus arteriosus, and descending aorta to oxygenate brain. With such a trick, deoxygenated blood is efficiently moved into either of two umbillical arteries to be then reoxygenated in placent a.

Changes in Fetal Circulation at BirthReactive hypoxic vasoconstriction relieved: The low oxygen tension causes vasoconstriction in the pulmonary vasculature. Once the newborn makes the first breath, the increased oxygen tension in the lungs causes vasodilation, consequently dropping the pulmonary resistance and pressure.

Decreased pulmonary pressure: This in turn decreases the right heart pressure. As the left heart pressure becomes relatively higher, the foramen ovale closes.

Closure of the ductus arteriosus: Mechanically closed at birth, the ductus then obstructs anatomically through fibrosis, turning into the ligamentum arteriosum. This closure takes place due to the decreased prostaglandins. In a cardiac pathology, where a patent ductus arteriosus is needed, prostaglandin E1 (Alprostadil) is administered to keep the ductus open. In the opposite cases, with the necessity of closing the ductus, Indomethacin is administered to prevent prostaglandin production.

Closure of the ductus venosus: At birth, the liver shunt is no longer necessary. The ductus venosus closes to become the ligamentum venosum. 25

TWINNING: The 3 and 8 Days Rule● Twinning concerns the zygote (monozygotic, dizygotic), the chorion

(monochorionic, dichorionic), and the amnion (monoamniotic, diamniotic).

● Dizygotic twins (fraternal twins) are formed from two different ova and different sperm. They have their own placenta (dichorionic) and amniotic sac (diamniotic). Monozygotic twins occur when a single zygote splits and forms two embryos. These are identical twins. Depending when the split has occurred, they may or may not share the chorion and amnion. The later the split, the more structures will be shared. The key marks to remember: the chorion forms on day 3 and the amnion on day 8.

● Examples below exclusively concern the monozygotic twins:

- Dichorionic, diamniotic: The split has occurred before day 3.

- Monochorionic, diamniotic: The split has occurred between days 3 and 8.

- Monochorionic, monoamniotic: The split must have occurred after day 8. Examples, conjoined twins, or twin-twin transfusion syndrome (TTTS). Most cases are fatal. 26

TWINNING: Monochorionic Variances

Figure 13

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Cardiac Embryology: The Loop Formation● Nearly on days 22-23, the fetal heart starts beating as it has

grown to a size at which diffusion alone fails to fit the nutrition and oxygenation requirements.

● Although the heart starts pumping, the chambers are not in proper spatial orientation. “Twisting” of the cardiac loop allows the chambers to move to the right place. This requires certain gene coordination and proper distribution of the neural crest cells of the ectoderm (see Slide 12). That is why there are congenital syndromes with combined cardiac and craniofacial anomalies.

● The neural crest cells are responsible for twisting of the aorticopulmonary septa that divide the truncus arteriosus (common RV-LV outflow) into the ascending aorta and pulmonary artery.

● Failure of the proper neural crest cell migration to the truncus arteriosus region may lead to transposition of the major vessels and Tetralogy of Fallot. 28

Cardiac Embryology: Pivotal Stages

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Figure 14: Stages of Cardiac Development

(A) Day 15; (b) Day 21; (C) Day 28; (D) Day 50.

A (atria), Ao (aorta), AVV (atrioventricular valves), CT (conotruncus), DA (ductus arteriosus), LA (left atrium), LCA (left carotid artery), LSCA (left subclavian artery), LV

(left ventricle), PA (pulmonary artery), RA (right atrium), RCA (right carotid artery), RSCA (right subclavian artery), RV (right ventricle), V (ventricle).

Cardiac Embryology: Septation● The fetal ventricle starts as a single chamber. The muscular interventricular

septum begins as a cardiac apex and grows upward. At this stage, it has an interventricular foramen. By the end of week-7, the foramen closes when the membrane of interventricular septum forms by joining of neighboring tissues (including endocardial cushion and bulbar ridges).

● Below is the interpreting of Figure 15 ( forthcoming Slides 31 – 34).

(A) The foramen primum is the first hole between the atria. The septum primum is the first septum to form to close the foramen.

(B) The foramen primum is now almost closed by the septum primum with some perforations in it (the second set of holes).

(C) The perforations coalesce and become the foramen secundum.

(D) The foramen primum is now closed. The septum secundum is developing.

(E) The septum secundum leaves a space between the atria (the foramen ovale).

(F) The lower limb of septum primum forms the foramen ovale.

(G) Once the left atrial pressure is higher than the right atrial pressure, the valve shuts the oval foramen.

(H) Failure to close leads to the patent foramen ovale. 30

Formation of the Atrial Septum SAGITAL CUT Fig. 15 (A-B) TRANSVERSE CUT

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SAGITAL CUT Fig. 15 (C-D) TRANSVERSE CUT

32

SAGITAL CUT Fig. 15 ( E - F ) TRANSVERSE CUT

33

SAGITAL CUT Fig. 15 ( G - H ) TRANSVERSE CUT

34 34

Vascular EmbryologyBlood vessels develop through two separate ways: vasculogenesis and angiogenesis. Vasculogenesis involves angioblasts grouping to form the major vessels (Fig. 16). Angiogenesis involves new vessels growing from existing ones and is the major array of vascular development.The aortic arches are six paired embryonic arteries supplying their corresponding branchial arches and eventually forming major vascular structures (Table in Slide 36). They emanate from the distal portion of truncus arteriosus (Fig. 16, A). The aorticopulmonary septum divides the truncus arteriosus into ascending aorta and pulmonary trunk (Fig. 16, B). The 3rd aortic arch forms the common carotid and internal carotid arteries (Fig. 16, C). The left 4th forms the aorta. The right 4th forms the branchio-cephalic artery. The 5th arch regresses early. (Fig. 16, D).

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Vascular Embryology: Aortic Arch Derivatives

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FETAL ARTERIAL STRUCTUREFETAL ARTERIAL STRUCTURE ADULT ARTERIAL STRUCTUREADULT ARTERIAL STRUCTURE1st aortic arch Maxillary artery

2nd aortic arch Hyoid artery, Stapedial artery

3rd aortic archCommon carotid artery, Internal carotid artery

4th right aortic arch Branchiocephalic artery

4th left aortic arch Aortal arch

5th aortic arch N/A

6th right aortic arch Right pulmonary artery

6th left aortic archLeft pulmonary artery,Ligamentum arteriosum

Truncus arteriosus Ascending aorta,Pulmonary trunk

Neuroembryology

- forebrain (prosencephalon)

- midbrain (mesencephalon)

- hindbrain (rhombencephalon).● The forebrain is later divided into telencephalon (future cranial hemisphere)

and diencephalon (future thalamus/hypothalamus). ● The midbrain develops into limbus, hippocampus, medulla, tectum, tegmentum.● The hindbrain is divided into two parts: metencephalon (future pons and

cerebellum) and myelencephalon (future medulla).● Sometimes, primitive masses of paraxial mesoderm flank the neural tube. 37

The cephalic portion of the neural tube dilates into three structures:

Neuroembryological DisordersPITUITARY GLAND: The posterior pituitary is a neural structure formed from the downward growth of diencephalon. The anterior pituitary develops from Rathke pouch (see Slide 12) of oral cavity (derived from the surface ectoderm). Persistence of Rathke pouch may lead to craniopharyngiomas, benign suprasellar tumors that compress pituitary (causing endocrine disorders) or optic chiasm (causing visual disturbances, like bitemporal hemianopsia).

NOTOCHORD: Longitudinal structure lying ventral to the neural tube, and polarizing the spinal cord with the help of the sonic hedgehog homologue protein which induces the formation of motor neurons along the ventral aspect of spinal cord. Notochord persists in adults as nucleus pulposus of intervertebral discs.

HOLOPROSENCEPHALY: A failure of midline formation due to incomplete cleavage of the prosencephalon into telencephalon. It can be associated with sonic hedgehog gene mutations. In severe expressions (cyclopia, absent nose, fused cerebral hemispheres) it is incompatible with life. In milder forms, midline structures are affected but two cerebral hemispheres are developed (the case with a single incisor).

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Neuroembryological Disorders (continued)

DANDY-WALKER SYNDROME: A spectrum of genetic conditions presenting loss of the cerebellar vermis and eventually dilation of the fourth ventricle. This can be asymptomatic, yet, the absence of cerebellar vermis may lead to ataxia, and increased intracranial pressure. The use of ventral shunt can drain the cerebra-spinal fluid (CSF), alleviate the hydrocephalus and normalize the intracranial pressure.

ARNOLD - CHIARI MALFORMATION: Congenital herniation of the cerebellar tonsils through the foramen magnum. This may occlude the CSF passage causing hydrocephalus. Always present in spina bifida, this condition is highly associated with syringomyelia.

SYRINGOMYELIA: Loss of pain and temperature sensation in a capelike pattern around the back of the arms, due to cystic dilation of the central canal compressing the spinothalamic tract as it crosses the midline. Touch/vibration (dorsal columns) and motor function (corticospinal tract) are intact.

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Gastrointestinal EmbryologyBasic embryonic divisions of the gastrointestinal structures:

DIVISIONDIVISION EMBRYONAL EMBRYONAL ORIGIN ORIGIN (Fig.18)(Fig.18)

ADULT STRUCTURESADULT STRUCTURES ARTERIAL ARTERIAL SUPPLYSUPPLY

INNERVATIONINNERVATION

FOREGUT Buccopharyngeal membrane

Pharynx (esophagus, trachea)StomachProximal duodenumLiverGallbladderPancreas

Celiac trunk

PSN: vagusSN: thoracic splanchnic (T5-T9)

MIDGUT

Yolk sac allantoisCoelomHepatic diverticulumVitelline ductUmbillical hernia

Distal duodenumJejunumIleumProximal transverse colonMesentery (lesser omentum, falciform ligament)

Superior mesenteric

SN: vagusPSN: thoracic splanchnic (T10-T12)

HINDGUT CloacaUrogenital sinus

Distal transverse colonDescending colonSigmoid colonRectum

Inferior mesenteric

PSN: pelvic splanchnic (S2-S4)SN: lumbar splanchnic (L1-L2)

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Gastrointestinal Embryology Highlights● ALLANTOIS: An outpouching of the hindgut that is nonfunctional and

get obliterated (Fig. 19). It connects to the apex of developing bladder and moves through the umbilical cord. The proximal portion is known as urachus, which spans from the umbilicus to the bladder. Once obliterated, it becomes the median umbilical ligament and is used by the surgeons as the marker of the abdominal midline.

● VITELLINE DUCT (Omphalomesenteric duct): A tube connecting the yolk sac to the midgut to nourish the embryo. It gets obliterated in the 7th week, and lefts a remnant known Meckel diverticulum.

● CLOACA: Terminal portion of the hindgut. It later divides into the rectum and urogenital sinus.

● CONGENITAL DIAPHRAGMIC HERNIA: Incomplete formation of pleuroperitoneal membrane of diaphragm allowing the abdominal contents to herniate into the thorax. This hernia presses on the lungs causing pulmonary hypoplasia and hypertension. Neonates experience respiratory distress. Mortality rate is 50%. continued 41

Gastrointestinal Embryology Highlights (continued)

Fig. 18: A 5-week embryo. Urachus is the proximal portion of allantois.

Fig. 19: Allantois appears on day -16 as a tiny, fingerlike outpouching extending from the caudal wall of the yolk sac.

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Gastrointestinal Embryology Highlights● OMPHALOCELE: Failure of the GI viscera to enter the abdominal

cavity after physiologic herniation during the early fetogenesis. This results in a midline, peritoneal-coated sac protruding through the umbilicus and containing abdominal organs. It is distinguished from

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the common (benign) umbilical hernia as the latter is covered by skin. Omphalocele alone is not lethal. Complications are related to its severe congenital associations such as heart and neural tube defects, and chromosomal abnormalities.

● GASTROSCHISIS: Incomplete fusion of the body wall leading to protrusion of the GI viscera. While distinguishing it from omphalocele or umbilical hernia, consider that here the protrusion is:1) lateral to the umbilicus

2) not covered by peritoneum 3) not associated with chromosomal abnormalities.

Renal Embryology There are three distinct stages in cranial-to-caudal chronology (Fig. 20):

● PRONEPHROS: At week-4, the formed vestigial nephron-like units start regressing without ever functioning.

● MESONEPHROS: The ureteric bud, developed from mesonephric ducts, penetrates the metanephrons to form renal pelvis, collecting duct system,

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(Wolffian) ducts then persist to form the reproductive tract.

METANEPHROS: A system of nephron and kidney parenchyma formation. Metanephric tissue develops into the organized nephrons (Bowman capsules, proximal and distal tubules, and the loops of Henle). At week-12, distal tubules are connected with collecting ducts (ureteric buds) and the glomeruli are formed.

and ureters (Fig. 21). In males, the mesonephric

Renal Agenesis and Oligohydramnios● You may wonder why defects of

renogenesis are associated with oligohydramnios (the scarcity of amniotic fluid, defined when the amniotic-fluid index is < 4cm and where between the fetal body parts there is no pocket > 1cm in two perpendicular planes).

● Importantly, it is placenta, not the kidneys, responsible for removing the fetal body waste. Fetal urine is excreted into the amniotic sac, where it is swallowed and recycled. This explains why renal agenesis leads to

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oligohydramnios, as fetal urine is a major component of the amniotic fluid.● POTTER SEQUENCE: Decreased amniotic fluid may lead to facial

deformities (due to mechanical stress) and pulmonary hypoplasia (due to decreased nutrients and hydrostatic pressure). Although oligohydramnios is multifactorial (infections, placentation defects, placenta previa), its causality chiefly relies on the urogenic anomalies and Potter Sequence shows the cross-impact (Fig. 22).

Reproductive EmbryologyReproductive system emerges at week-5 in the form of paired gonadal ridges, with migrating primordial germ cells to build sex cords (indifferent gonad, Slide 48, Fig. 23). Genetic determination of sex begins with fertilization when the ovum (X) binds the sperm (either X or Y). Phenotype determination of sex begins with the formation of gonads that coordinate the maturation of the duct system (Wolffian and Müllerian), external genitalia, and secondary sexual features. Female phenotype is considered as default; male phenotype requires presence of the testis-determining factor or the SRY-gene.

46

● MALE EMBRYOLOGYThe SRY-gene encodes the Y-protein transcription to turn the indifferent gonad into the testes. The testes begin to produce testosterone that makes the mesonephric (Wolffian) duct turn into epididymis, vas deferens, and seminal vesicles. Testosterone is converted to dihydrotestosterone (DHT) by the powerful enzyme 5 α-reductase that also virilizes the genital tubercle. The antimüllerian hormone causes regression of the Müllerian ducts.

● FEMALE EMBRYOLOGYAbsence of the SRY-gene allows the indifferent gonad turn into ovaries by default. Ovaries start producing estrogen that turn the Müllerian ducts into Fallopian tubes, uterus, cervix, and upper vagina. Estron (E1) also turns the genital tubercle into lower vagina and the labioscrotal swelling into vulva. Lack of estrogens interferes with the descent of ovaries and gubernaculum, which leads to the formation of the patent canal of Nuck (technically, a hernia).

Reproductive Embryology HighlightsEMBRYO ADULT MALE ADULT FEMALE NOTES

Indifferent gonad Testicle Ovary Gender-determining gene is SRY

Wolffian duct

Urinary collecting system, Epididymis, Vas

deferens, Seminal vesicles

Urinary collecting system

Male structures are formed under the

influence of testosterone

Müllerian duct RegressFallopian tubes, Uterus, Cervix, Upper vagina

In males, this duct regresses under the

antimüllerian hormone

Genital tubercle Penis Clitoris Virilized by DHT

Urogenital sinusBladder, Proximal

urethra, Prostate glandBulbourethral gland

Bladder, Proximal urethra, Bartholin

glands, Skene glands

The urogenital sinus is partitioned off the

cloaca.

Labioscrotal bulge Scrotum Labia majora

Influenced by DHT or E1. In females they become

posterior labial commusure.

Urogenital folds Mons pubis Labia minora In both M and F, the labioscrotal bulges merge.

47

Congenital Gonadal Anomalies● UROGENITAL SINUS: By the end of

embryonic period (week-8), the ventral part of cloaca has been partitioned off into the urogenital sinus, later to form the bladder and proximal urethra. It will form the prostate and bulbourethral glands in males, and Bartholin glands and glands of Skene in females.

48

● HYPOSPADIA: Incomplete fusion of the urethral folds leading to the urethral meatus on the inferior portion of penis (Fig. 24). Surgically curative.

● EPISPADIA: Rare malformation where defective

migration of the genital tubercle results in the urethral meatus opening on dorsum of penis.

● MICROPENIS: Insufficient androgen stimulation from any part of the hypothalamic-gonadal axis.

48

Congenital Gonadal Anomalies (continued)● BLADDER EXSTROPHY: Always associated

with epispadia, this is the outcome of incomplete migration of primitive streak's mesoderm (later the abdominal wall) around the cloaca membrane. The bladder extends off the body.

● CRYPTORCHIDISM: 30% of males are born with undescended testicle(s). Most of those descend within the first months without any surgical intervention. Of note, any cause of intrabdominal testicle (androgen insensitivity syndrome) puts the male at increased risk for testicular cancer.

● UTERINE ANOMALIES: Failure of the paired Müllerian ducts to fuse results in uterus didelphus (double uterus, double cervix, double vagina). Partial fusion results in bicornuate uterus (two uterine cavities share a single cervic and vagina) (Fig. 25, Class 3 and 4, Slide 50).

● NUCK CANAL CYST: A fluctuant, thin-walled, well-defined cyst (peritoneal hernia) in the labium majus pudendi or inguinal area, due to lack of E1, E2, and related insufficient descend of the ovaries and gubernaculum.

● MESOPHRIC DUCT REMNANT: Cyst extending up lateral to vagina.● ACCESSORY BREAST TISSUE: Small non-specific subcutaneous nodule

in vulva, usually unnoticed until pregnancy. 49

Müllerian Anomalies

50

50

Head & Neck Embryology● Six branchial (pharyngeal) arches develop the musculoskeletal compo-

nents of the head & neck region. Each arch contains three layers: ectoterm (outer), endoderm (inner), and neural crest cells (middle). Separated from each other by the branchial clefts, each arch is supplied by numerically corresponding aortic arch and not corresponding cranial nerve. Only the first cleft contributes to growth and later forms the external acoustic meatus.

● On the endodermal side, between the pharyngeal arches, lie the pharyngeal pouches that later form the key structures of head & neck (Fig. 26, also see Slides 52, 53).

51

51

Head & Neck Embryology: BRANCHIAL ARCHES ARCHARCH ADULT STRUCTUREADULT STRUCTURE CRANIAL NERVECRANIAL NERVE NOTENOTE

1st

Mastication muscles (temporalis, masseter, pterygoid)

Malleus and incus bones (from Meckel cartilage)

Tensor tympani, Maxilla, Anterior tongue

V2 (maxillary)V3 (mandibular) “Chewing and

listening” arch

2nd Mimicry musclesStapes, Upper hyoid VII (facial) “Facial expression”

arch

3rd Lower hyoidStylopharyngeus muscle

IX (glossopharyngeal)

“Stylopharyngeus” arch

4th Pharynx constrictorsLaryngeal cartilage (thyroid, epiglottic)

X (vagus)Superior laryngeal

(swallowing)“Swallowing” arch

5th N/A N/A No significance

6thLaryngeal cartilage (cricoid, arytenoid,

corniculate, cuneiform), Intristic laryngeal muscles

X (vagus)Recurrent

laryngeal (speech)“Speech” arch

52

Head & Neck Embryology: BRANCHIAL POUCHES

POUCHPOUCH ADULT DERIVATIVESADULT DERIVATIVES

1stTympanic membrane

Middle ear cavityEustachian tube

2ndPalatine tonsilTonsillar fossa

3rdInferior parathyroid gland

Thymus

4th Superior parathyroid gland

5th C - cells of thyroid

53

Head & Neck Embryology: The TongueThe tongue formation starts at approximately the same time as the palate's. The tongue develops of the 1st to 4th arches. Per the medial fusion of the first (mandibular) and second (hyoid) pharyngeal arches, a medial protuberance (tuberculum impar) appears on the lower edge of the mandibular arch. Two swellings, lateral lingual prominences, form on both sides (Slide 55, Fig. 27, 28).

The swellings extend to form the anterior 2/3 of the tongue. This part of tongue consists of both ectodermic and endodermic portions. At the caudal end of the tuberculum impar arises the primordium (anlage) of the thyroid ventral endodermic bud. It further migrates in front of the larynx and leaves behind the foramen cecum at the invaginated base. The posterior 1/3 is formed from the fusion of the 2nd and 3rd pharyngeal arches, the copula, and a small portion of the 4th pharyngeal arch. It only consists of endodermic parts. The 3rd pharyngeal arch probably grows over the 2nd, thus the second has no mesenchymal contribution to the tongue formation. Between the anterior 2/3 and posterior 1/3 is the terminal sulcus. The tongue is delimited caudally by the hypopharyngeal eminence that marks the entrance into the trachea (laryngeal inlet).

54

Tongue EmbryologyTACTILE (touch)

Anterior 2/3 1st pharyngeal arch N. lungualis (CN V3)

Posterior 1/3 2nd pharyngeal arch N. glossopharyngeus (CN IX)

Base 3rd pharyngeal arch N. vagus (CN X)

SENSORY (taste)

Anterior 2/3 4th pharyngeal arch Chorda tympani (CN VII)

Posterior 1/3 5th pharyngeal arch N. glossopharyngeus (CN IX)

MOTOR (movement)

Enture musculture 6th pharyngeal arch N. hypoglossus (CN XII)

55

55

Thyroid Embryology● Thyroid is the first of the endocrine glands to develop nearly

on the 24th day of gestation. It originates from two main structures: the primitive pharynx and the neural crest. The rudimentary lateral thyroid develops from the neural crest cells, while the median thyroid, which forms the bulk of the gland, arising from the primitive pharynx.

● Thyroid forms as a proliferation of endodermal epithelial cells on the median surface of the developing pharyngeal floor. The site of this development lies between two key structures, the tuberculum impar and the copula, and is known as the foramen cecum (see Fig. 27, 29 in Slides 55, 57). Thyroid initially arises caudal to the tuberculum impar, which is also known as the median tongue bud. This embryonic swelling develops from the 1st pharyngeal arch and occurs midline on the floor of the developing pharynx, eventually helping form the tongue as the two lateral lingual swellings overgrow it.

56

Thyroid (continued)The foramen cecum begins rostral to the copula, also known as the hypobranchial eminence. This median embryonic swelling consists of mesoderm that arises from the 2nd pharyngeal pouch (although the 3rd. And 4th pouches are also involved). Thyroid, therefore, originates from between the first and second pouches.

An initial thyroid precursor, thyroid primordium starts as a simple midline thickening and develops to form the thyroid diverticulum. This structure is initially hollow, although it later solidifies and becomes bilobed. The stem usually

57

has a lumen, the thyroglossal duct, that does not descend into the lateral lobes. The two lobes are located on either side of the midline and are connected via isthmus.

Parathyroid Embryology● Parathyroids originate from the

endoderm (the 3rd and 4th pharyngeal pouches), with a little ectoderm (neural crest cells) involvement. This type of genesis generates multiple small parathyroid clusters in addition to the main parathyroid glands.

● At 6 weeks a diverticulum elongates from the proliferating pouch. Fetal parathyroids appear functional as they respond to the calcium levels , which eventually are higher than the maternal Ca.

58

● The inferior parathyroids are also known as parathyroid thirds, because they arise from the dorsal wing of the 3rd pharyngeal pouch. The superior parathyroid glands are known as parathyroid fourths, because they arise from the dorsal wing of the 4th pharyngeal pouch. Adult anatomical position is the opposite of the pharyngeal roster-caudal order. This occurs due to the 3rd pharyngeal pouch also giving rise to the thymus.

Thymic Embryology● Thymus has two origins for its lymphoid

thymocytes and epithelial cells. The thymic epithelium begins as two flask-shape endodermal diverticula that form from only the 3rd pharyngeal pouch (Fig. 30, 31) extending side-ward and backward into the surrounding mesoderm and neural crest-derived mesenchyme (capsule) in front of the ventral aorta.

59

● The mature thymic epithelium has two main cell types: cortical thymic epithelial (cTECs) and medullary thymic epithelial cells (mTECs) or stromal cells. These provide signals for T - cell differentiation.

● Complex thimyc embryology explains why the thymic medulla phagocytes negatively select auto-reactive CD4+ and CD8+ thymocytes and eliminate T-cells bearing autoreactive T-cell antigen receptors (TCRs), and why the thymic cortex positively selects T-cells in their early stages of development.

Pharyngeal Embryology Highlights● TREACHER COLLINS SYNDROME: Lack of neural cell migration into the

1st branchial arch causes syndromic facial malformations, including micrognathia and conductive hearing loss. Originated from the 1st branchial arch, the Meckel cartilage forms the malleus and incus, and also guides development of the mandible.

● PIERRE ROBIN SYNDROME: Lack of neural crest migration into the 1st branchial arch causes syndromic facial malformations, including micrognathia and cleft palate, as the hard palate is partially of the maxillary bone - a 1st arch derivative.

● DiGEORGE SYNDROME: Failure of the 3rd and 4th pharyngeal pouch differentiation results in the absent parathyroid glands (fatal hypocalcemia) and thymic aplasia (T-cell immunodeficiency). This pesky syndrome is accompanied by facial (1st arch derived) and cardiac anomalies (Tetralogy of Fallot). Mnemonic: CATCH-22 (Cardiac anomalies, Abnormal facies, Thymic aplasia, Cleft palate, Hypoparathyroidism/ Hypocalcemia due to the Chromosome-22 deletion-defect).

● BRANCHIAL CLEFT CYST: Failure of obliteration of one of the branchial clefts leads to a cystic structure of the lateral neck along the anterior border of the m. strenocleidomastoid (the 2nd branchial cleft is involved).

60

Ear Embryology● EAR develops from the 1st pharyngeal pouch and six small swellings or

otic placodes, which are derived from the ectoderm (Fig. 32) to perform two functions: hearing and body balancing.

● INNER EAR: Originates from the ectoderm on the 22nd gestation day. It derives from two lateral thickenings (otic placodes). Each placode recedes below the ectoderm and forms the otic pit and otic vesicle. This entire mass will be surrounded by mesenchyme to form the bony labyrinth (Fig. 32, Slide 63).

Around the 33rd day the vesicles begin to differentiate. On the dorsal side of the embryo they form what will become the utricle and semicircular canals. On the ventral side of the embryo the vesicles differentiate into a rudimentary saccule, which will become the saccule and cochlea. Cochlear duct appears during the 6th week and connects to the saccule through the ductus reuniens.

As the cochlear duct’s mesenchyme begins to differentiate, three cavities are formed: the scala vestibuli, the scala tympani and the scala media. The first two contain an extracellular fluid perilymph, and the third contains endolymph. The vestibular basilar membranes develop to separate the cochlear duct from the vestibular and tympanic ducts. Parts of the otic vesicle in turn form the vestibulocochlear nerve. 61

Ear Embryology (continued)● MIDDLE EAR: Develops from the ectoderm (neural crest) and endoderm,

in particular from the 1st and 2nd pharyngeal arches. The tympanic cavity and auditory tube develop from the first part of the pharyngeal pouch between the first two arches in an area (tubotympanic recess) which will develop to pharynx. The ossicles (malleus, incus and stapes) normally appear during the first half of fetogenesis. The first two derive from the 1st pharyngeal arch and the third derives from the 2nd. All three ossicles develop from the neural crest. Eventually cells from the tissue surrounding the ossicles will experience apoptosis and a new layer of the endodermal epithelial wall constitute the tympanic cavity wall.

● EXTERNAL EAR: Ear canal originates from the dorsal portion of the first pharyngeal cleft (not pouches, not arches, but cleft). It is fully expanded in the 18th week. The eardrum is made up of three layers (ectoderm, endoderm and connective tissue). The pinna originates as a fusion of six hillocks. The first three hillocks are derived from the lower part of the first pharyngeal arch and form the tragus, crus of the helix, and helix, respectively. The final three hillocks are derived from the upper part of the 2nd pharyngeal arch and form the antihelix, antitragus, and earlobe. The outer ears develop in the lower neck.

62

Ear Embryology Highlights BRANCHIAL ARCH 1:

Incus, malleus, tensor tympani muscle (dampens sound).

BRANCHIAL ARCH 2:

Stapes, stapedius muscle (dampens sound).

PHARYNGEAL POUCH 1:Middle ear cavity, Eustachian tube.

63

PHARYNGEAL POUCH 2: External audirory meatues.

BRANCHIAL MEMBRANE 1: Tympanic membrane.

Eye Embryology● The eye formation begins at 3 weeks and

continues through the 10th week and involves both mesoderm and ectoderm (Fig. 33). Eye is derived from neuroepithelium, surface ectoderm, and extracellular mesenchyme which consists of both neural crest and mesoderm. Eye begins to develop as a pair of optic vesicles on each side of the forebrain. Optic vesicles are outgrowing of the brain which at the end of the 4th week make contact with the surface ectoderm to induce changes necessary for further development (Fig. 33, 34). Specifically:

64

● NEUROPEITHELIUM forms the retina, ciliary body, iris, and optic nerves;

● SURFACE ECTODERM contributes to the lens, corneal epithelium and skin of the eyelid;

● EXTRACELLULAR MESENCHYME produces the sclera, the corneal endothelium and stroma, blood vessels, muscles, and vitreous.

Eye Embryology (continued)NEURAL CREST:

● Sclera

● Cornea (Descemet's membrane and endothelium)

● Connective tissue and bony structure of the orbit.

MESODERM:

● Extraocular muscles

● Endothelial lining of blood vessels of the eye

● Blood vessels in sclera and choroid

● Sclera and choroid

● Vitreous

● Suspensory fibres

● Cornea: Bowman's membrane and stroma.65

TERATOLOGYTeratology is a study about the abnormalities of physiological development. The term stems of the Greek (“teras”), for τέρας"monster" or "marvel.” Such an outcome-oriented epistemology is correct (for including the word abnormality instead of anomaly), as with that it dismisses confusions between “teratology” with the “study of human congenital defects.” Teratology is broader, as it includes all manifestations of abnormal development that are caused by environmental insult. These may include growth retardation, delayed mental development or other congenital disorders with or without structural malformations.Teratogens are substances that may cause birth defects. While most of the congenital birth defects are genetically programmed, teratogens are potentially avoidable causes of defects. Where the law of malpractice (torts) or employment law, a careful distinction is required between defect / deformity/ dysfunction. A person can have a deformity (structural anomaly), yet have a good functionality of that body part or region. Defect is the combination of deformity (anomaly) and dysfunction (abnormality). 66

DEFECT = DEFORMITY + DYSFUNCTION● The short 4th and/or 5th finger syndrome (Fig.

33) is multifactorial (idiopathic, or in utero mechanical trauma,or Turner syndrome - 45 XO, or pseudohypoparathyroidism, or pseudopseudohypoparathyroidism, or perinatal infections such as osteomyelitis, yaws, tuberculosis causing fetal dactylitis). Person with such a visible structural deformity of

67

metacarpal phalanges may have a functional hand, may play musical instruments, sew, type, print, even perform surgeries with those hands. Thus, this syndrome is not assessed as a defect, as the deformity is not combined with dysfunction (unless there is Turner syndrome).

● A person with diabetes mellitus or myopia does not have visible structural or cosmetic anomalies (except histological) but suffers serious dysfunctions. Yet, diabetes or myopia are viewed as disorders (not defects) as there are no visible deformities, although a person with short 4th phalanges may have a better quality of life than the one with myopia or diabetes.

● While a rigorous etiological evaluation is the cornerstone of medical assessment, in the eyes of law the cosmetic defect alone has lesser value than a dysfunction in assessing teratogenic damages.

TERATOGENICITY: GENERAL PRINCIPLESDEFINITIONTeratogen is an agent extrinsic to the embryo or fetus, and that increases the risk of the following: - Malformation - Carcinogenesis - Mutagenesis - Altered function (including mental) - Growth deficiency (IUGR, SGA, SFS) - Pregnancy wastage (miscarriage, stillbirth, perinatal death).

EVERYTHING OR NOTHING RULETeratogens may exert their effect at any time in pregnancy. Effects between conception and the 18th postconceptional day, or during fertilization and implantation, typically produce spontaneous abortion. Organogenesis is affected during the embryonic period (18 to 55 days after conception), while the fetal growth and maturation are affected thereafter.

68

TERATOGENS: BASIC PRINCIPLESCLASSES - Licit medications (prescribed, over-counter) - Illicit substances - Infectious agents - Paternal exposures - Radiation - Food / metabolic - Mechanical compression, deformation, disruption of fetal growth.

MECHANISM OF TERATOGENESIS

Cell death or reduced proliferative rate (viral infections)

Altered biosynthetic pathways (chromosomal or gene disorders)

Abnormal cellular or tissue interactions during crises (diabetes)

Extrinsic factors (hypoxemia, cell hypoxia, or tissue compression)

Threshold interaction of multiple genes with known or unknown environmental factors (drugs, radiation). 69

GENERAL RULES OF TERATOGENICITYTERATOGENIC EFFECT DEPENDS ON:

Dose exposed/administered Gestational age at the exposure Duration of exposure Maternal genotype, fetal genotype Maternal-fetal circulation Placentation defects Maternal and fetal immune response Simultaneous exposure to other teratogenic agents (1) Agent A = Defect A

(2) Agent B = Defect B

(3) Agent A + B + C = No defect

(4) Agent A + B at different gestational age = No defect

INTERPRETING:A given defect may result from several different agents.A given agent may have multiple effects. Proof of teratogenicity is very strenuous.

70

TERATOGENIC AGENTS● (I) SUBSTANCES

Alcohol: Fetal alcohol syndrome represents the most common birth defect caused by a teratogen. Along with mental retardation, newborns have the typical smooth philtrum, epicanthal folds, a thin upper lip, a saddle-shape nose(flat nasal bridge) and maxillary hypoplasia (Fig. 36).

Cocaine: By preventing the

71

reuptake of catecholamines, cocaine is a potent sympathomimetic. Increasing vasoconstriction (through 1-agonist effect ofα catecholamines), it decreases the placental circulation which is an obstetric emergency. The sequential perinatal hypoxia may lead to mental retardation and number of birth defects.

● Opioids: These are not teratogenic, however, their use leads to the fetal opioid withdrawal syndrome, and sudden infant death syndrome (SIDS). Heroin leads to intrauterine growth retardation (IUGR), premature rupture of the membranes, and chorioamnionitis. The 75% of newborns show clinical signs of withdrawal within the first 48 hours after birth: diarrhea, tremors, respiratory distress.

TERATOGENS (continued)Methadone, along with producing fetal dependence and withdrawal in the majority of exposed infants, is associated with higher rates of neonatal morbidity and mortality; yet the average birth weight for methadone-addicted neonates is higher than that for heroin-dependent infants. Neonatal withdrawal from methadone may be treated with 1 - 2 mg of methadone given twice daily.

● Marijuana: Greater than 25% of women admit to marijuana use. Although marijuana exposure in pregnancy has been associated with few short-term or long-term effects on fetus, its risks are dose-dependent, with an increased incidence of IUGR and SIDS.

● Illicit Hypnotics/Sedatives: Maternal use of sedatives/hypnotics leads to physical dependency in the fetus characterized by the neonatal abstinence/withdrawal syndrome (NAS): behavioral and autonomic nervous system dysfunction plus gastrointestinal, respiratory, and central nervous system involvements. Women using sedatives/hypnotics during pregnancy may need to be hospitalized during detoxification because the risk for seizures and other CNS symptoms is high.

● Tobacco: No distinct birth defects are related, yet smoking causes damage to the vascular endothelium in the entire body which leads to fetal hypoxia, IUGR, and prematurity. In average, nicotine reduces birth weight on 300 g. Significant associations with neonatal respiratory distress and scrotal skin cancer are described. 72

(II). TERATOGEN MEDICATIONSAGENT INDICATION FETAL EFFECTS

SAFER ALTERNATIVES *

Acne medication (Accutane, Isotretinoin, Retin-A)

Hair follicle blockage with sebum,Propionibacterium

Hox-gene distruption,Spontaneous abortion, IUGR, Cleft palate

Salicic acid or Hydroquinone belong to the FDA Category-C

Alcohol injected chronically

Binge Fetal alcohol syndrome(Slide 71) Abstinence

Aminoglycoside antibotics

Maternal infecions

Ototoxicity, Deafness Nephrotoxicity, Sensory (cranial n. VIII damage)

Macrolides

Androgenes (Diethylstilbestrol)

Morning after abortifacient

Adenosis, Clear cell adenocarcinoma of the fetal vagina

-

* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or recommend therapy. All drugs must be assessed, prescribed, and supervised by your health

provider. Remember: the benefit must outweigh the risk.

73 continued

TERATOGEN MEDICATIONS (continued)

74

AGENT INDICATION FETAL EFFECTS SAFER ALTERNATIVES *

Angiotensin - converting enzyme (ACE) inhibitors

Hypertension,Congestive heart failure

Renal agenesis, Oligohydramnios, Bone malformations, Pulmonary hypoplasia, IUGR, Death,

Acebutolol,Chlorthalidone Pindolol

Anticonvulsants(Valproic acid, Phenytoin for grand mal, Trimethadione for petit mal)

Epilepsy, Anxiety, Bipolar disorder

Fetal hydantion syndrome, Facial defects, Mental retardationNeural tube defects

Monotherapy with Carbamazepine, Lamotrigine, Phenobarbital

Antidepressants (Lithium, 2nd SSRIs)

Unipolar and bipolar depression

Ebstein's anomalyTherapy sessions, Exercise, Tricyclis, 2nd generation SSRI


provider. The benefit must outweigh the risk.

continued

TERATOGEN MEDICATIONS (continued)

75

AGENT INDICATION FETAL EFFECTSSAFER ALTERNATIVES *

Antimetabolics (Methotrexate, Arava, Pevalite, Kineret ) - FDA Category-X

Cancer, Rheumatoid arthritis, Lupus,Misdetected ectopic pregnancy, Antiphospholipid syndrome (AFS)

Combined anomaliesDeath

Tumor necrosis factor (TNF) inhibitor,

Certolizumab pegol (Cimzia) does not cross

the placenta

Antythyroid drugs (Carbimazole, Thiouracil)

Myxedema, Grave's disease, Hyperthryroidism

Aplasia cutis, Choanal atresia, Tracheal - esophageal fistulae, Facial anomalies,Psychomotor delay

Iodine-modified diet,Selenium supplement,Coleus Forskohlii

AnticoagulantsWarfarin, Coumadin)

Facial and bone dismorphism, Cranial hemorrhage, Abortion

SQ Heparin, Aspirin (before 30 weeks, and

less 100mg/day)


provider. Remember: the benefit must outweigh the risk.

continued

TERATOGEN MEDICATIONS (continued)76

AGENT INDICATION FETAL EFFECTS ALTERNATIVES *

Acetylsalicylic acid (FDA category-C)

Various (pain, fever, migraine headache, preeclampsia**)

Pulmonary hypertension, Premature closure of ductus arteriosus, Renal failure, Oligohydramnios

Acetaminophen (Tylenol)

Sulfa antibiotics A wide range of infections

Bilirubin binding, Jaundice

Penicillin Macrolides

Tetracycline antibiotics(FDA category-D) Infections Tooth staining, Bone

malformations Penicillin, Macrolides

Thalidomide Sedation, Hypnosis Phocomelia Tryptophan

Tranquilizers (Diazepam, FDA category-D)

Anxiolysis, Hypnosis, Anticonvulsant, GABA enhancement

Delayed neurobehavioral adaptation

Tricyclics, Hydroxizine

* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or recommend therapy. All drugs must be prescribed by your health provider.

** The use of Aspirin for tocolysis or in preeclampsia is erroneous, because Aspirin: (1) unselectively blocks both COX-1 and COX-2; (2) isn't an alpha-1 blocker; and (3) decreases platelet

alpha 2-receptor affinity for both agonists and antagonists.

(III). INFECTIOUS AGENTS AS TERATOGENSAGENT CONGENITAL DEFECTS, OBSTETRIC COMPLICATIONS

B-streptococcus Premature rupture of membranes, Preterm birth, Low birth weight, Sepsis

Chagase disease (Trypanosoma cruzi)

Cardiac or gastrointestinal symptoms in mother transmittable to the fetus.

Chlamydia trachomatis Premature rupture of membranes, Preterm birth, Low birth weight, Cardiac anomalies

Cytomegalovirus (CMV)Blindness, Cerebral calcification, Chorioretinitis, Deafness, Hydrocephalus, IUGR, Microphthalmia (transmission risk 33%)

Hepatitis B, C Fulminate hepatic failure in mother in peripartum, Prematurity (transmission risk 10 - 34%)

Listeria Spontaneous abortion, Prematurity, Low birth weight, Chorionamnionitis, Increased perinatal mortality (10x)

Lymphocytic choriomeningitis virus (LCMV)

Chorionitis, Hydrocephalus, Macrocephaly, Retinopathy, Increased risk of perinatal mortality (7x)

continued77

INFECTIONS (continued)

78

RubellaAutism, Cataract, Cardiovascular defects, Chorioretinitis, Deafness, Hepatosplenomegaly, Microcephalus, Mental retardation, Osseous defects

Toxoplasma gondii Cerebral calcification, Cerebral palsy, Chorioretinitis, Blindness, Hepatosplenomegaly, Hydrocephaly, Microcephaly, Prematurity

Syphilis

Cutaneous lesions, Deafness, Dental-Maxillae anomalies, Hydrocephalus, IUGR, Mental retardation, Non-immune hydrops fetalis, Osseous lesions, Saddle nose, Spontaneous abortion, Stillbirth, Increased perinatal mortality (14 x)

Varicella zoster CNS impaired, Meromelia (lib deformities), Microphthalmia, “Scalded skin” (transmission rate is 12%)

Zika virusGuillain-Barré syndrome, IUGR (mostly symmetric), Lymphadenopathy, Microcephaly, Pruritus, Increased premature mortality (33 x)

AGENT CONGENITAL DEFECTS, OBSTETRIC COMPLICATIONS

(IV). RADIATION AS A TERATOGEN: Basic ConceptsTYPES OF RADIATIONRadiation is fast-moving energy emitted as particles or waves. It is commonly divided into two categories: nonionizing and ionizing radiation.

- Nonionizing is low-frequency radiation that disperses energy through heat and increased molecular movement. It includes visible light, ultraviolet rays, microwave, ultrasound, radio waves, and infra waves.

- Ionizing radiation includes particles (alpha and beta) and electromagnetic waves (gamma rays, x-rays, terahertz). The higher electromagnetic wave frequency, the increased is ionizing effect.

In average, the Americans are exposed to approximately 0.001 Gy (0.1 rad) of annual radiation/per capita, from cosmic rays, environment, medical procedures, and naturally occurring radiation in the human body.

RADIATION TYPES IN MEDICINE:Ionizing Radiation: Gamma rays (Nuclear Medicine, Positron Emission Tomography, Single Photon Emission CT); X-rays (CT, Computed Radiography, Digital Subtraction Angiography, Pulsed-field Gel Electrophoresis [PFGE], Duel-energy X-ray Absorptiometry, Fluoroscopy, Mammography; Radiography; Radiation Therapy).Nonionizing Radiation: Radio Frequency Waves (Magnetic Resonance Imaging [MRI]), Ultrasound Waves (Ultrasonography). 79

RADIATION (continued)GENERAL MECHANISMS OF ACTION:

● Nonionizing radiation interacts with tissue through the generation of heat. A causal linkage is found between prenatal exposure to electromagnetic fields and birth defects, miscarriage, or childhood leukemia. Ultrasound and MRI should be performed only per medical indications.

● Prenatal exposure to ionizing radiation can be teratogenic, carcinogenic, or mutagenic. Ionizing radiation acts directly with biochemical structures in tissue (proteins, DNA) or indirectly by causing the formation of free radicals, which in turn break the cell structures (mitochondria). The effects of exposure may be classified as deterministic or stochastic. Deterministic effects result from radiation-induced cellular injury or death, and are characterized by a threshold dose. For a given threshold dose, there is loss of organ/tissue functionality leading to pregnancy loss, congenital malformations, neurobehavioral abnormalities, and fetal growth restriction. Thus, in deterministic theory the dose matters.Stochastic effects are caused by radiation-induced changes in cells that maintain their capability for replication. Over time, these cells can become malignant. Unlike deterministic effects, stochastic effects do not have a threshold dose. Their effect probability depends on simple, linear models, which are the basis for current radiation protection standards and practices. This model theory suggests that any exposure dose to ionizing radiation may be harmful. 80

RADIATION (continued)TIME OF EXPOSURE:

(a) From day 1 to day 18 after conception, there is “everything or nothing rule” (the conceptus either dies, or does not sustain any teratogen effect).

(b) Between days 18 – 55, the most sensitive period (organogenesis), the risk of teratogen, growth-retarding or lethal effects of radiation is the highest.

(c) Between weeks 9 – 40 (fetal period) there is decreased radio-sensitivity for the organ systems, but overall fetal growth retardation (symmetric), CNS dysfunction, or postnatal neoplastic effects may occur.

BASIC CONSIDERATIONS IN RISK ASSESSMENT:● Gestation age at time of exposure.● Type of radio-diagnostic exam (X-ray, radionuclide, PFGE). Does the isotope

concentrate on the fetal side of placenta? ● Is the radiation dosage estimated by an expert radiologist or physicist?● Radiation exposure from a single diagnostic imaging procedure does not

increase the risk of fetal anomalies or pregnancy loss.● Prenatal ultrasonography may only be performed if medically indicated and

when the lowest possible exposure setting is used.● A dosimetry specialist should be consulted for calculation of the estimated

fetal radiation dose when a patient is undergoing multiple diagnostic procedures. Single procedure estimates are provided in Slide 82. 81

MEDICAL PROCEDURES & RADIATION DOSES

TARGET, PROCEDURE Average Uterine Dose (mrad) Reported Range (mrad)

Dental exam 0.06 0.03-1.0

Head & Neck 0.5 0.5- 3.0

Extremities 0.5 0.5-1.8

Thorax, Thoracic Spine 11.0 10.0 - 55.0

Lumbosacral Spine 721.0 20.0 - 2900.0

Cholecystogram 78.0 14.0 - 1600.0

Intravenous Pyelogram 588.0 50.0 - 4000.0

Abdomen 221.0 18.0 - 1400.0

Pelvimetry 600.0 160.0 - 4000.0

Barium Enema 900.0 20.0 - 9200.0

- Table shows the range of fetal radiation doses from common procedures (not including fluoroscopy). - The data are modified from the National Council on Radiation Protection and Measurements (NCRP Rep N 54). - The presented estimates cannot be used for individual calculations of fetal irradiation without counseling with a radiologist.

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PRENATAL RADIATION RISKCommon Risk Measures (including carcinogenic)

● Less than 5 rad (5000 mrad): no increased risk for malformations, but other teratogen effects (mutation, carcinogenesis) may occur.

● 5 to 10 rad: no increased risk for malformations.● 25 rad > : definite risk for malformations.● 100 rad >: definite IUGR, malformations● There is no threshold dosage for the risk of carcinogenesis, mutagenesis, and

miscarriage.

Non-carcinogenic Risk of the Acute Fetal Irradiation

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ACUTE DOSE BLASTOGENESIS ORGANOGENESIS WEEKS 8 -15 WEEKS 16-36

0.05 Gray (Gy)or 5 Rad - - - -

0.05 – 0.5 Gy5-50 Rad

Implantation failure

Higher risk of malformations, IUGR

IUGR, Severe mental retardation (25%)

-

0.5 Gy > Implantation failure

Miscarriage, Major malformations, IUGR

IUGR, Major malformations

Increased risk for neonatal death

Note: A fetal dose of 1 Gy (100 rad) will likely kill 50% of embryos. The dose necessary to kill 100% of human embryos before 18 weeks' gestation is about 5 Gy (500 rad).

(V). MECHANICAL TERATOGENS● Mechanism of action

- Deformation: Mechanical molding of tissues (oligohydramnios, uterine structural anomalies and tumors, corsages)

- Disruption: Destruction of normal tissue (amniotic band syndrome)

● Amniotic Band Syndrome (ABS):

A congenital disorder caused by entrapment of fetal parts in fibrous amniotic bands. Defects are usually asymmetric, do not follow the sequence of embryonic development, are often associated with annular constrictions or congenital amputations of fetal limbs or digits (Fig. 37).

Torpin et al propose the following stages of the ABS:

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Rupture of the amnion => Fetus enters chorionic cavity => Oligohydramnios => Clubbing => Spinal deformities => Mesodermic band formation => Days 28-45: Craniofacial defects, Visceral defects, Abortion. // Day 45- Week 18: Limb constriction, Digital constriction, Amputations.

TERATOGENS (continued)● (V). PATERNAL EXPOSURE- Effects of paternally-mediated factors are dual: fertility (sperm kinetics alteration), and fetal anomalies (sperm genome alteration). - Agent Orange is a common concern of the Vietnam War veterans. - Other concerns: Chemotherapy, Smoking, Illicit substance ab/use, Ionizing radiation, Cryopreservation, Occupational hazards (lead, arsenic, mercury, heat, vibration). - Due to bioethical rules, experimental studies or randomized controlled trials on human reproductive toxicity are unfeasible. Existing data are based on the observational, epidemiological, retrospective studies.There are three main mechanisms of male reproductive toxicity: non-genetic (presence of drugs in seminal fluid), genetic (gene mutation or chromosomal abnormality), and epigenetic (effect on gene expression, genomic imprinting, DNA methylation).Some common occupational exposures (1,3-butadiene) are linked to increased risk of leukemia in offspring.

● (VI). MULTIFACTORIALDefects result from Mendelian, chromosomal, and teratogen causes. For example, congenital cardiac anomalies may be drug induced (Lithium), infection related (Rubella), or chromosomal (Trisomy 21).Other multifactorial conditions: Cleft lip/Cleft palate, Neural tube defects, Renal anomalies, Müllerian fusion defects, GI anomalies, Orthopedic anomalies (club foot, hip dysplasia, scoliosis).

85

INHERITED ANOMALIESMitochondrial inheritance (primary, secondary)

Basic Mendelian inheritance: Chromosomal numerical, single gene disorders (aneuploidy, polyploidy)

Chromosomal structural anomalies (nondisjunctions)

Single gene mutations (modifier genes, triplet repeat expansions, threshold traits, mixed polygenic and variable expressions)

Heme synthesis disorders (porphyrias)

Glycogen storage diseases (penthose phosphate pathway alterations)

Sphingolipid storage diseases (lisosomal storage disorders)

Histone modification disorders86

(I). MITOCHONDRIAL INHERITANCEMitochondrial inheritance is related to two basic principles:

- all mitochondria in the offspring are from the mother's ovum (female gamet)

- the smermatozoid (male gamet) does not contain mitochondria.

Therefore, affected females (mothers) with mitochondrial diseases will have 100% of their offspring affected; yet, the affected males (fathers carrying mitochondrial diseases from their mothers) will have 0% of their offspring affected. (See specifics in Slide 88).

Examples of mitochondrial hereditary diseases:

– Leber hereditary optic neuropathy (LHON)– Mitochondrial encephalopathy with lactic acidosis and stroke-like

episodes (MELAS)– Myoclonic epilepsy and ragged red fibers (MERRF).

Primary Mitochondrial Diseases: Are caused directly by mutated, damaged, or deleted mitochondria. The mutated genes can be inherited or sporadic (when disease occurs for the first time in a family, or is an isolated episode due to an unknown cause - a spontaneous mutation). Sporadic occurrences are less common and often correlated with actual deletion of mitochondria.

Secondary Mitochondrial Diseases: Occur when mitochondria are damaged or under stress due to other diseases, like Parkinson's or Alzheimer's. 87

Are mitochondrial diseases always inherited?Mitochondria has two types of genomes: Mitochondrial DNA Genome and Nuclear DNA Genome.

- Mitochondria DNA Genome appears as double stranded organelle, a very small piece of DNA that makes only 13 proteins which are part of the electron transport chain. They continue to mix in a mosaic-like pattern in zygote formation. Mitochondrial DNA may also sustain a deletion (due to injury/trauma/physiologic stress). This type of deletion disease is not familial, not inherited. The loss of specific Mitochondrial DNA may result in very specific problems/symptoms.

- Nuclear DNA Genome, which we link to the chromosomes, is what we commonly (erroneously) associate with inherited diseases through maternal line. Yet, if problems occur in the Nuclear DNA, the transference to the next generation would not be just through the mother (egg) but would follow standard Mendelian laws of inheritance. Currently there are 55 identified Nuclear Genes (there may be as many as 1200), occurring primarily in electron transport chain, and which cause very complex Nuclear DNA Mitochondrial syndromes.

- In summary, mitochondrial disease may be inherited from the (1) mitochondrial DNA (strictly maternal inheritance), (2) nuclear DNA (standard Mendelian inheritance), or may (3) occur as spontaneous mutations.

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MITOCHONDRIAL (continued)

BASIC MENDELIAN INHERITANCEChromosomal abnormalities are single-gene disorders and can be:Numerical – chromosomes are either missing or in excess than the regular pairs.Structural – fragments of chromosomes are excessive or missing.

● NUMERICAL - Occur from nondisjunction that may take place in both meiosis -I (leading to monosomy) and meiosis-II (leading to trisomy) (see Slide 90). - May involve autosomes (chromosomes 1-22) or sex chromosomes (X, Y). - A chromosomal complement that is not the multiple of the haploid number 23 is aneuploidy (see Slide 90). - A chromosomal complement that involves an entire haploid set of 23 is polyploidy (see Slide 91).

● STRUCTURAL 1) Rearrangement of chromosomes may or may not produce phenotypic abnormality, depending where the excessive or missing genetic info is.

2) Balanced rearrangements yield phenotypically normal individuals who have an increased risk of producing unbalanced gametes, which leads to reproductive loss or abnormal children. 89

Nondisjunction during Meiosis I and II90

● A): Nondisjunction occurs in meiosis-I. A pair of homologous chromosomes fails to separate which leads to formation of four affected eggs. Taken Down Syndrome as an example, two eggs will have an additional 21st chromosome and will produce trisomy-21 child from a non-affected father. The other two eggs will produce monosomy-21 child from a non-affected father. Autosomal monosomies are lethal and are miscarried. X-linked monosomies survive (Turner, monosomy X). Most autosomal trisomies are also lethal (except Down -21, Patau -13, and Edwards -18 syndromes).

● B): Nondisjunction takes place in meiosis-II. The first division is appropriate, producing two unaffected eggs which will then divide normally. Thus, out of four gametes, two will be normal, one will have trisomy 21, and the other - monosomy 21.

NUMERICAL CHROMOSOMAL ABNORMALITIESANEUPLOIDY: 1) Trisomy (A) Sex chromosome trisomy - Klinefelter syndrome (47 XXY) (B) Autosomal trisomy - Patau syndrome (Trisomy 13) - Edwards syndrome (Trisomy 18) - Down syndrome (Trisomy 21) 2) Monosomy

(A) Sex chromosome monosomy - Turner syndrome (Monosomy 45 X0) - Bonnevie-Ullrich syndrome (Monosomy 45 XO) (B) Autosomal monosomy (most of the conditions are lethal) - 1p36 deletion syndrome (Monosomy 1) - Cri du chat (cat cry) syndrome (Monosomy 5)

POLYPLOIDY: - Cutaneous syndactyly and respiratory distress (Triploidy, XXX 69) - Acute nonlymphocytic leukemia (Tetraploidy, XXXX92).

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NUMERICAL ANOMALIES (continued)● Pedigree analysis helps deduce whether a condition is autosomal

dominant, autosomal recessive, X-linked dominant, or X-linked recessive.● In Punnett square, the alleles of each parent are drawn in a 2 x 2 table. The

main principles of pedigree assessment are these:

X – linked Disorders:

(1) There can't be father-to-son transmission.

(2) Dominant:

a) Both males and females may be affected.

b) An affected male will have normal sons,

yet all daughters will be affected.

c) Offspring of an affected female will be

normal or carrier, with 1:1 ratio.

d) Example: D-resistant rickets.

(3) Recessive:

a) Only males are affected (there's a room for a rare homozygous female)

b) An affected male will have all normal sons, and all daughters-carriers.

c) Examples: Duchenne's/Becker muscular dystrophy, Hemophilia-A and B.92

● Autosomal Disorders

(1) Both sexes are equally affected.

(2) Dominant:

a) Penetrance and expressivity may vary from one individual to another.

b) Affected individuals will produce either normal or affected offspring, in a ratio of 1:1.

c) The affected individual either has an affected parent or represents a new mutation.

d) The affected parent poses a 50% risk.

e) An affected child born to unaffected parents presents a new mutation and there is no increase in the recurrence risk.

f) Older father ( > 50 years) form the risk group for the new mutations involving autosomal-dominant inheritance.

g) Examples: Achondroplasia, Huntington's Disease, Tuberous Sclerosis, Marfan Syndrome, Polycystic Kidnet Disease, Acure Intermittent Porphyria, Osteogenesis Imperfecta (some types).

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NUMERICAL ANOMALIES (continued)

Autosomal Disorders(3) Recessive:

a) Both parents of affected infant must be carriers. b) Offspring of two carrier parents will be either unaffected, or carrier, or affected in 1:2:1 ratio. c) Siblings may be affected; however, affected relatives are uncommon unless there is consanguinity in the pedigree. d) The couple with an affected child has 1:4 chance of recurrence in each next pregnancy. e) Birth of a child with rare or bizarre anomalies should always prompt consideration of an autosomal recessive disorder. f) For women with other affected relatives, the risk depends on frequency of gene population.

Hardy-Weinberg equation

is used to estimate gene frequency from incidence of disease:

p2 + 2pq + q2 =1

where p2 is the frequency of noncarriers (almost always <1), q2 is the frequency of the affected individuals, and 2pq is the frequency of carriers.

g) Examples: Cystic Fibrosis, Sickle Cell Anemia, Tay-Sachs, Meckel-Gruber Syndrome, Thrombocytopenia-absent Radius (TAR) and other single-gene defects. 94

Structural Chromosomal AnomaliesThe two major chromosomal mutations are: (1) insertion, (2) translocation.

Chromosome aberration or mutation is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes.

While missing or extra DNA mutations take place during the meiotic phases of the ova, some anomalies can happen after conception, resulting in Mosaicism (where some cells have anomaly and some do not). Such anomalies are “de novo,” not inherited from a parent.

Rearrangement of chromosomes may or may not produce phenotype abnormality, depending where the excessive or missing genetic information is. Balanced rearrangements yield phenotypically normal individuals.

● Examples of structural anomalies:

- Most cancers, either with formation of hybrid genes and fusion proteins, deregulation of genes and over-expression of proteins, or loss of tumor suppressor genes.

- Malignant Paraganglionic Neoplasm - chromosome-11 deletion.

- Pallister Killian syndrome, part of the chromosome-12 is duplicated with elements of mosaicism.

- Cri du Chat or "Cat Cry” syndrome - deletion of chromosome 5p.95

Some genetic conditions are caused by expansion of a DNA segment that contains a repeat of three nucleotides (triplet repeat), such as VAT.VAT.VAT.Healthy individuals have a variable number of triplet repeats, but there is a threshold beyond which a high number of repeats causes disease. This threshold varies from one disorder to another.The triplet repeat expansion (TRE) is also known as dynamic or unstable mutation because the number of triplet repeats may increase as the gene is passed from a parent to offspring. In this way, the condition may worsen or have an earlier onset from generation to generation (genetic anticipation).Where there is a number of repeats in normal range, TRE is not expected. However, when the number of repeats falls in the premutation range (normal, but unstable number of repeats), the repeats may or may not expand upon transmission to the next generation. Therefore, normal individuals with premutation are at risk of having an affected child with a triplet repeat in full mutation range.Sometimes the premutation range and the affected range overlap. In this gray area, someone may or may not express symptoms of disorder.The premutation size and source matter in inheritance. For example, the Myotonic Dystrophy triplet repeat is most likely to expand when inherited from mother. The Huntington Disease triplet repeat is most likely to expand when inherited from father.

TRIPLET REPEAT EXPANSION

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HEME SYNTHESIS DISORDERSHeme is composed of a tetrapyrrole ring (4 linked pyrrole rings) of protoporphyrin IX, with one coordinating ferrous (Fe 2+) iron ion in the center. Heme is found not only in hemoglobin and myoglobin but also in cytochromes and catalase. Synthesized primarily in liver (cytochrome P-450 protein) and bone marrow (delta-aminolevulinic acid and protoporphyrin), the first and the three last stages of heme formation occur in mitochondria. The rest occur in cytosol.

That explains why some of the heme-synthesis disorders (porphyrias, both hepatic and erithropoetic) are hereditary. All are autosomal dominant except the erythropoietic porphyria which is autosomal recessive. Some of these are photosensitive and accumulate deleterious free radicals from tetrapyrrole intermediates.

continued

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The Best Known Types of Porphyrias:

TYPE of DISEASE DEFICIENCY H/E CLINICAL FEATURES

Acute intermittent porphyria (AIP)

Uroporphyrinogen I synthetase Hepatic CNS effects, Abdomonal

pain

Congenital erythropoietic porphyria

Uroporphyrinogen III synthetase Erythropoietic Hemolytic anemia,

Photosensitivity

Porphyria cutanea tarda Uroporphyrinogen decarboxylase Both Red-brown urine,

Photosensitivity

Hereditary coproporphyria Coproporphyrinogen oxidase Hepatic CNS effects, Abdominal

pain, Photosensitivity

Porphyria variegate Protoporphyrinogen oxidase Hepatic CNS effects, Abdominal

pain, Photosensitivity

Erythropoietic protoporphyria Ferrochelatase Erythropoietic Liver dysfynction,

Photosensitivity

Crigler-Najjar syndrome Bilirubin glucoronyltransferase

Hepatic CNS effects, Kernicterus, Jaundice, Death

Gilbert (zheel BAR) syndrome

Bilirubin glucoronyltransferase

HepaticCommon in females, Nonhemolytic jaundice, No treatment is required

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GLYCOGEN STORAGE DISEASES● IN DEFAUT:

The substrate for glyconeogenesis is uridine diphosphate (UDP) glucose. Glycogen synthase adds to the nonreducing ends of chains in (1=>4) linkages. Yet, branches of the α

(1=>6) linkages are facilitated by α amylo- (1=>4)- α α(1=>6)-transglucoside. Glyconeogenesis is stimulated by insulin and is inhibited by glucagon and epinephrine.

Glycogenolysis starts from the cleavage of (1=>4) bonds αbetween glucosyl residues' nonreducing ends, and forming of glucose-1-phosphate. The latter converts to glucose-6-phosphate, then to glucose by releasing (1=>6) bonds αunder the debranching enzyme. Glycogenolysis is stimulated by glucagon, epinephrine, and is inhibited by insulin.

continued

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Six Glycogen Storage Diseases (all are autosomal recessive):

TYPE of DISEASETYPE of DISEASE DEFICIENCYDEFICIENCY GLYCOGEN IN GLYCOGEN IN AFFECTED CELLSAFFECTED CELLS

CLINICAL FEATURESCLINICAL FEATURES

Von Gierke (type I) Glucose-6-phosphatase

Increased - with normal structure

Hepatomegaly, Hypoglycemia

Pompe (type II) α-1,4-glucosidase Increased - with normal structure

Cardiac and respiratory failure, Early death

Cori (type III) Debranching enzyme

Increased, shortened branches

Similar to Von Gierke, but in midler forms

Anderson (type IV) Branching enzyme Increased, prolonged branches

CNS effects, Abdominal pain, Photosensitivity

McArdle (type V) Phosphorylase Slightly increased, with normal structure

Muscle cramps while exercising

Hers (type VI) Phosphorylase Increased Similar to Von Gierke, but in milder forms

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SPHINGOLIPID STORAGE DISEASESSphingolipids are derived from ceramide, a molecule formed by coupling a fatty acid and sphingosine:

Fatty Acid + Sphingosine = Ceramide

● Sphingolipids are found in the white matter of CNS. Lysosomal enzymes degrade those to sphingosine through several hydrolytic reactions.

● SPHINGOLIPIDOSIS are a group of hereditary lysosomal enzyme deficiency diseases with defects of one of above noted hydrolytic enzymes in degrading pathways. Deficiencies of sphingolipid-degrading enzymes in lysosomes lead to the accumulation of substrates therein, which results in lysosomal storage diseases.

● All are autosomal-recessive, except Fabry Disease which is X - linked. In most of these diseases neurological deterioration and early death occur.

continued

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Sphingolipid Degradation Disorders 102

SPHINGOLIPIDOSISSPHINGOLIPIDOSIS DEFICIENT ENZYMEDEFICIENT ENZYME ACCUMULATED ACCUMULATED MATERIALMATERIAL

CLINICAL FEATURESCLINICAL FEATURES

Tay - Sachs disease Hexosaminidase-A GM2 gangliosides

Developmental regression, Muscle weakness, Blindness, Cherry-red macular spot, Deafness, Absence of Hepato-splenomegaly, Death

Gaucher disease β -Glucosidase Glucocerebrosides

Joint and limb pain, Hepatosplenomegaly, Macrophages look like “crinkled paper”

Niemann-Pick disease Sphingomyelinase Sphingomyelin

Failure to thrive, Hepato-splenomegaly, Cherry-red spot in retina, Developmental delays, Macrophages look like “bubbly”

Fabri disease α - Galactosidase Ceramide trihexosides

Cataract, Kidney and heart failures, Paresthesia

Krabbe disease β - Galactosidase GalactocerebrosidesProgressive psychomotor retardation, “Globoid bodies” in brain white matter, Death

Metachromatic Leukodystrophy Arysulfatase -A Sulfatides Mental retardation, Peripheral

neuropathy

HISTONE MODIFICATION DISORDERSHistones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units, nucleosomes. The chief protein components of chromatin, they act as spools around which DNA winds, and participate in gene regulation.

● The linkage between histone methylation pathways and immune and neuronal signaling explains the greater genetic basis of neuropsychiatric disorders than previously recognized.

● Whole exome screens of lymphoma, multiple myeloma, renal carcinoma and other malignancies identify genes encoding diverse histone modifiers as targets of somatic mutation.

- Wiedemann-Steiner syndrome (autosomal dominant) – IUGR, psychomotor tardiness, hypotonia, facial dysmorphism (flat, assymetric face, dolichocephaly, telecanthus, thick eyebrows, short nose, hypertelorism, long philtrum, heavy jaw, ptosis, low-set ears, epicanthal folds, mild clinodactyly), short stature, sacral dimple short and thick limbs. - Kabuki syndrome (X-linked) – mental retardation, postnatal dwarfism, facial dysmorphism (reminiscent of Kabuki make-up), scoliosis, short 5th finger.

- Cornelia de Lange syndrome (autosomal dominant) – facial dysmorphism (synophrys), intellectual deficit, IUGR, digital defects and splanchnic malformations. - Other: Weaver syndrome, Sotos syndrome, Coffin-Siris syndrome, Nicolaides-Baraitser syndrome. 103

ANTENATAL FETAL ASSESSMENT: ERRORSChallenges in assessing fetal condition are often related to type-1 and type-2 errors which may be analytic (timing, interpreting) and technical (i.e. sensitivity and specificity of the chosen method).

Type-1 error (false positive result, Fp)

Type-2 error (false negative result, Fn)

Sensitivity (given the disease/anomaly is present, the probability that the test will be positive)

Specificity (given the disease/anomaly is absent, the probability that the test will be negative).

Marking true-positive (Tp) and true-negative (Tn) as well, we can then define sensitivity as Tp/(Tp + Fn).

A highly sensitive test, therefore, can rule-out the disease. Consider the mnemonic SN-N-OUT – for a test that is SeNsitive, a Negative result rules OUT a disease.

Specificity s defined as Tn/(Tn + Fp).

Thus, tests with high specificity rule-in the disease. The corresponding mnemonic, SP-P-IN, stands for – a test that is Specific, a Positive result rules IN a disease.

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FETAL ASSESSMENT: PREDICTIONPositive predictive value (PPV) – given the test is positive, the probability that the disease/anomaly is present.

PPV = Tp/(Tp + Fp)

For example, if the amniocentesis has 78% specificity for cystic fibrosis, then given a positive finding of cystic fibrosis the offspring will truly have the disease in 72% of the time.

Negative predictive value (NPV) – given the test is negative, the probability that the disease/anomaly is absent.

NPV = Tn/(Tn + Fn)

For instance, if a mid-pregnancy scan (ultrasound) has a 67% NPV for the fetal limb defect, then given the negative result, the fetus will truly not have a limb defect in 67% of the time.

105

FETAL ASSESSMENT: BASIC MEASURESThe red-line between miscarriage (including late miscarriage) and preterm birth, as well as between stillbirth or perinatal death is the 22nd

gestation week (formerly, before the ICPD of 1995, it was the 28th week).

At the end of 22nd gestation week, a regularly growing fetus weighs ~ 453 g (1 pound) and is ~ 28 cm (11-inches) long. Intrauterine growth retardation (IUGR) is when the estimated fetal weight (EFW) is at least 10% lesser than the expected normal. IUGR can be symmetric (fetal head and body are equally affected), and asymmetric (a milder form, where head is less affected than the torso).Table below shows ultrasound-assigned parameters for the:

106

GESTATIONAL AGE FETAL GROWTH● Biparietal diameter ● Head circumference● Femur length ● Crown-rump length ● Outer orbital diameter● Transcerebellar diameter

BPDHCFLCRLOODTCB

EFW

HC /ACFL /ACEFW

● Estimated fetal weight assessed by nomograms that combine AC and either FL or BPD.

● > 95% is an asymmetric IUGR● > 0. 24 is IUGR● > 90% I macrosomia - if dates are

population- adjusted and accurate.

ANTENATAL FETAL ASSESSMENT: ULTRASOUNDLateral Ventricular Width (LVW) / Hemisphere Width (HW) ratio is used in detection of ventriculomegaly and fetal hydrocephalus (Fig. 39). Bilateral indentations of the fetal skull in the frontal region (“lemon sign”) before 24 weeks of estimated gestation age (EGA) are suggestive of neural tube defect.

107

Occipitofrontal Diameter (OFD) is used (Fig. 40) for estimating Cephalic Index (CI).

CI = BPD / OFD

CI < 0.75 - dolichocephaly

CI > 0.85 - brachycephaly

(OFD + BPD) / 2 x 3.14 = Head Circumference (HC).

HC is used to estimate gestation age in settings with abnormal CI.

CRANIAL ULTRASOUND (continued)

Outer Orbital Diameter (OOD), Interorbital Distance (IOD), and Ocular Diameter (OD) are used for estimating gestational age (Fig. 41). The abnormal IOD suggests hypertelorism or hypotelorism. An abnormally small OD suggests microphthalmia.

108

Transcerebellar Diameter (TCD) is used for estimating gestational age (Fig. 42). It is spared to some degree in the IUGR. Abnormal shape of cerebellar hemisphere (“banana shape,” instead of regular round shape) is associated with neural tube defects.

THORACIC ULTRASOUND Fig. 43: Four-chamber Heart

View

Cross section of fetal chest shows four-chamber view of the fetal heart and the spine – to assess cardiac anatomy and measure thoracic circumference (TC).

A normal four-chamber image rules out most (81%) cardiac anomalies. Absence of fetal head motion is an irrefutable indicator of the intrauterine

109

fetal demise.

TC = (D1 + D2)/2 x 3.14

TC helps predict the presence or absence of pulmonary hypoplasia -- together with the AC/TC ratio.

ABDOMINAL ULTRASOUNDFig. 44: Fetal Abdomen

This cross section view at the level of liver and stomach shows ductus venosus in the liver and is the adequate place for measuring abdominal circumference (AC).

AC= (D1 + D2)/2 x 3.14

AC can be used for estimating gestational age but it's more sensitive to the fetal growth disorders. Common measures:

● Higher than normal HC/AC – asymmetric IUGR● Lower than normal HC/AC – macrosomia or microcephaly● Higher than normal FL/AC – IUGR, lower than normal FL/AC – macrosomia● Lower EFW but normal HC/AC - symmetric IUGR.

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AMNIOTIC FLUID, DOPPLER, FETAL VESSELS & PLACENTAL PERFUSION● Qualitative Amniotic Fluid Volume – is ultrosonographically observed after

30-32 gestation weeks and is the pocket of the fluid that measures at least 1 cm in two perpendicular planes.

● Amniotic Fluid Index (AFI) – is the sum of 4 quadrant vertical measurements. It is one of the 5 biophysical profile metrics.

● Oligohydramnios – there is no pocket > 1cm in two perpendicular planes, and AFI is < 4cm. Polyhydramnios - largest pocket is > 8cm in two perpendicular planes.

● Angle-independent Doppler indices: S/D = systolic/diastolic ratio; (S-D)/S = resistance index, (S-D)/Mean =pulsation index (Fig. 45).

● Uterine and Arcuate Arteries: S/D is normally < 2.6 after 26 weeks.

● Umbilical Arteries: S/D decreases with advancing gestation and normally

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is less 3.0 after 30 weeks.● Fetal Descending Aorta: Peak velocity of

flow is decreased with fetal hypoxia.● Carotid Artery & Cerebral Circulation: In

hypoxic states, blood flow to fetal head increases, PI decreases, and S/D of umbilical artery increases.

END OF MEDICAL SURVERY: Questions● Q1: During a well-child exam, a 4 year-old male is found to have a cyst on the

lateral side of the neck along the m. sternocleidomastoid border. What is the embryological origin of this condition?

● Q2: A man with Leber hereditary optic neuropathy consults for the odds of his condition being passed to his sons or daughters. What is your advice?

● Q3: An increase in the uterine artery PI or S/D is always indicative of:

a) IUGR

b) Fetal compromise

c) Increase in vascular resistance

d) None of the above.

● Q4: What is involved in the classic triad of congenital rubella syndrome?

● Q5: True or false? The IUGR may be detected by measuring HC/AC and FL/AC, and by estimating the fetal weight (EFW).

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END OF MEDICAL SURVERY: Answers● A1. A branchial cleft cyst has likely been growing because of the 2nd

branchial cleft's obliteration failure (see Slides 35, 36, 58).

● A2: Mitochondrial disease such as Leber hereditary optic neuropathy, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), or myoclonic epilepsy and ragged red fibers (MERRF) are transmitted only from the affected females to their offspring. The egg has mitochondria, not the sperm. The chance of passing on the male patient's condition to his offspring is 0% (see Slides 87, 88).

● A3: Correct answer is D. Not necessarily. In this case, increased PI and S/D are more indicative of preeclampsia (see Slide 111).

● A4: The classic triad consists of (1) Cataracts, (2) Congenital cardiac defects, (3) Sensorineural deafness. Other complications include: Autism, Chorioretinitis, Hepatosplenomegaly, Microcephalus, Mental retardation, Osseous defects (see Slide 78).

● A5: True (see Slides 106, 110).

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TERATOLOGY & MALPRACTICE LAW

At the interface of two disciplines, Teratology and The Law of Torts, at least three challenges manifest in relation to the:

Recognition of the purpose of Teratology as a science related to a measurable human problem.

Communication and conflicts between Teratology and other sciences (obstetrics, perinatology, occupational health, oncology, radiology, mental health, genetics, toxicology, environmental health, others) in addressing a legal inquiry.

Assessment of Teratogenesis beyond the frames of the cause-and-effect relationship, by recognizing alternative consequences that could take place under the same causation.

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Torts in the NutshellThe easiest way to understand what tort is, is to define what it is not. Tort is almost every civil action except of contract. Some differences are illustrated below.

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ATTRIBUTES THE LAW OF TORTS THE LAW OF CONTRACTS

WrongIs defined by the social norms

and public policiesIs defined by the private

parties

Intent May count or may not Counts

Actions for breach of duty Ex delicto Assumpsit

Indefiniteness Applies Does not apply

Consideration May apply Must apply

Doctrine of legal unconscionability

Does not apply Applies

Doctrine of moral unconscionability

Applies May not apply

Promissory estoppel May apply Must apply

Mental competence Is not required Is required

Assumption of risk Must apply May apply

Table Copyright © 2016 with Naira R. Matevosyan 115

4 IMPERIOUS ELEMENTS OF PRIMA FACIE SHOWING OF MEDICAL NEGLIGENCE

To recover on a theory of negligence or malpractice, the injured party (with standing) carries the burden of proving that:

(1) defendant had duty to conform his conduct to a standard of care;

(2) defendant failed to conform his conduct to the requisite standard of care required by the relationship;

(3) defendant's negligent act was the proximate cause of injury, and

(4) damage was transferred.

Where congenital anomaly is the matter of a legal dispute, the roles of plaintiff and defendant are intricate.● PLAINTIFF – can be parent(s) petitioning on behalf of the affected child, or

the affected child filing after his/her 18th birthday, or the state (ex patre, on behalf of the unborn fetus) against the negligent pregnant woman.

● DEFENDENT - can be the healthcare provider (GP, obstetrician, any other specialist in charge of a woman's medical or mental conditions in pregnancy), radiologist, toxicologist, nutritionist, pharmaceutical company, pharmacist, medical educator, trial researcher, employer, landlord, spouse; simply anyone or any entity with linkage to the cause-effect chain.

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DUTYIn general, there are two key aspects of physician-patient relationships:

● voluntary agreement (there is no obligation without consent),

● once created, such a relationship raises unwaivable obligations.

The voluntary relationship doctrine has sprung from Hurley v. Eddingfield. [1] The issues were: (1) whether the licensed doctors were obligated to help patients in dire medical need; and (2) whether there was an affirmative duty to be a good citizen and help others in peril without a predicament?

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The Montgomery Circuit Court of Indiana ruled that:

a physician has no duty to enter into relationships with a patient;

the license permits, but does not require provision of medical services;

a physician can't be forced to practice at all, or on terms he may choose to accept.

(1) Hurley v. Eddingfield, 156 Ind. 416, 59 N.E. 1058, 1901 Ind

NOTE: In obstetrics or antenatal care, the voluntary relationship doctrine does not apply. A pregnant woman applying for care can't be rejected.

THE INTRAUTERINE VICTIM ● In malpractice law, the three forms of liability (intentional torts, negligent

torts, and strict liability) may merge in assessment of damages. Where there is a gross medical error, absence of intent or but-for rules are unimportant and plaintiff may be awarded for punitive damages in addition to simple compensation.

● If the case involves maternal-fetal conflicts (a pregnant woman smokes or uses illicit substances, or knowingly/unknowingly exposes herself to toxic hazards, employment hazards, or radiation), the wrong act may potentially be prosecuted as criminal offense in the states with fetal custody laws, where the government represents the “unborn victim.”

● In 2004, President G.W. Bush signed into law the Unborn Victims of Violence Act, which - coded in two sections [2, 3] - recognizes a child in utero as a legal victim if s/he is injured or killed during the commission of any of over 60 federal crimes of violence listed in the Model Penal Code [2, 3].

(2) Title 18, Chapter 1 (Crimes), §1841

(3) Title 10, Chapter 22 (Uniform Code of Military Justice), Article 119a.

● Slides 119 -120 list the states that have “offense against the unborn” statutes and jurisdiction: 118

States With Fetal Custody LawsRULE OF LAW / EVENTS STATE(S) NOTES

Substance abuse during pregnancy is a crime. AL, SC, TN

Until July 2016, Tennessee was the only state to have a statute upon using drugs while pregnant. In Alabama and South Carolina, high courts have interpreted existing child endangerment and toxic tort statutes to allow prosecution of drug-using pregnant and nursing women.

Substance abuse during pregnancy is child abuse.

AL, AR, CO, FL, IA, IL, IN, LA, MN, NE, OK,

RI, SC, SD, TN, TX, VA, WI

In Wisconsin, a woman can be detained against her will for the duration of her pregnancy; fetus has its own court-appointed lawyer; a woman can lose custody of her child after birth, and the proceedings are mostly sealed. [4]

States where pregnant women were prosecuted for illicit drug use.

45 states, except DE, IA,

ME, RI, VT

Since 1973, such efforts continue under a wide variety of laws even in the liberal states. (continued)

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(4) Miranda L, Dixon V, Reyes C (2015). How states handle drug use during pregnancy. Project ProPulica

States with Maternal-Fetal Conflict Jurisprudence

RULE OF LAW STATE(S) NOTES

Substance abuse during pregnancy is a private matter between the woman and her child

MN, SD, WI

In listed three states, pregnant women using illicit drugs can be (under heightened circumstances) coerced to a treatment program.

Health care providers aremandated to report drug abuse during pregnancy

AZ, AK, IA, IL, LA, MA, MD, MI, MT, ND,

OK, RI, UT, VA, WI

Fifteen states have laws requiring health care workers to report to authorities if they suspect a woman is abusing drugs during pregnancy.

Testing is mandatory in pregnancy if the woman is suspected of using anillicit drug

IA, KY, MN, ND, SCIn Minnesota and North Dakota, a test is mandatory if there are drug-related complications at birth.

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The word “tort” means wrong in French. It covers a broad list of actions that the law considers as wrong: misdiagnosis, prescribing wrong drug, marketing a defective or hazardous product. If the conflict is between the patient and the provider(s), the case is tried in a private (civil) suit; where there is a maternal-fetal conflict, the negligence is assessed as a criminal matter (especially in conservative sates).

DISCOVERY RULE & STATUTES OF LIMITATIONSThe United States, its insular territories and DC, have a limited amount of time in which a patient can make a malpractice claim against a health provider (professional, facility).

Tort claims have filing time limitations varying from one state to another: one year (KY, LA, TN), 1 - 3 y (CA), 1-4 y (OH), 2 y (AK, AZ, CO, DE, GA, ID, IA, IL, KS, MI, NJ, OK, OR, PA, SD, TX, UT, WV, The Virgin Islands, American Samoa, Baker Island, Guam, Howland Island, Jarvis Island, Johnston Atoll, Kingman Reef, Midway Atoll, The Commonwealth of Northern Mariana Islands, Wake Atoll), 2.5 y (NY), 2-3 y (CT), 2-4y (AL, FL, NV), 2-6y (HI, ND), 2-7y (MS), 2-10 y (MO, VA), 3 y (AR, DC, MA, MT, NH, NM, RI, SC, VT, WA, WI, WY), 3-5 y (MD), 3-10 y (NC), 4 y (MN), 6 y (ME), 12 y (Navassa Island), one year for torts and 15 years for contracts (Puerto Rico).

When it comes to a teratogenicity dispute, time-gap between the discovery and filing the claim is the most challenging.

The discovery rule for malpractice claims does not apply in all insular territories. For example, in the U.S. Virgin Islands, it doesn't apply for the wrongful death actions, [5] but does apply for personal injury cases.[6]

(5) Richardson ex rel. Felix v. Knud Hansen Mem. Hosp., 744 F.2d 1007, 1984 U.S. App. LEXIS 18132 (3d Cir. 1984)

(6) Joseph v. Hess Oil, 867 F.2d 179, (3rd Cir. 1989) 121

STATUTE OF LIMITATIONS (continued)● If a wrongful act involves conspiracy, the statute of limitations may extend to

10 or more years in any state. ● Section 3293 of Title 18, United States Code provides for a ten-year statute for

certain financial offenses which involve conspiracy that violates (1) 18 USC §§ 215, 656, 657, 1005 -1007, 1014, 1033, 1344; (2) 18 USC §§ 1342 or 1343 if the offense affects a financial institution; or (3) 18 USC § 1963 to the extent that the racketeering activity involves a violation of 18 USC § 1344.

● For statutes, such as 18 USC § 371, which require an overt act in furtherance of conspiracy, the statute of limitations begins to run on the date of the last overt act. [7, 8] For conspiracy statutes which do not require proof of an overt act, such as RICO (18 USC §1961) or 21 USC § 846, the government must prove that the conspiracy continued into the limitations period. [9, 10]

● An individual's "withdrawal" from a conspiracy starts the statute of limitations running as to that individual. "Withdrawal" means that the conspirator must take affirmative action by making a clean breast to the authorities or communicating his or her disassociation to the other conspirators.[11]

(7) United States v. Northern Imp. Co., 814 F.2d 540 (8th Cir. 1987)(8) United States v. Coia, 719 F.2d 1120, 466 U.S. 973 (1984)(9) United States v. Gonzalez, 797 F.2d 915 (10th Cir. 1986)(10) Toussie v. United States, 397 U.S. 112 (1970); (11) Gabelli v. SEC, 568 US ___ (2013)

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DISCOVERYCertain congenital anomalies of teratogenetic origin (especially neuro-endocrine or cognitive), will not be readily apparent until months or even years after-birth. In such cases, most states allow extra time for the discovery of medical negligence beyond the limited period. This is called the discovery rule or the “awareness doctrine.”

When a discovery request is objected to, the requesting party may seek assistance of the court by filing a motion to compel discovery. Not all states provide time for the discovery of negligence. In those states, the statutes begin when the negligent care is performed, not when the patient reasonably becomes aware of it. The extension period depends on the state.

Tolling a Statutory Limitation Period:

● All is not lost, if the patient has run out of time on the statute of limitations period. There are three last resort options for deferring time limit:

a) tolling the statute of limitations

b) having it waived by the court

c) having it waived by the opposing party.● Whether tolling is acceptable depends on the corresponding state law. The

discovery rule could be considered tolling in the sense that it delays the running of the statute of limitations. (continued)

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TOLLING THE STATUTE● Before 2013, pursuant to the 28 U.S.C. §2642, the government could extend

the statute of limitations on five years for civil penalty enforcement actions in fraud cases. This privilege was reversed by the Supreme Court.[12]

● There are other situations that warrant tolling:

a) Minors cannot use the statute of limitations before their 18th birthday.b) Childhood sexual abuse (CSA) - could serve as a collateral cause where there is a claim against a provider treating a CSA survivor. Commonly, the victim of CSA can recover damages for emotional harm (in some cases even somatic) within the 1-6-year period after the victim's 18th birthday. There are laws [12-14] allowing even adult survivors of CSA to employ the discovery rule to toll the statute to defer the filing of a suit.c) Equitable tolling - while pursuing several remedies, the statute of limitations on remedies not pursued (especially, when plaintiff was mislead by defendant) will be equitably tolled if plaintiff can show: (1) Timely notice to the adverse party is given within the statute of limitations in filing of the first claim; (2) Lack of prejudice to defendant; (3) Reasonable good faith conduct on part of plaintiff.

(11) Gabelli v. SEC, 568 US ___ (2013) ; (12) Restatement (Second) of Torts, § 899 Comment (1979); (13) Hagen AM (1990). Tolling the Statute of Limitations for adult survivors of childhood sexual abuse. Iowa Law Review; 76, 355; (14) Bickel L (1991). Tolling the Statute of Limitations in actions brought by adult survivors of childhood sexual abuse. Arizona Law Review; 33, 427

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STANDARD OF CARE● Standard of care is "...the type and level of care

an ordinary, prudent health care professional with the same training and experience would provide under similar circumstances and in the same community." [15]

In malpractice law it has four levels:

(1) Rationale Care: Under the Rule § 156, Restatement (2nd) of Conflicts of Laws, the Rule §145 is applied to determine circumstances per which

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the provider's conduct is tortious, or how a reasonable man would have conducted under similar or identical circumstances.(2) General Standard: A commonlaw rule assessing provider's negligence. (3) Precise Standard: Prescribed by the statute of ordinance, it decides whether the actor was negligent under the circumstances. In interstate cases, the ordinance code or the common-law rule will belong to the state where the injury occurred because of the tortious conduct.

(4) Strict Liability: In commonlaw, this refers to the wrong acts regardless the “intent” prescribed. No proof of fault is required. (15) Ewing v. Goode, 78 Fed. 442 (W.D. Ohio 1897); 442, 443-444

STANDARD OF CARE IS DETERMINED BY THE EXPERT WITNESSThree types of witness scientists (reporting, educating, interpreting) are called to establish whether the causal connection between the deviation from applicable standard of care and patient's injuries is a reasonable medical probability. Ergo, teratology litigation requires an expert testimony on whether the exposure at issue caused abnormalities. Under the Federal Rule of Evidence 702, the educating witness testifies at a higher plane of abstraction about the validity of an underlying theory. This witness, in minimum, needs to have (1) heavy academic credentials (H-index, number of publications, referrals), (2) moral capacity (integrity); (3) capacity to observe (perception); (4) capacity to relate (narration).There are exceptions to expert testimony requirement. Where the propriety of treatment is such that the lack of skill or care of a health provider is so apparent for a laymen and requires only common knowledge to evaluate it, expert testimony is not necessary.[15-17] “Imaging cases” are inclusive under this (strict liability) prong.[18, 19]

If scientific evidence falls within the Federal Evidence Rule 901(b)(9), 901 (a), it governs the normal standard for authentication. If a scientific theory qualifies as a 'readily verifiable certainty,' the Judge can establish the validity theory. Under the Federal Rule of Evidence 104 (a), Judge's decision is final.

(15) Garfield Memorial Hosp. v. Marshall, 204 F.2d 721 (D.C. Cir. 1953); (16) Dean v. Dyer, 64 Cal. App. 2D 646, 149 P.2d 288 (1944); (17) Covington v. James, 214 N.C. 71, 197 S.E. 701 (1938); (18) Hubach v. Cole, 133 Ohio St. 137 (1938); (19) Morgan v. Sheppard , 91 Ohio Law Abs. 579 (1963) 126

EXPERT TESTIMONY ON CAUSATIONCommon inquiries in teratology litigation:

● Time, chronicity, and dosage of the exposure● Parents' age, age-gap, ethnicity, occupation, and income● Awareness of the parent(s) in specific types of teratogens ● Gene penetrance, established familial/hereditary predisposition,

consanguinity, thorough pedigree analysis● Number and combination of teratogenic factors (see Slide 70) ● Assumption of risk and provable expenses (precaution) sought to

prevent teratological effects ● Plaintiff's contributory fault● Number of the antenatal care visits● Available transportation to the antenatal care center● Obstetric and perinatal problems● Health insurance coverage● Loss of future earnings related to the offspring's disability● Future expenses related to the care of the disabled child(ren).

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CAUSALITYThe issue of actual causation (“causation -in- fact”) requires application of the but-for test. “But-for physician's breach of duty, would the patient's injury still have occurred?”

The proximate cause is applied to those more or less undefined considerations which limit liability even where the fact of causation is clearly established. The proximate cause is part of the actual cause, like yolk in the egg.

The actual cause can be remote or proximate. There can be multiple proximate causes, each of them serving as the basis for liability.

In actual cause, the issue is whether a particular causal factor is “sufficiently close" or "proximate" to the injury to justify the imposition of liability?

In proximate cause, the issue is whether defendant's liability directly reasons the foreseeable consequence?

Put differently:

✔ In actual cause, but for defendant's negligence accident would not have occurred.

✔ In proximate cause, the causal contributions are not too remote to justify imposition of liability. 128

The output of litigation is a determination that an exposure did or did not cause specific injuries in plaintiff. Yet, experts think of the risk as a probabilistic measure derived of observations in a population or community.An example: If 600 pregnant women were exposed to carbimazole, about 27 children are expected to be born with facial anomalies (as statistically established risk is 4.5%). Out of these 27, three children may have other genetically inherited causes (tetrades) with 72 various etiological factors, and the other 24 children may have a carbimazoe-induced anomaly. In public heath setting, it is easy to say that “carbimazole causes facial defects in offspring because the risk of disorder is eleven-fold higher in the population of exposed individuals.” (Sadly, many public health researchers still do not know that epidemiology is the science of confounding, not a science of easy and quick ratios or percentiles).In the courts of law, however, the scientist will not be required to determine that a child's facial abnormality was definitely caused by a teratogenic exposure. Absolute certainty is not anticipated. Courts require reasonable certainty (“more likely than not,” or a > 50% likelihood). In our example, if the scientist determines that the chance that the congenital facial defects were caused by carbimazole was 88.9% (24 : 27), i.e. > 50%, then s/he me say that “carbimazole caused the child's malformations to a reasonable degree of scientific certainty.”

ASSESSING CAUSALITY

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ASSESSING CAUSALITY (continued) Conventionally, experts follow Braford Hill's criteria in assessing causality in medical torts. These are nine principles established by an English epidemiologist Sir Austin Bradford Hill: [19]

Strength (effect size): A small association does not mean that there is no causal effect, though the larger the association, the more likely that it's causal.Consistency (reproducibility): Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, the effect must occur after that delay). Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.Plausibility: A plausible mechanism between cause and effect is helpful but limited by current knowledge. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. Yet, lack of it does not nullify the theory. Experiment: Occasionally it is possible to appeal to experimental evidence. Analogy: The effect of similar factors may be considered. (20) Bradford HA (1965). The Environment and Disease: Association or Causation?. Proceedings of the Royal Society of Medicine. 58 (5): 295–300

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ASSESSING FAULTDefense is given opportunity to reason why the plaintiff's proposed amount of recovery must be barred or adjusted. In other words, defense relies on plaintiff's own negligence (fault) and mental competence doctrines. Accordingly, tort jurisdiction has contributory and comparative fault systems.

● CONTRIBUTORY FAULT is any amount of negligence by the

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plaintiff which is a complete bar to recovery in most of the cases. In pure contributory negligence systems, defendant's liability - reduced by the percentage of injury - is attributable to negligence (as determined by jury). If even plaintiff contributed to the 90% of damage and only 10% was imposed by defendant, plaintiff still can recover for that 10%. Thirteen states use this system.

● COMPARATIVE FAULT ensures that plaintiff fully or partially recovers for damages, even if plaintiff too, was negligent. Plaintiff's negligence does not constitute an absolute bar to recovery. Instead, the monetary award is reduced (adjusted). If 51% of the jury believes the cause, plaintiff wins. If the jury is split on 50% / 50%, plaintiff must establish more likelihood standards. The recovery is 100% for damages if 51% of the jury believes plaintiff's theory. If only 49% of the jury agrees, plaintiff gets nothing.

FAULT SYSTEMSComparative fault system has gradual applications:

● Pure comparative fault: negligent plaintiff can recover from defendant only when his share of fault is less than 50%. If plaintiff's contributory fault is 40% and defendant's is 60%, plaintiff recovers at 60%. Twenty-one states follow the 51% Bar Rule under which a damaged party cannot recover if it's 51 % or more at fault: CT, DE, HI, IL, IN, IA, MA, MI, MN, MT, NV, NH, NJ, OH, OK, OR, PA, TX, VT, WI, WY.

● Modified comparative fault (“proportionate responsibility”) is the 50% Bar Rule. If there is a 50% / 50% negligence, plaintiff gets 50% recovery. Twelve states follow this rule: AR, CO, GA, ID, KS, ME, NE, ND, SC, TN, UT, WV.

● In joint liability system, multiple defendants (providers, regents, hospital, curbside, etc) are involved. Plaintiff can recover any portion of total damages from any of defendants (until the 100% of damages are recovered).

● Lastly, negligence per se (res ipsa loquitur) refers to imposition of liability without a proof of fault. To successfully invoke it, plaintiff must show that:

(1) There is no evidence of the actual cause of injury; (2) The injury is not the kind that ordinarily occurs in the absence of negligence; (3) Plaintiff was not responsible for his or her own injury; (4) Defendant or its employees or agents had exclusive control over the instrumentality that caused the injury; (5) The injury could not have been caused by any instrumentality other than that over which the defendant had control. 132

MATERNAL-FETAL CONFLICTS● These are dilemmas with a greater presentation in medical ethics than in

torts law or criminal justice, because a woman's bodily integrity and autonomy in making informed decisions about her health are protected by the 1st, 5th and 14th Amendments to the U.S. Constitution and common-law precedents. In order to hold a woman accountable for her injurious behavior posed to the viable fetus, local statutes are imposed.

● The degree of maternal-fetal attachment (the “umbilical effect” )[21] may decide the degree of mother's fault in fetal damage. Serious mental illnesses may deteriorate woman's perceptions of pregnancy. [22] And there are conflicts, where woman's careless antenatal behavior may cause physical or mental abnormalities in the fetus:

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smoking, illicit substance use, alcoholism, poor nutrition, acquiring sexually transmitted infections (STI) from random relationships, night-time jobs. Most of these cases involve moral turpitude and are assessed in criminal justice.

(21) Matevosyan NR (2010). Pregnancy and postpartum specifics in women with schizophrenia. Archives of Gynecology & Obstetrics; 283(2):141-147 (22) Matevosyan NR (2012). Legal causes and council in reproductive health. International Journal for the Semiotics of Law; 1-21

THE PREGNANT ADOLESCENTWhat if a poor antenatal behavior involves a pregnant teenager?

Imposition of laws depends on the state. For example, Delaware recognizes the concept of mature minor. [23] "Person under the legal age of majority may have a right to make their own medical decisions if they are [mature enough to exercise the judgment of an adult]." [24]

As of 2014 only 38 states have separate statutes for "emancipated minors." Even less number of states have statutes for "independent minor,” "minor living apart," "married minor" or "minor parent." Under specific circumstances, these states give teenagers the right to make medical decisions, without any need to demonstrate a particular level of maturity. The statues of minors govern the following aspects: abortion; blood donation; treatment of chemical dependence; financial responsibility; reproductive health care; outpatient mental healthcare; treatment for communicable diseases.Thirteen states (ID, MA, MD, MN, MO, ND, NH, NY, OH, PA, RI, SC, WI) do not have "emancipated minor" statues. Here, disputes around teenage pregnancy are solved pursuant to the commonlaw precedents (MA, MD, MO, OH, PA), Mental Hygiene Laws (NY), or General Statutes (ID, MA, MD, NH, RI, SC, WI). States where a teen's consent to treatment is governed by the commonlaw, require parental consent for the abortion -- unless there is a Judicial Bypass mechanism. [24]

(23) In the Matter of S.L., A Minor Child v. A. and Sh. L., 735 A. 2d 433 (1999)(24) Colo. Rev. Stat. § 19 1 103, Emancipated Minor‐ ‐

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DAMAGE● Special damages cover the quantifiable expenses caused by malpractice,

including medical bills and past missed work. Expert witnesses are also required to estimate the special-need expenses (in teratology torts).

● Punitive damages: In strict liability cases, the imposed rule varies from state to state, but the general requirement is the presence of intent. The exact amount of punitive damages is up to the jury, but typically cannot be more than ten times the amount of special and general damages. In states without statutory limits on punitive damages, Judges decide the amount.

● When it comes to punitive damages, malpractice law is full of controversies. Medical negligence suits increase the costs of malpractice insurance for doctors and hospitals. Consequently, the costs of treatment (and therefore health insurance premiums) increase.

● Statutory Limitations: Many states place a cap on the maximum amount of damages the patient can recover. Some states put a cap on all damages combined, saying a patient cannot recover more than, for example, $500,000. Others have a cap only on "general damages," also known as “non-economic” damages, as usually those can't be measured by a dollar amount. For example, California sets a $250,000 limit on non-economic damages in medical malpractice cases. But there is no limit on economic damages, including compensation for past and future medical care, loss of past earnings, and diminished future earning capacity.

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DAMAGES● Survival Statutes allow the estate or heir to recover damages that

occurred during the time period from initial medical malpractice to death of the patient. These damages generally include everything allowed in a malpractice suit had the patient survived, except for damages relating to the future, like earning capacity.

● Wrong Death Statutes are designed to compensate the patient's family for their future monetary loss. Compensation for loss of companionship or emotional harm is typically not allowed under the wrongful death statues, although some states allow that kind of recovery. Depending on the state, not all family members can recover.

● Pure Economic Loss refers to the unplanned and unexpected monetary losses that either the patient or the provider have suffered during the treatment process. Pure economic loss rule applies by showing privity. In order to succeed under pure economic loss doctrine, plaintiff (patient, provider) must prove a much closer relationship with defendant than s/he would have to prove in a claim for physical damage. Where there is pure economic loss, recovery incurred through the tort of negligence is very limited.

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DEFENSE● There are three common defense strategies:

1) plaintiff's negligence

2) statute of limitation bar

3) assumption of risk.

(1) Plaintiff's negligence was discussed in “Causality” slides (128-134).

(2) Statute of limitation bar was discussed in slides 122-124.

(3) Assumption of risk: The risk of damage can be express or implied.● Express - a written waiver of liability, a covenant not to sue. This type is

uncommon in medical practice. However, the hospitals (not the physicians) may ask the patient to release liability for the falls and accidents, or contraction of airborne infections deleterious to the fetus. Whether such a waiver will be enforced depends largely on jurisdiction and circumstances. In denying a release of liability (waiver), the courts reason that the waiver is contrary to the public policy.

● Implied liability has to types: (A) Primary assumption of risk - a person in full awareness of danger cannot recover damages under this theory. The defense affirmatively shows that plaintiff acted negligently. (B) Secondary assumption of risk - when plaintiff was hesitant of danger, yet did not avoid it when there was an alternative.

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DISCLOSURE OF RISKCan implied, secondarily assumption of risk bar recovery if contributory negligence has been replaced with comparative fault?

The Carolinas (NC, SC) agree with this approach. In Rhode Island, plaintiff's assumption of risk is an absolute bar to recovery. In the majority of states, secondary implied assumption of risk is compared against defendant's negligence.

In malpractice law, informed consent defense relies on two standards

Professional Disclosure Standard: [25, 26] “what a reasonable practitioner would have disclosed under similar circumstances”?

Under this jurisdiction, the jury is required to establish whether the disclosure standard was met, regardless what other practitioners would reasonably do. If certain information is not customarily disclosed in medical community, the jury is required to find for defendant. Also, a peer witness testimony is required.

Patient's Reasonableness Standard (Canterbury Standard): [27] “what a reasonable patient would consider material to making an informed decision”?

(25) Tarasoff v. Regents of University of California, 551 P. 2d 334 - Cal: Supreme Court (1976)

(26) Cobbs v. Grant, 502 P. 2d 1 - Cal: Supreme Court (1972)

(27) Canterbury v. Spence, 464 F. 2d 772 - Court of Appeals, DC Circuit (1972) 138

Canterbury Standard● Established in Canterbury v. Spence (1972),[28] it grants the jury freedom in

making a determination that failure to disclose amounts a liability - regardless what is the customary standard in that medical community. Under this standard, expert testimony is not required. Obviously, the Canterbury standard is more favorable for plaintiff.

● Canterbury court has also established, inter alia, standards measuring performance of duty of disclosure:

✔ It is unrealistic to expect doctors to discuss with patients every risk of proposed treatment. A risk is material when a reasonable person, in what the doctor knows or should know to be the patient’s position, would be likely to attach significance to the risk in deciding whether or not to forgo the proposed therapy. ✔ A doctor bears no responsibility for the discussion of hazards the patient has already discovered. ✔When a genuine emergency arises, the impracticality of conferring with the patient dispenses a need for it. ✔ A doctor does not have to disclose the risk of treatment if the disclosure would make the patient become ill or emotionally distraught. (28) Canterbury v. Spence, 464 F. 2d 772 - Court of Appeals, DC Circuit (1972)

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MEASURING FAULT EMPIRICALLYThere are more sensible and specific solutions in assessing fault than the Calculus of Negligence (USA v. Carrol Towing) or Hand's Burden/Benefit Formula (B < PL). [29]

Testable predictions concerning the effects of negligence include the private and social costs of care.

Under the comparative fault system, plaintiff's (x) private cost (Cx) is

C(x) + (x)s(x)Dλ ___ (x2) + [1 r(x)]D− μ ___ (x1)

i.e. the socially efficient level of care C(x) occurs where the social cost (D) of accidents is minimized.

Under the contributory negligence system, plaintiff's private cost (Cx) is

C(x) + (x)s (y)Dλ ___(x2) + [1 (x)r(x)]D− μ ___(x1)

i.e. defendan't (y) liability qua injurer (Cy) chiefly depends on plaintiff's (x) level of care (Cx). Plaintiff (x) is awarded for damages (D) only if s/he was non-negligent.

(29) United States v. Carroll Towing Co. 159 F.2d 169 (2d. Cir. 1947)140

CASE 1Brock v. Merrell Dow Pharmaceuticals, Inc [30]

● PROCEDURAL HISTORY: Plaintiffs (parents) filed a suit in Federal District Court on behalf of their minor child, to recover damages for birth defects (Poland's Syndrome) that allegedly resulted from the prenatal injection of an anti-nausea drug, Bendectin (an anticholinergic), manufactured by Merrell-Dow Pharmaceuticals, Inc (defendant). The negligence theory included: improper inspection, design defect, and failure to warn. Causation of teratogenicity was contested with expert testimonies of both sides. Plaintiffs obtained a jury verdict in the amount of $550,000 against Merrell-Dow, of which $240,000 in compensatory damages and $310,000 in punitive damages. Merrell-Dow appealed in the 5th Circuit, arguing that plaintiffs did not present sufficient evidence to allow the jury to conclude that Bendectin caused the defect (limb reduction) in the child.

● HOLDING: Defendant was entitled to judgment notwithstanding the verdict.

● DISPOSITION: Judgment in favor of plaintiffs was reversed and the case was dismissed.

● REASONING: Lack of measurable/convincing evidence.(30) Brock v. Merrell Dow Pharmaceuticals, Inc., 874 F. 2d 307 - Court of Appeals, 5th Circuit 1989 141

CASE 2Chikovsky v. Ortho Pharmaceutical Corp [31]

● PRINCIPLE FACTS: During her pregnancy, plaintiff applied Retin-A twice daily to her face & neck for her acne treatment. The child was born with imperforate anus and multiple deformities of external ear and toes (also see Slide 73).

● LEGAL PROCEEDINGS: Plaintiff filed a negligence suit on behalf of her affected child. Defendant entered for summary judgment based on the absence of genuine issue of material fact with respect to causation.

● HOLDING:Under the Rule 56(c) of the Federal Rules of Civil Procedure, summary judgment shall be granted "if the pleadings, depositions, answers to interrogatories, and admissions on file, together with the affidavits, if any, show that there is no genuine issue as to any material fact and that the moving party is entitled to a judgment as a matter of law."

● DISPOSITION: Defendant's motion for summary judgment was granted.● REASONING: Plaintiff's expert opinions were not based on scientifically

valid/gravid principles and did not meet the reliability requirements of Rule 702 as interpreted in Daubert. [32]

(31) Chikovsky v. Ortho Pharmaceutical Corp., 832 F. Supp. 341 - Dist. Court, SD Florida 1993(32) Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 US 579 - Supreme Court 1993

142

END OF LEGAL SURVERY: Questions● Q1: ________ allows defendant to present evidence that plaintiff's condition

resulted from factors other than defendant's negligence:

a) Promissory estoppel

b) Contributory fault doctrine

c) Comparative fault doctrine

d) Affirmative defense.

● Q2: A defense strategy that prevents plaintiff from recovering damages if plaintiff voluntarily accepts a risk associated with his/her conduct:

a) Contributory fault

b) Assumption of risk

c) Mirror image rule

d) Remand.

● Q3: In Chikovsky v. Ortho Pharmaceutical Corp, [31] why did the plaintiff fail in causation theory? 143

Questions (continued)

● Q4: A continuous sequence of events, unbroken by any intervening cause that produced an injury, and without which the injury would not have occurred:

a) Implied liability c) Actual cause

b) “But-for” rule d) Direct cause.

● Q5: Also known as Last Clear Chance, _____________ is an entity that operates independently and becomes the proximate cause of an accident. For an event to fall within this doctrine, four conditions must be met: (I) The injured party has to be in a perilous position; (II) the tortfeasor in exercising ordinary prudence must be aware that the party in peril cannot safely avoid injury; (III) the tortfeasor has the opportunity to save the other person; and (IV) the tortfeasor fails to exercise such care.

a) Strict liability c) Supervening cause

b) Plaintiff's negligence d) Good Samaritan.

144

END OF LEGAL SURVERY: Answers● A1: D A2: B ● A3: Under the Federal Rule of Civil Proceeding (Rule 56) as well as Adickes v. S.H.

Kress & Co (1970), Celotex Corp. v. Catret (1986) and Daubert v. Merrell Dow Pharmaceuticals, Inc (1993), once the moving party has met its burden of showing absence of a genuine issue of material fact, the party opposing the summary judgment (nonmoving party) must go beyond the pleadings and adduce some evidence showing that material facts are in dispute.

Under the Federal Rule of Evidence (Rule 702), the evidence or testimony must “assist the trier to determine a fact in issue.” This implies to the “relevance” standard. The "helpfulness" standard in insufficient, as it imposes a prerequisite to admissibility of testimony as a valid scientific connection to the pertinent inquiry.

Pursuant to the Federal Rule 104 (a), a trial judge must determine whether the expert is proposing to testify to (1) scientific knowledge that (2) will assist the trier of to determine a fact in issue. et, in Chikovsky v. Ortho Pharmaceutical Corp, plaintiff's witness was an ob/gyn, not specialized in embryology or teratology, and who did not rely on any scientific evidence in forming his opinion that “the topical application of Retin-A causes birth defects.” The nonmovant failed in meeting her burden of prima facie showing material facts on causality, and her theory was not testable enough to fit the “relevance” standard.

● A4: D A5: C 145

DISCLAIMER

This presentation does not constitute a medical or legal advice. The burden for determining its completeness, suitability or appropriateness for intended use or purpose rests solely on the reader accessing this information.

The author declares no commercial, strategic, or financial trusteeship with the names of entities - either used or omitted.

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TERATOLOGY: An abridged medical-legal survey (by Naira Matevosyan)

Health & Medicine