disorders of early development

Question 1

What are some causes of pregnancy loss?

Answer 1

• Errors in embryo fetal development
• failure of embryo to implant on uterine lining
• inability to sustain development of implanted fetus

Question 2

What is a miscarriage defined as?
Early clinical pregnancy loss?
Late clinical pregnancy loss?

Answer 2

• Miscarriage is loss of pregnancy before 23 weeks gestation.
• Early clinical pregnancy loss is <12 weeks gestation
• late clinical pregnancy loss is >24 weeks gestation

Question 3

Recurrent pregnancy loss definition (RPL)?

Answer 3

In UK defined by 3 or more pregnancy losses (consecutive or not)

Question 4

What are pre-clinical pregnancy losses? When are they detected?

Answer 4

• Some lost prior to implantation and some after implantation but before missed period.
• Cant detect pregnancy until implantation when hCG produced

Question 5

What is major cause of early pregnancy loss?

Answer 5

• Aneuploidy - chromosome number errors.

- Many IVF embryos are aneuploid and early pregnancy loss shows chromosomal errors

Question 6

What increases risk of trisomic pregnancy?

Answer 6

maternal age

Question 7

What is the mechanism underlying risk of aneuploidy with maternal age?

Answer 7

• Meiosis of oocytes start during fetal life and then arrests, starting again before ovulation.
• During meiotic arrest, chromatids of homologous chromosomes held together by cohesin
• loss of cohesion of cohesin with age, so chromatids can separate and drift during division rather than being segregated properly by spindle.

Question 8

What signalling pathways underpin recurrent pregnancy loss? What other hypotheses for recurrent pregnancy loss?

Answer 8

• LIF pathway.
• Failed implantation in LIF deficient mice.
• Reduced levels of LIF in uterine secretions of subfertile women.
• Non-selective uterus hypothesis states uterus permits implantation of poor quality embryos & changes in uterine mucin expression may affect permissibility of uterus to implantation

Question 9

Why do embryos require maternal and paternal derived genomes to be viable?

Answer 9

• Genomic imprinting.
• Some genes only expressed on maternal copy and others on paternal copy.
• Paternal genes promote embryo fitness at expense of mother (androgenetic embryo)
• maternally inherited copy restricts embryo fitness to conserve resources for mother (parthenogenetic embryo)

Question 10

What are gestational trophoblastic diseases GTDs? What are they divided into?

Answer 10

• Group of disorders with overgrowth of trophoblastic tissue.
• Benign or malignant.
  1. Benign - hydatiform mole.
  2. Malignant - gestational trophoblastic neoplasias (invasive mole, choriocarcinoma, placental site trophoblastic tumour, epithelioid trophoblastic tumour)

Question 11

What is a complete hydatiform mole due to? What does it cause?

Answer 11

• Empty egg fertilised by 1x sperm and sperm genome duplicated or by 2x sperm without duplication.
• Lacks any female genetic material.
• Overdevelopment of placenta - massive overgrowth of trophoblasts with withered/no embryo at all

Question 12

What is a partial hydatiform mole due to? What does it cause?

Answer 12

• Normal egg fertilised by 1x sperm + duplication or by 2x sperm without duplication
• double amount of male material

Question 13

What mutation may underly recurrent hydatiform moles and why?

Answer 13

NLRP7 mutation - failure to recognise and clear failed pregnancy

Question 14

What is seen in a molar pregnancy placenta?

Answer 14

grape-like villi

Question 15

What is an ectopic pregnancy?

Answer 15

• Implantation of embryo at site other than uterine endometrium.
• Most in fallopian tube but can be ovary, intra-abdominal sites, cervix.

Question 16

What is management for an ectopic pregnancy? What can rupture cause?

Answer 16

• Chemotherapy (methotrexate)
• surgery to remove trophoblast & or tube.
• Rupture can lead to severe internal bleeding

Question 17

What are risk factors for ectopic pregnancy?

Answer 17

-Smoking, cannabis use by mother, previous ectopic pregnancy, prior fallopian tube surgery, some STIs, PID, endometriosis, >35yrs, infertility history, IVF or other assisted reproductive tech

Question 18

How does smoking cause ectopic pregnancy? How does it affect the fallopian tube?

Answer 18

• Cotinine present in cigarette smoke regulates expression of PROKR1 - regulator of fallopian tube smooth muscle contractility
• cotinine also induces pro-apoptosis protein expression in fallopian tube explants.
• Tobacco smoke inhibits ciliary function reducing tubal transit of embryo.

Question 19

How does cannabis affect the fallopian tube and contribute to ectopic pregnancy?

Answer 19

• Endocanabinoid receptors CB1 reduced in ectopic pregnancy in fallopian tubes.
• Endocannabinoid tone (balance of synthesis & breakdown - signalling needed for normal fallopian tube function).
• Adding exogenous cannabinoid changes levels/amount of ligand signalling and affecting transit of embryo down tube.
• Or THC and other components may act directly on fallopian tube to disrupt embryo transit