Disorders of Early development

Question 1

What can cause pregnancy loss?

Answer 1

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

Question 2

Define Miscarriage

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

What is the criteria for a recurrent miscarriage?

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

How common is preclinical pregnancy loss?

Answer 4

30% conceptions lost prior to implantation

30% following implantation but before the missed menstrual period (3-4wks gestation)

Question 5

How common is clinical pregnancy loss?

Answer 5

~15% of conceptions
10% in 20-24 year olds
51% in 40-44 year olds

Question 6

What is the major cause of pregnancy loss?

Answer 6

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

Question 7

What is the biggest risk factor in trisonomy pregnancy?

Answer 7

Exponential increase in risk of trisomic pregnancy with increasing maternal age

Question 8

When does Meiosis begin?

Answer 8

Commences in Oocytes during foetal life

Question 9

What happens during prophase in the first trimester

Answer 9

Paternal and maternal homologous chromosomes pair up, and DNA is replicated generating two chromatids per chromosome.
Genetic material is exchanged between homologues through recombination

Question 10

What happens as you go from the first to second trimester?

Answer 10

Meiosis then arrests, resuming just before ovulation (up to 50 years later

Question 11

Why does Aneuploidy increase with maternal age?

Answer 11

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 12

Which Cohesin Proteins are involved in maintaining cohesion between chromatids within chromosomes?

Answer 12

REC8 and SMC2

Question 13

What signalling pathways underpin recurrent miscarriage?

Answer 13

Normal embryo development but failed implantation in Lif-deficient mouse models

Reduced levels of LIF in the uterine secretions of subfertile women

Non-selective uterus hypothesis
Uterus permits implantation of poor quality embryos
Changes in uterine mucin expression in women with RM/RPL

Question 14

What is the cause of Molar pregnancy?

Answer 14

Imprinted genes

Question 15

How do genes get imprinted?

Answer 15

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

Commonly genes involved in placentation and nutrition

Question 16

What do embryos require to become viable?

Answer 16

Maternal and paternally derived genes

Question 17

What are Gestational Trophoblastic diseases GTD’s?

Answer 17

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

Question 18

What happens in benign GTD’s?

Answer 18

hydatidiform moles
Incidence of 1/500-1/1500 pregnancies, depending on geography.

Complete hydatidiform mole
Fetal tissue absent

Partial hydatidiform mole
Fetal tissue present

Question 19

What happens in malignant GTD’s?

Answer 19

Gestational Trophoblastic Neoplasias
Arise following ~20% of cases of hydatidiform mole

Rare:
Invasive mole
Choriocarcinoma

Very rare:
Placental Site Trophoblastic Tumour (PSTT)
Epithelioid Trophoblastic Tumour

Question 20

How do you form a Complete Hydatidiform mole?

Answer 20

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

Question 21

How do you form a Partial Hydatidiform mole?

Answer 21

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

Question 22

What could underpin recurrent hydatidiform mole formation?

Answer 22

NLRP7 mutations may underly recurrent HM

Failure to recognize and clear failed pregnancy?

Question 23

What is an ectopic pregnancy?

Answer 23

Implantation of the embryo at a site other than the uterine endometrium.

Question 24

Where do most ectopic pregnancies take place?

Answer 24

98% of these implantation events occur in the fallopian tube.
Other sites include ovary, cervix, other intra-abdominal sites.

Question 25

What is the incidence of ectopic pregnancies?

Answer 25

1-1.5% of pregnancies

Question 26

What is the treatment for ectopic pregnancies?

Answer 26

Treatment ranges from expectant management, through chemotherapy (methotrexate) to surgery to remove the trophoblast and/or tube.

Question 27

What can happen if an ectopic pregnancy ruptures?

Answer 27

severe internal bleeding

Question 28

What is the impact of smoking on the Fallopian tube?

Answer 28

Continine, 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&raquo_space; reduce tubal transit of the embryo?

Epidemiological studies: OR: 1.7-4 for tubal pregnancy in smokers

Question 29

How can cannabis effect the Fallopian tube?

Answer 29

Fallopian tube expresses cannabinoid receptors CB1 and

CB1 levels are reduced in ectopic pregnancy patients,

CB1 knockout mice display embryo retention in the fallopian tubes.

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 the ‘endocannabinoid tone’) in the tube leading to a disrupted embryo environment

Question 30

What are the risk factors for ectopic pregnancy?

Answer 30

Prior ectopic pregnancy
Prior fallopian tube surgery

Certainsexually transmitted infections (STIs)

Pelvic inflammatory disease

Endometriosis

Question 31

What factors increase the risk of ectopic pregnancy?

Answer 31

Cigarette smoking

Cannabis use?

Age older than 35 years

History of infertility

Use ofassisted reproductive technology, such asin vitro fertilization (IVF)