DRUGS IN PREGNANCY – A COMPLETE GUIDE :- PART 1

In general, drugs unless absolutely necessary should not be used during pregnancy because drugs taken by a pregnant woman can reach the fetus and harm it by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the growth and development of fetus

Congenital Intestinal Defects

MIDGUT MALFORMATIONS

  • Rotation defects
  • Omphalocele
  • Meckel’s diverticulum
Recall that, typically, the primary intestinal loop undergoes 270 degrees counterclockwise rotation as it elongates; in the final position, the large intestine “frames” the small intestine.

Rotation Defects

  • Non-rotation
    • When rotation does not occur, the small intestine lies to the right of the large intestine (thus, it this defect is sometimes referred to as “left-sided colon”).
  • Reversed rotation
    • When rotation occurs clockwise; in this case, the duodenum will pass ventral to the transverse colon, instead of dorsal to it.
  • Mixed rotation
    • When rotation of the cranial and caudal intestinal segments is not coordinated: only the cranial end undergoes the first rotation, and only the caudal end undergoes the second. The cecum lies at the midline, just inferior to the pyloric region of
      the stomach. Because the mesentery is pulled with the intestine as it rotates, mixed rotation can resort in volvulus, aka, torsion, of the mesentery around the superior mesenteric artery. Bands of mesentery can constrict and obstruct the digestive tract; the duodenum is particularly susceptible to entrapment by the mesentery of the cecum.

Omphalocele

  • Occurs when the abdominal viscera protrude through the umbilical ring
    • The viscera is covered in a vascular membrane, which is susceptible to rupture (not to be confused with gastroschisis, in which the viscera protrude from the anterior body wall but are not covered by a membrane).
    • Omphalocele is often present in conjunction with other abnormalities, and is thought to occur as result of failure to fully retract during midgut rotation, lateral body folding failures, or failure of connective tissues in the abdominal wall.

Meckel’s diverticulum

  • Present when the vitelline duct fails to fully regress.
    • Its location and length are variable, and, in many cases, is asymptomatic. However, if the diverticulum contains pancreatic or gastric tissues, bleeding ulcers can form.

HINDGUT MALFORMATIONS

  • Fistulas
  • Imperforate anus

Fistulas

  • Rectourethral fistulas occur when the urinary and digestive tracts are connected.
    • Thus, both urine and feces are directed through the urethra, and surgery is required.
  • Rectovaginal fistulas are characterized by a connection between the vagina and rectum.
    • The connection between the rectum and vagina channels rectal contents to the vagina; surgery is required to form a separate outlet for feces.
      Imperforate anus

Presents in various permutations; corrective surgeries are necessary to treat imperforate anus, which is often accompanied by fistula.

Agenesis

  • Characterized by the formation of a blindly ending anorectal canal.

Anal atresia

  • Occurs when the anal membrane is abnormally thick, and prevents the anus from opening to the external environment.

The Pharyngeal Arches – Part 1

  • There are 5 pharyngeal arches, numbered 1 – 4 and then 6.

(There is NO 5th pharyngeal arch.)

  • They comprise:
    • Aortic arches, the arterial connections between the ventral and dorsal aortae.
    • Skeletal structures (derived from neural crest cells).
    • Muscle (derived from mesoderm).
    • Cranial nerves (derived from neural crest cells).

THE PHARYNGEAL ARCHES AND THE NEURAL CREST CELL MIGRATIONS TO FORM CNS 5, 7, 9, AND 10

We draw the differentiated neural tube from cranial to caudal:

  • Telencephalon
  • Diencephalon
  • Mesencephalon
  • Metencephalon
  • Myelencephalon

And we include the caudal neural tube

  • The notochord induces the overlying ectoderm to differentiate into the neural tube.
  • There are 5 pharyngeal arches, from cranial to caudal: 1, 2, 3, 4, (skip 5) and then 6 [No 5th Pharyngeal Arch exists!]

Neural crest cells migrate into the pharyngeal arches and to form the pharyngeal arch cranial nerves.

  • CN 5 (the trigeminal nerve) migrates into arch 1
  • CN 7 (the facial nerve) migrates into arch 2
  • CN 9 (the glossopharyngeal nerve) migrates into arch 3
  • CN 10 (the vagus nerve) migrates into arches 4 and 6 – the superior laryngeal branch lies within the 4th pharyngeal arch and the recurrent laryngeal branch lies within the 6th pharyngeal arch.

In addition to the cranial nerves being a part of this migration, so are the skeletal elements.

  • The mandibular prominence forms pharyngeal arch 1 (if we know CN 5’s role in mastication, this will help us remember the association between this arch and nerve).
  • Although the maxillary prominence is sometimes listed as a portion of pharyngeal arch 1, indicate that it actually lies rostral to the 1st arch.

Key placodes (which are areas of thickened surface ectoderm) derive CNs 1, 2, and 8 (the solely sensory set of CNs), from cranial to caudal.

  • At the nasal prominence, lies the olfactory placode, which derives the olfactory epithelium and olfactory nerve (CN 1).
  • The optic placode forms the optic nerve (CN 2); it originates from the diencephalon.
  • The otic placode forms the vestibulocochlear nerve (CN 8); it originates from the hindbrain.

THE PHARNGYEAL APPARATUS (AKA THE PHARYNGEAL REGION): THE PHARYNGEAL POUCHES AND AORTIC ARCHES.

Whereas the neural tube lies dorsal to the notochord, the structures we’ll focus on here (the vasculature and pharyngeal apparatus) lie ventral to it.

  • The long endodermal tube follows the cephalic bend ventral to the notochord.
    • Cranially, lies the pharynx.
    • Caudally, label the esophagus.
  • The trachea branches from the endodermal tube anterior to the esophagus.

4 pharyngeal pouches lie along the endoderm

We specify that the 1st pharyngeal pouch lies posterior to the 1st pharyngeal arch.
  • The pouches are outpouchings of endoderm that fill the pharyngeal grooves; we’ll understand this anatomy better in part 2 of our diagram in which we draw the pharyngeal apparatus in coronal view.

Arterial vasculature

  • Each pharyngeal arch has an aortic arch that runs within it.
  • From the heart emanates the truncus arteriosus, aortic sac, and the ventral aorta.
  • The dorsal aorta bifurcates to become the bilateral internal carotid arteries, cranially – they form the primary supply of blood to the brain (the anterior 2/3rds of the brain’s vascular supply). For reference, the posterior blood supply to the brain comes from the basilar artery, which is supplied by the vertebral arteries.
  • Connect the ventral and dorsal aortae with the aortic arches that pass in between the pharyngeal pouches and specify the 1st aortic arch (these are sometimes referred to simply as the arch arteries) – they connect the dorsal and ventral aortae.

THE PITUITARY GLAND

  • Rathke’s pouch is an ectodermal placode along the roof of the stomodeum (the site of the future mouth – the cranial opening of the pharyngeal apparatus). Rathke’s pouch stretches towards the floor of the 3rd ventricle (the infundibulum). Later, it disconnects from the stomodeum and its stalk regresses: ultimately, forming the anterior pituitary gland. And the infundibulum descends and develops into the posterior pituitary gland.
    • Clinical Correlation: Craniopharyngioma
These fascinating embryological migrations help us to remember that the pituitary gland is acutely in touch with the external environment and works to keep our body in physiological homeostasis.

THE THYROID GLAND

  • The thyroid primordium lies in between the 1st and 2nd pharyngeal pouches, along the ventral surface of the pharyngeal apparatus, draw. It forms at the apex (the ventral tip) of the foramen cecum.
  • The thyroid primordium develops into the thyroid gland, which descends within the thyroglossal duct (which quickly breaks down) and then migrates beneath the thyroid cartilage to its ultimate anatomical site: beneath the cricoid cartilage.

Clinical Correlation –

The cricoid cartilage is an important anatomical landmark when palpating for a thyroid goiter!

Embryonic Folding

The trilaminar embryo at approximately day 21

Using standard embryological convention:

  • The ectoderm in blue (within the amniotic cavity)
  • The endoderm in yellow (within the yolk sac)
  • Intraembryonic mesoderm lies in between them.
  • Extraembryonic mesoderm surrounds the embryo.

Day 23

  • The extraembryonic mesoderm forms a mushroom shape (forming what appears to be a cap and the beginning of a stalk)
  • The ectoderm-lined floor of the amniotic cavity curls under at its edges the endoderm-lined roof of the yolk sac, also tucks under.
  • Accordingly, so does the intraembryonic mesoderm.

Day 26

  • The extraembryonic mesoderm further curls and the stalk (the vitelline duct) narrows.
  • The curling of the amniotic cavity accentuates and so does the yolk sac and the intraembryonic mesoderm.

THE TRILAMINAR GERM DISC STRUCTURES AT DAYS 21, 23, AND 26

Day 21

from top to bottom

  • The trilaminar germ disc comprises ectoderm, mesoderm (which is intraembryonic), and endoderm.
  • Within the mesoderm, lies the the ectoderm-derived neural tube, notochord, bilateral somites, and neural crest.
  • There is folding of the neural tube.
    • the neural folds abut centrally, first, but remain open at their ends anteriorly and posteriorly.
    • the neural groove lies deep within the neural tube.
    • the neural crests form at the tips of the neural folds.

Day 23

  • The neural crest cells are now making their migrations.
  • Neural tube folding:
    • The neural tube is now folded a long distance along its center but remains open at the anterior and posterior neuropores.
    • We see the somites, centrally, where the neural folds abut; they generate bumps that appear on the surface of the overlying neural tube.

Day 26

  • The somites (the paraxial mesoderm) differentiate into the central musculoskeletal elements – (from medial to lateral): sclerotome (which forms bone), myotome (which forms muscle), and dermatome (which forms skin).

EMBRYONIC FOLDING WITH THE DEVELOPMENT OF THE KEY STRUCTURES OF THE TRILAMINAR GERM DISC

The trilaminar embryo at approximately day 21

Using standard embryological convention:

  • The ectoderm in blue (within the amniotic cavity)
  • The endoderm in yellow (within the yolk sac)
  • Intraembryonic mesoderm lies in between them.
  • Extraembryonic mesoderm surrounds the embryo.
  • The connecting stalk connects the embryo to the uterus.
  • The embryo lies within the chorionic cavity, which, itself, is lined with extraembryonic mesoderm.
  • The allantois is the tip of the posterior endoderm that extends into the connecting stalk – a hindgut diverticulum.

Day 23

  • The extraembryonic mesoderm forms a mushroom shape (forming what appears to be a cap and the beginning of a stalk)
  • The ectoderm-lined floor of the amniotic cavity curls under at its edges the endoderm-lined roof of the yolk sac, also tucks under, accordingly, so does the intraembryonic mesoderm.
  • The connecting stalk is tucked under the endo- and ectodermal folds.
  • The neural tube is now folded a long distance along its center but remains open at the anterior and posterior neuropores.

Day 26

  • The extraembryonic mesoderm further curls and the stalk (the vitelline duct) narrows.
  • The curling of the amniotic cavity accentuates and so does the yolk sac and the intraembryonic mesoderm.
  • There is further folding of the connecting stalk and outpouching of the endodermal allantois.
  • There’s further the growth of the neural tube, which is fully closed (anterior and posterior neuropores have closed).
  • The gut structures endoderm forms are visible: from anterior to posterior – the foregut, midgut (which attaches to the yolk sac via the vitelline duct), and the hindgut.

Neurulation

Definiton

  • The process of neurulation involves the formation of the neural plate and the folding of the neural plate into the neural tube.

Key Points

  • The notochord induces the overlying ectoderm to develop into the neural plate.
  • The neural plate folds into the neural tube and as it closes, the neural crests are pinched off.
  • The neural tube derives the central nervous system (the brain and spinal cord).
  • The neural crest cells derive the peripheral nervous system (eg, ganglion cells and Schwann cells) and also select other cell types (eg, melaoncytes).

THE DEVELOPING EMBRYO

Trilaminar germ disc

Three layers of the trilaminar germ disc.

  • Ectoderm (and amniotic cavity)
  • Mesoderm
  • Endoderm (and yolk sac)

THE NOTOCHORD

The prochordal knot

  • A strand of cells that extends toward the cranial end of the prochordal knot.
    • The prochordal knot lies within the mesoderm (in between the ectoderm and endoderm).

ASSOCIATED EMBRYONIC STRUCTURES

Key associated embryonic structures:

  • The primitive streak exists within the ectodermal layer of the germ disc; it dimples along the embryonic disc.
  • The primitive node (aka primitive knot, Hensen’s node) lies at the cranial end of the primitive streak.
  • The prochordal knot lies farther cranially.

NOTOCHORD DEVELOPMENT

  • The notochord develops cranially, (towards the head of the embryo) and because it is blocked at the prochordal plate, it also develops caudally (towards the tail of the embryo) as the primitive streak regresses. There are multiple stages of notochord development, which we omit, here, for simplicity.

Key notochord actions:

  • Forms the embryonic central axis,
  • Induces neural plate formation,
  • Establishes the central column of the spine and then degenerates to become the nucleus pulposus of the intervertebral discs.

DAY 17 OF EMBRYOGENESIS

  • Early regression of the primitive streak.
  • Development of the neural plate.
  • The notochord lies within the mesoderm (it induces neural plate formation).

DAY 18 OF EMBRYOGENESIS

  • The primitive streak has regressed.
  • The neural plate invaginates to form the neural groove (the dip, centrally) and the neural folds (the peaks, laterally). The neural crests lie at the tips of the neural folds.
  • Within the mesoderm, somites develop.

Somite differentiation

  • Sclerotome (which derives bone and cartilage),
  • Dermatome (which derives dermis),
  • Myotome (which derives skeletal muscle).

DAY 21 OF EMBRYOGENESIS.

  • The primitive streak has nearly completely regressed and the neural groove starts to fully fold to form the neural tube, which enters the mesoderm.
  • It closes off in the center first, with the cranial and caudal ends still open at this point, and resides within the mesoderm.
  • The neural crest cells have pinched off and reside in the ectoderm layer.

DAYS 23 – 26 OF EMBRYOGENESIS

  • The anterior (cranial) neuropore closes at approximately Day 24.
  • The posterior (caudal) neuropore closes at approximately Day 26.
  • The somites form ridges underneath the ectoderm.
  • The neural crests migrate to within the mesoderm.

CONGENITAL NEURO EMBRYOLOGICAL DISORDERS

  • Chordoma
  • Chiari Malformation
  • Dandy Walker Malformation
  • Encephalocele
  • Holoprosencephaly
  • Lissencephaly
  • Schizencephaly
  • Septo-Optic Dysplasia
  • Zellweger Syndrome

Gastrulation

GASTRULATION

The embryonic disc develops from bilaminar (2 layers) to trilaminar (3 layers).

The bilaminar disc comprises epiblast + hypoblast.

The trilaminar disc comprises ectoderm, mesoderm, endoderm.

All of which derives from the epiblast (none from the hypoblast).

BLASTOCYST FORMATION

The blastocyst is a circular cyst; it’s divisions are:

  • Trophoblast: the outer cell mass.
  • Embryoblast: the inner cell mass.

The blastocyst resides within the uterine cavity and eventually invades the uterus.

The uterine walls, from inside to outside, are:

  • Endometrium
  • Myometrium
  • Perimetrium

TROPHOBLAST DIVISION

Trophoblast divides into:

  • Cytotrophoblast, the inner cell line, which maintains a similar shape as the trophoblast.
  • Syncytiotrophoblast, the external cell line, which invades the uterine wall to lay the foundation of the placenta.

Within the cytotrophoblast, the embryoblast transforms into:

  • The epiblast (which are columnar cells) – the original mass of inner cells
  • The hypoblast (which are small cuboidal cells) – a new layer of cells underneath the epiblast.

The bilaminar germ disc exists where the epiblast and hypoblast meet.

At this stage, the syncytiotrophoblast invades into the uterine wall.

EPIBLAST DIVISON

The epiblast generates cells that become:

(1) Ectoderm

  • Amniotic cavity fills the cavity internal to the ectoderm.
    (2) Endoderm
  • Yolk sac fills the cavity internal to the endoderm.
    (3) Mesoderm

GASTRULATION

Ectoderm forms the primitive streak: a dimpling at the germ disc – the site of gastrulation.

  • Gastrulation is a process of invagination, wherein ectodermal cells pass from the ectodermal surface to the primitive streak. Mesodermal cells spread out between the ectoderm and endoderm and also surround these cell lines.

The germ disc is now trilaminar.

In addition to the mesoderm mentioned previously, there also exists an additional mesoderm layer: the extraembryonic mesoderm just internal to the cytotrophoblast.

GERM LAYER DERIVATIVES

The key germ layer derivatives (note that these are numerous and we only list the highlights):

Ectoderm

  • Skin + derivatives (hair, nails, etc…)
  • Adrenal medulla
  • Nervous tissue
  • Sense organs

Mesoderm

  • Musculoskeletal (including heart muscle)
  • Adrenal cortex
  • Testes + ovaries
  • Kidneys + ureters

Endoderm

  • Epithelial lining of: GI, Respiratory, Urinary, Reproductive systems

The Germ Layers

ECTODERM

Epidermis:

  • The skin, specifically the surface layer (meaning NOT the dermis, the underlying layer)
  • The skin appendages (eg, the hair, nails, and other appendages).

The neural crest cell derivatives:

  • Select cranial nerves the pharyngeal arch derivatives (which are cranial nerves 5, 7, 9, and 10).
  • The dorsal root ganglia, which are the pseudounipolar sensory neurons.
  • The sympathetic chain ganglia, which supply the sympathetic portion of the autonomic nervous systems, responsible for “Fight or Flight”.
  • The adrenal medullary cells, which are activated along with the sympathetic nervous system during stress.
  • The enteric nervous system, which is the intrinsic nervous system activator of the gut.
  • Additional nerve and cartilaginous derivatives.

Neural tube derivatives and the placodes (which are ectodermal thickenings):

From cranial to caudal, they are the:

  • Telencephalon
  • Diencephalon
  • Mesencephalon
  • Metencephalon
  • Myelencephalon
  • The caudal neural tube

* The Telencephalon and Diencephalon derive from the prosencephalon.

* The metencephalon and myelencephalon derive from the rhombencephalon.

  • Key placodes (which are areas of thickened surface ectoderm), which form CNs 1, 2, and 8 (the solely sensory set of CNs), from cranial to caudal
    • At the nasal prominences lies the olfactory placode, which derives the olfactory epithelium and olfactory nerve (CN 1).
    • The optic placode forms the optic nerve (CN 2); it originates from the diencephalon.
    • The otic placode forms the vestibulocochlear nerve (CN 8); it originates from the hindbrain.

ENDODERM

The foregut

Derives the linings of many important gastrointestinal and respiratory structures:

  • The pharyngeal region
  • Divides distally into the esophagus and trachea and includes 4 key pharyngeal pouches of the head and neck.
  • Stomach
  • Proximal duodenum,
  • Liver buds, which ultimately form the liver,
  • The gallbladder,
  • The pancreas, which forms from the ventral and dorsal pancreatic buds (aka, diverticula).
  • The linings of the respiratory system (with a drawing of the trachea and lungs).

The midgut

  • Distal duodenum,
  • Jejunum,
  • Ileum,
  • Ascending colon,
  • Proximal 2/3 of the transverse colon.

The hindgut

Gives rise to the allantois before ending blindly at the cloaca.

  • Distal 1/3 of the transverse colon,
  • Descending and sigmoid colons, and,
  • The proximal 2/3 of the anorectal canal. The ectoderm gives rise to the distal 1/3 of the anorectal canal is derived from ectoderm; it invaginates the area around the proctodeum (aka, anal pit).

MESODERM

From medial to lateral:

The somites (the paraxial mesoderm) form the axial musculoskeleton and dermis as follows:

  • Sclerotome derives the bone of the axial skeleton: the spine and the posterior base of the skull.
  • Myotome derives the paraspinal and abdominal musculature.
  • Dermatome derives the axial dermis.

Intermediate mesoderm:

  • The urogenital and reproductive systems
    (we signify them with a kidney and ureter and an illustration of the uterus, a fallopian tube and ovary).

The lateral plate mesoderm derives

  • The cardiovascular system
  • The linings of the body walls and organs (the parietal and visceral pleura and peritoneum)
  • The appendicular musculoskeleton: the limb muscles and bones.
    (We draw the heart tube inside of the chest to signify the cardiovascular system and the body walls and organ linings. And we draw an arm in flexion to signify the appendicular musculoskeleton.)

Early Gut Tube & Mesenteric Attachments

GI & MESENTERY ORGANIZATION

~ Weeks 4 through 6

Three embryologic divisions of the thoracic and abdominal gastrointestinal tube:

The pharyngeal region comprises the cranial-most portion of the GI tube; because it gives rise to the structures of the head and neck, this region is discussed in detail elsewhere.

Foregut

  • Supplied by the celiac artery
  • Gives rise to the:
    • Esophagus
    • Stomach
      – Liver buds, which ultimately form the liver
    • Gallbladder
    • Ventral and dorsal pancreatic buds (aka, diverticula), which will later fuse to form the pancreas
    • Proximal duodenum

Midgut

  • Supplied by the superior mesenteric artery
  • Comprises primary intestinal loop, which connects to the yolk sac via the vitelline duct
  • Gives rise to the:
    • Distal duodenum
    • Jejunum
    • Ileum
    • Ascending colon
    • Proximal 2/3 of the transverse colon

Hindgut

  • Supplied by the inferior mesenteric artery
  • Gives rise to the allantois before ending blindly at the cloaca
  • Gives rise to the:
    • Distal 1/3 of the transverse colon
      – Descending and sigmoid colons
    • The proximal 2/3 of the anorectal canal

The distal 1/3 of the anorectal canal is derived from ectoderm that invaginates the area around the proctodeum (aka, anal pit).

INNERVATION

The enteric nervous system, which is derived from neural crest cells, regulates motility to propel the contents of the GI tract.

MESENTERIES

Mesenteries divide the peritoneal cavity and suspend the gastrointestinal tract.
Additionally, they provide a protective covering for neurovascular structures.

  • The ventral mesentery is derived from the septum transversum, and will give rise to ligaments associated with the liver.
  • The dorsal mesentery secures the gastrointestinal tract to the posterior body wall.
    • The meso-esophagus attaches the esophagus to the dorsal wall
    • The mesogastrium anchors the stomach
    • The mesoduodenum anchors the duodenum
    • The mesentery proper anchors the primary loop of the midgut
    • The dorsal mesocolon anchors the hindgut