A. Implantation and Development

1. Embryo reaches uterus in blastocyst stage
   1. Inner cell mass: fetus and amniotic sack
   2. Trophoblastic cells: placenta and chorion
2. Implantation is mediated by trophoblastic layers
   1. Inner cytotrophoblast (cell trophoblast; CTB)
   2. Outer Syncytiotrophoblast (STB)
3. Syncytiotrophoblast forms invading front for implantation
   1. Blood vessels are destroyed in the process
   2. The blood from these vessels from lacunae which surround columns of STB
4. Cytotrophoblasts grow into the STB columns, followed by mesenchymal tissue
   1. This tissue is eventually populated by embryonic blood vessels
   2. The columns continue to grow and advance in the mileau of maternal blood
5. Trophoblast growth of placenta closest to myometrium outstrips more distant growth
   1. Thus, the more distal regions atrophy
   2. The result of atrophy is a membranous remnant called the chorion
   3. The inner lining of the chorion is called the amnion
   4. Results in a discoid placenta
6. Amniotic Cavity [1]
   1. The amniotic cavity develops from inner cell mass
   2. Consists of amniotic fluid, amnion, and chorion
   3. Amnion and chorion are called fetal membranes
   4. Amniotic fluid cushions the fetus during gestation
7. Amnion Cell Layers
   1. Five layers without blood vessels or nerves
   2. Nutrients derived from anionic fluid
   3. Innermost layer (towards fetus, touches amnionic fluid) is amniotic epithelium
   4. Amniotic epithelium makes collagen types III and IV, laminin, nidogen, fibronectin
   5. Below these cells is the basement membrane (second layer of amnion)
   6. Compact layer is next with collages I, III, V, VI including cross links
   7. Below this layer is a fibroblast layer (the thickest of the 5 layers)
   8. Fibroblast layer contains macrophages, fibroblasts, extracellular matrix
   9. Final amniotic layer is intermediate (spongy) layer, with collagen and proteoglycans
   10. Matrix metalloproteinases and endogenase proteinase inhibitors found in various layers
8. Chorion Cell Layers
   1. Three layers, thicker overall but weaker strength than amnion
   2. Reticular Layer contains collagen and proteoglycans
   3. Basement membrane layer with Type IV collagen, fibronectin, laminin
   4. Trophoblast layer abuts basement membrane, includes matrix metalloproteinase 9
9. Weakness in fetal membranes can lead to premature rupture

B. Maternal Adaptations

1. Increased progesterone secretion by corpus luteum
   1. Endometrial stromal cells respond with decidualization
   2. Decidualization = swelling and enlargement of cells, storage of glycogen and lipids
2. Maternal Vessel Changes
   1. Endovascular Trophoblastic Migration: invasion of uterine spiral arteries
   2. Leads to destruction of muscular and elastic elements
   3. Uterine vessels increase in size and lose ability to respond to pressor agents
   4. Leads to decrease in vascular resistance and marked increase in blood supply

C. Villus Maturation

1. Villi branch and mature; terminal villi become more numerous and smaller
2. Fetal capillaries occupy increasing proportions of villus area
3. Also move to more peripheral villus locations
   1. CTB disappear and syncytiotrophoblast (SCT) thin considerably
   2. STB and capillary walls fuse forming vasculosyncytial membranes
4. Some maternal diseases such as diabetes associated with abnormal villus structures

D. Role of Placenta in Parturition [7]

1. Placenta produces CRH and secretes most of it into maternal circulation
2. During pregnancy, CRH levels increase exponential through positive feed-forward loop
   1. CRH stimulates pituitary corticotropin (ACTH) production
   2. ACTH stimulates adrenal cortex to release cortisol (and stimulates DHEA-S production)
   3. Glucocorticoids further stimulate production of CRH by placenta
   4. Estrogen, progesterone and nitric oxide inhibit placental CRH production
   5. CRH availability is modulated by circulating CRH-binding protein (CRH-BP)
   6. Towards the end of pregnancy, CRH-BP levels fall, increasing available CRH
   7. Exponential increases in CRH signal end of pregnancy (parturition)
3. In an individual woman, rate of change of CRH level is best predictor of onset of labor
4. Dehydroepiandrosterone sulfate (DHEA-S) is converted to estrogen
5. CRH levels also rise in the fetus
   1. CRH in the fetus stimulates fetal cortisol production
   2. This stimulates lung maturation, with production of surfactant A and phospholipids
   3. Surfactant A and phospholipids are inflammatory, stimulating myometrial contractions
6. Combination of maternal and fetal events driven by CRH stimulate myometrial activity
7. Myometrial Activity
   1. Uterus is normally in queiescent phase during pregnancy
   2. Quiescent phase composed of irregular, long-lasting contractions
   3. At onset of labor, regular, high-intensity, long-lasting contractions occur

1. Twins
   1. ~33% monozygotic (identical; maternal) due to division of single zygote
   2. ~67% dizygotic ("fraternal") due to fertilization of two separate ova
   3. Dizygotic twins are due to genetic and environmental factors causing polyovulation
2. Monozygotic Twins
   1. Placenta status determined by timing of twinning event relative to amnion and chorion formation
   2. Dichorionic-diamniotic placentas: twinning occurs very soon after fertilization
3. Monochorionic-diamniotic placentas
   1. Chorion normally forms before amnion
   2. Implies that twinning event occurred after chorion, but before amnion formation
   3. Placentas contain vascular anastomoses permitting twin-twin transfusion
4. Monochorionic-monoamniotic placenta
   1. Twinning after both sacs form
   2. No dividing membrane
   3. Rate of fetal death high, often due to entanglement of fetal cords
5. Dizygotic twins
   1. Factors which encourage polyovulation including fertility medications
   2. All have dichorionic-diamniotic placentas

B. Placenta Previa

1. Implantation site partially or completely covers cervical os
2. Etiology
   1. Prior scarring of lower uterine segment (C-section, curetttage)
   2. Associated with advanced maternal age, smoking, multiparity
3. Significance
   1. Third trimester vaginal bleeding - can be fatal
   2. Increased fetal mortality

C. Placental Abruption [2]

1. Premature separation of placenta from uterus prior to delivery
2. Incidence is ~1% of pregnancies
3. Effect of Premature Placental Separation
   1. Associated with massive hemorrhage into decidua
   2. Severe hemorrhage requires evacuation of uterus; recurrence 17%
   3. Extent of placental separation has a profound effect on complication rates
4. Etiology associated with the following:
   1. Multiparity
   2. Advanced age
   3. Cocaine use
   4. Toxemia (pre-eclampsia, eclapsia)
   5. Trauma
   6. Hypertension
5. Complications
   1. Stillbirth risk increased ~9 fold
   2. Preterm birth risk increased ~4 fold
   3. Growth restricted neonates increased ~2 fold
   4. Sudden decompression of uterus (rupture of membranes, first twin delivery)

D. Pre-Eclampsia

1. Substantial trophoblast abnormalities appear to play a major role [3]
   1. Increased production of inhibin A, activin, and pro(a)C may contribute to disease
   2. These hormones act on the pituitary to regulate FSH and LH production
   3. Inhibin A and activin are members of the TGFß superfamily normally produced in ovary
   4. Role of these peptides in pre-eclampsia is unclear, but may be of diagnostic help
2. Cytotrophoblast fails to induce normal spiral artery invasion of placenta [4]
   1. In addition, trophoblast in pre-eclampsia undergoes premature apoptosis
   2. Heparin-binding epidermal growth factor like growth factor (HB-EGF) may be involved
   3. HB-EGF is found in high levels in trophoblast throughout placenta in first trimester
   4. HB-EGF inhibits apoptosis and stimulates trophoblast invasion
   5. HB-EGF levels are reduced ~5X in pre-eclamptic pregnancies
3. Characteristics of Pre-eclampsia
   1. Abnormal spiral arteries with reduced invasion (angiogenic) activity
   2. Vasoconstriction
   3. Large placental mass
4. Angiogenic Factors [6]
   1. Soluble fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor
   2. sFlt-1 binds to and blocks vascular endothelial (VEGF) and placental (PlGF) growth factors
   3. Elevated levels of sFlt-1 have been found in patients with preeclampsia
   4. Reduced angiogenic activity may partially explain failureo spiral artery invasion
5. Key Abnormalities in Preeclampsia
   1. Abnormal prostacyclin (dilator) to thromboxane (constrictor) ratio
   2. Reduced functional levels of angiogenic factors

1. Two arteries and one vein
   1. Arteries from inferior vena cava
   2. Vein enters liver and connects into circulation through ductus venosus
2. Vessels are surrounded by myxoid tissue called Wharton's jelly
   1. Resists compression and torsion; protects the vessels
   2. Local defects in Wharton's jelly are a major cause of some fetal defects
3. After Birth:
   1. Umbilical arteries become medial umbilical ligaments
   2. Umbilical vein becomes falciform ligament

B. True Knots

1. Associations
   1. Excessive volumes of amniotic fluid
   2. Long cord
   3. "Overactive" fetus
2. Most of these are insignifcant
3. About 0.5% of perinatal deaths associated with true knots

C. False Knots

1. Ectatic (dilated) surface vessels give cord a gnarled appearance
2. No clinical significance

D. Other Problems

1. Torsion and Stricture - Usually found in macerated Still births (post-mortem event)
2. Entangled Cord - Cord tightly wrapped around neck or limbs

E. Velamentous insertion

1. Cord inserts onto free membranes instead of placenta
2. Unprotected fetal vessels run some distance before passing into placental surface
3. High risk of trauma to these vessels
   1. Especially if exposed vessels near cervical os
   2. If near cervical os, this is called Vasa previa

F. Single Umbilical Artery

1. Due to primary aplasia or secondary atrophy
2. Associated with 20% risk of other congital anomalies

References

1. Parry S and Strauss JF III. 1998. NEJM. 338(10):663
2. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. 1999. JAMA. 282(17):1646
3. Muttukrishna S, Knight PG, Groome NP, et al. 1997. Lancet. 349:1285
4. Leach RE, Romero R, Kim YM, et al. 2002. Lancet. 360(9341):1215
5. Hall JG. 2003. Lancet. 362(9385):735
6. Levine RJ, Maynard SE, Qian C, et al. 2004. NEJM. 350(7):672
7. Smith R. 2007. NEJM. 356(3):271