10.3 - Disorders of Early Development

Question 1

What are three causes of pregnancy loss?

Answer 1

• errors in embryo-foetal development
• failure of the embryo to implant in the uterine lining
• inability to sustain development of an implanted embryo/foetus

Question 2

What is miscarriage?

Answer 2

• loss of pregnancy prior to 23 weeks gestation
• up to 23 weeks is the time period for which the foetus is not viable to sustain itself outside of the uterus
• early clinical pregnancy loss is defined as <12 weeks gestation
• late clinical pregnancy loss is defined as >24 weeks gestation

Question 3

What is recurrent miscarriage (RM) / recurrent pregnancy loss (RPL)?

Answer 3

• UK - three or more pregnancy losses (consecutive or non-consecutive)
• USA / Europe - two or more pregnancy losses (consecutive or non-consecutive)
• 0.8-1.4% pregnancies

Question 4

What is a preclinical pregnancy loss?

Answer 4

• a loss we have not been able to detect either biochemically or by a foetal heartbeat
• 30% conceptions are lost prior to implantation
• 30% are lost following implantation but before the missed menstrual period (3-4 weeks gestation)

Question 5

What percentage of clinical pregnancy losses happen in women 20-24 years vs 40-44 years?

Answer 5

• clinical pregnancy losses occur in 10-15% of all conceptions
• 10% in 20-24 year olds
• 51% in 40-44 year olds

Question 6

What is the major cause for early pregnancy loss?

Answer 6

• likely to be aneuploidy (chromosome number errors) in embryo
• 53% of 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
• this reflects the increasing number of eggs within the ovary developing chromosomal errors as the egg ages

Question 7

Describe how oocytes experienced prolonged meiotic arrest.

Answer 7

• in foetal female, meiosis commences in oocytes
• paternal and maternal homologous chromosomes pair up, and DNA is replicated to generate two chromatids per chromosome
• genetic material (DNA) is exchanged between homologues through recombination
• meiosis then arrests, resuming just before ovulation (which could be up to 50 years later)

Question 8

Why does aneuploidy increase with maternal age?

Answer 8

• throughout meiotic arrest, the chromatids of homologous chromosomes are held together by cohesin proteins
• these cohesin proteins are broken down as the eggs get older
• these cohesin proteins are not replaced, leading to loss of cohesion between chromatids with increasing age of oocytes
• if cohesion has been lost, chromatids can separate and drift during meiotic division, rather than being segregated accurately by the spindle
• REC8 and SMC2 are cohesin proteins involved in maintaining cohesion between chromatids in chromosomes

Question 9

What is an ectopic pregnancy?

Answer 9

• the 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, and other intra-abdominal sites
• incidence of 1-1.5% of pregnancies
• rupture can lead to severe internal bleeding

Question 10

What treatment options are there for an ectopic pregnancy?

Answer 10

• expectant management
• chemotherapy (methotrexate)
• surgery to remove trophoblast and/or tube

Question 11

What risk factors are there for an ectopic pregnancy?

Answer 11

• previous history of ectopic pregnancy
• prior fallopian tube surgery
• certain STIs
• pelvic inflammatory disease
• endometriosis
• increasing maternal age >35 years
• smoking cigarettes by mother
• cannabis use by mother
• history of infertility
• use of IVF or other assisted reproductive technology

Question 12

What is the impact of smoking on the fallopian tube?

Answer 12

• cotinine is a component of cigarette smoke
• regulates the expression of PROKR1, a cell surface receptor
• signalling by PROK proteins through the PROKR1 receptor regulates contractility of the smooth muscle layer surrounding the fallopian tube (oviduct)
• contraction of the fallopian tube is needed to push fertilised embryo down to uterus - if disrupted then the embryo may stay and lodge in wall of fallopian tube
• cotinine also induces pro-apoptosis proteins in fallopian tube explants in vitro
• tobacco smoke inhibits cilia function - reduces fluid movements in fallopian tube = tubal transit of the embryo = stuck in fallopian tube

Question 13

How might cannabis use affect the fallopian tube?

Answer 13

• fallopian tube expresses cannabinoid receptors CB1 and CB2
• in ectopic pregnancy patients, CB1 levels are reduced - CB1 knockout mice display embryo retention in the fallopian tubes
• endocannabinoid levels are elevated in ectopic pregnancy fallopian tubes, which means:
• components like THC in cannabis may act directly on the fallopian tube to perturb embryo transit
• OR cannabis use alter the balance of endocannabinoids (the endocannabinoid tone - balance between making and breakdown of endocannabinoids) in the tube –> disrupted embryo environment