Disorders of Early Development

Question 1

What are 3 reasons pregnancy loss can occur?

Answer 1

1. Errors in embryo-fetal development
2. Failure of the embryo to implant in the uterine lining
3. Inability to sustain development of an implanted embryo/fetus

Question 2

Define miscarriage and the types there are

Answer 2

Miscarriage: loss of a pregnancy prior to ~23 weeks gestation
Early clinical pregnancy loss (<12 weeks gestation)
Late clinical pregnancy loss (>24 weeks gestation)

Question 3

Describe pre-clinical and clinical pregnancy loss

Answer 3

30% conceptions lost prior to implantation. 30% following implantation but before the missed menstrual period (3-4wks gestation). Around 15% of pregnancy losses are clinical.

Question 4

What are the major causes of early pregnancy loss?

Answer 4

Major driver likely to be aneuploidy (chromosome number errors) in embryo. ~53% embryos created using donor eggs in IVF are aneuploid. ~50% of lost early pregnancies display chromosomal errors. Exponential increase in risk of trisomic pregnancy with increasing maternal age.

Question 5

Why does aneuploidy increase with maternal age?

Answer 5

Throughout f meiotic arrest, the chromatids of homologous chromosomes are held together by cohesin proteins. These cohesin proteins are not replaced, leading to loss of cohesion between chromatids with increasing age of the oocyte. If cohesion has been lost, chromatids can separate and drift during meiotic division, rather than being segregated accurately by the spindle.

Question 6

What are cohesin proteins?

Answer 6

REC8 and SMC2 are cohesin proteins involved in maintaining cohesion between chromatids within chromosomes.

Question 7

What signalling pathways might underpin RPL/RM?

Answer 7

Normal embryo development but failed implantation in Lif-deficient mouse models indicating Lif could be important in successful to term pregnancy. Reduced levels of LIF in the uterine secretions of subfertile women.

Question 8

What is the non-selective uterus hypothesis?

Answer 8

Uterus permits implantation of poor quality embryos. Changes in uterine mucin expression in women with RM/RPL.

Question 9

What is the role of maternal and paternal genes in making an embryo viable?

Answer 9

Some genes only expressed from the paternally-inherited copy. Promote embryo fitness at the expense of the mother. Some genes only expressed from the maternally-inherited copy. Restrict embryo fitness to conserve resources for future pregnancies. Only viable maternal genes give rise to parthenogenetic embryo (low placenta) while only viable paternal genes give rise to androgenetic embryo (underdeveloped embryo but lots of placenta).

Question 10

What are Gestational Trophoblastic Diseases?

Answer 10

GTDs are a collection of disorders characterized by overgrowth of trophoblastic tissue.

Question 11

What is a benign form of gestational trophoblastic diseases?

Answer 11

Hydatidiform moles - Incidence of 1/500-1/1500 pregnancies, depending on geography. Complete hydatidiform mole has absence of fetal tissue. Partial hydatiform mole has some fetal tissue present.

Question 12

What is a malignant form of gestational trophoblastic disease?

Answer 12

Gestational Trophoblastic Neoplasias - Arise following ~20% of cases of hydatidiform mole. Rarely is a invasive mole or choriocarninoma. Very rare are Placental Site Trophoblastic Tumour (PSTT) or Epithelioid Trophoblastic Tumour.

Question 13

How do hydatidiform moles arise?

Answer 13

Complete:
Empty egg fertilised by: 1x sperm then sperm genome duplicated or 2x sperm (no duplication).

Partial:
Normal egg fertilized by 1x sperm then sperm genome duplicated or 2x sperm (no duplication).

Question 14

What underlies hydatidiform moles?

Answer 14

NLRP7 mutations may underly recurrent HM - may indicate a problem with failure to recognise and clear a failed pregnancy.

Question 15

What is an ectopic pregnancy?

Answer 15

Implantation of the embryo at a site other than the uterine endometrium. 98% of these implantation events occur in the fallopian tube. Other sites include ovary, cervix, other intra-abdominal sites. Incidence of 1-1.5% of pregnancies.

Question 16

What is treatment for ectopic pregnancies?

Answer 16

Treatment ranges from expectant management, through chemotherapy (methotrexate) to surgery to remove the trophoblast and/or tube. Rupture can lead to severe internal bleeding.

Question 17

What is the impact of smoking on the fallopian tube?

Answer 17

Cotinine, a component of cigarette smoke, regulates the expression of PROKR1, a regulator of fallopian tube smooth muscle contractility. Cotinine also induces pro-apoptosis protein expression in fallopian tube explants. Tobacco smoke inhibits ciliary function so may reduce tubal transit of the embryo as OR is 1.7-4 for tubal pregnancy in smokers.

Question 18

How might cannabis use affect the fallopian tube?

Answer 18

Fallopian tube expresses cannabinoid receptors CB1. CB1 levels are reduced in ectopic pregnancy patients. Shows embryo retention in mice.

Question 19

What in cannabis affects the fallopian tubes?

Answer 19

Endocannabinoid levels are elevated in ectopic pregnancy fallopian tubes. Components such as THC in cannabis may act directly on the fallopian tube to peturb embryo transit or alter the balance of endocannabinoids in the tube leading to a disrupted embryo environment.

Question 20

What are risk factors for ectopic pregnancies?

Answer 20

1. Prior ectopic pregnancy
2. Prior fallopian tube surgery
3. Certainsexually transmitted infections (STIs)
4. Pelvic inflammatory disease
5. Endometriosis

Question 21

What other factors increase risk of ectopic pregnancy?

Answer 21

Cigarette smoking
Cannabis use?
Age older than 35 years
History of infertility
Use ofassisted reproductive technology, such asin vitro fertilization (IVF)