Age + Dev - Disorders Of Early Development

Question 1

What are some common causes of pregnancy loss in humans?

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

What is a miscarriage?

Answer 2

loss of a pregnancy prior to ~23 weeks gestation

Question 3

What is counted as early clinical pregnancy loss?

Answer 3

< 12 weeks gestation

Question 4

What is counted as late clinical pregnancy loss?

Answer 4

> 24 weeks gestation

Question 5

What is categorised as recurrent miscarriage / recurrent pregnancy loss?

Answer 5

→ UK: three or more pregnancy losses (consecutive or non-consecutive)
→ USA/Europe: two or more pregnancy losses (consecutive or non-consecutive)

Question 6

What is counted as pre-clinical pregnancy loss?

Answer 6

→ pre-implantation

→ post-implantation

Question 7

What is counted as clinical pregnancy loss?

Answer 7

→ miscarriage

Question 8

How frequent are pre-clinical early pregnancy loss?

Answer 8

→ pre-implantation = 30%

→ post-implantation before the missed menstrual period = 30%

Question 9

How frequent are clinical early pregnancy loss?

Answer 9

→ miscarriage = 10% - 15%

Question 10

What are some of the major causes of early pregnancy loss?

Answer 10

→ 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 11

How common are clinical pregnancy losses in 20-24 year olds?

Answer 11

10% of pregnancies

Question 12

How common are clinical pregnancy losses in 40-44 year olds?

Answer 12

51% of pregnancies

Question 13

How do oocytes end up experiencing prolonged meiotic arrest?

Answer 13

→ Meiosis commences in oocytes during fetal life
→ Paternal and maternal homologous chromosomes pair up, and DNA is replicated generating two chromatids per chromosome.
→ Genetic material is exchanged between homologues through recombination
→ Meiosis then arrests, resuming just before ovulation (up to 50 years later)

Question 14

Why does aneuploidy increase with maternal age?

Answer 14

→ 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 15

What signalling pathways underpin RPL + RM?

Answer 15

→ 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

Question 16

What is non-selective uterus hypothesis?

Answer 16

→ Uterus permits implantation of poor quality embryos

→ Changes in uterine mucin expression in women with RM/RPL

Question 17

What are molar pregnancies?

Answer 17

molar pregnancy (hydatidiform mole) = rare complication of pregnancy characterised by the abnormal growth of trophoblasts (cells that normally develop into the placenta)

Question 18

What can cause molar pregnancies?

Answer 18

imprinted genes (commonly genes involved in placentation and nutrition)
→ some genes only express the paternal-inherited or maternal-inherited copy

Question 19

What is a GTD?

Answer 19

→ gestational trophoblastic diseases

→ collection of disorders characterised by overgrowth of trophoblastic tissue

Question 20

What are the 2 main types of GTD?

Answer 20

→ benign = hydatidiform moles

→ malignant = gestational trophoblastic neoplasias

Question 21

What are the 2 types of benign hydatidiform moles?

Answer 21

→ complete hydatidiform mole = fetal tissue absent

→ partial hydatidiform mole = fetal tissue present

Question 22

What are some rare types of malignant GTDs?

Answer 22

→ invasive mole

→ choriocarcinoma

Question 23

What are some very rare types of malignant GTDs?

Answer 23

→ placental site trophoblastic tumour (PSTT)

→ epithelioid trophoblastic tumour

Question 24

What causes a complete hydatidiform mole to form?

Answer 24

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

Question 25

What causes a partial hydatidiform mole to form?

Answer 25

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

Question 26

What could be the cause to underlying recurrent hydatidifirm moles?

Answer 26

→ NLRP7 mutations

→ failure to recognise + clear failed pregnancies

Question 27

What is an ectopic pregnancy?

Answer 27

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

Question 28

Where does the extra-uterine implantation often occur?

Answer 28

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

Question 29

What are the consequences of a rupture of an ectopic pregnancies?

Answer 29

severe internal bleeding

Question 30

How can you treat an ectopic pregnancy?

Answer 30

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

Question 31

What are some lifestyle risk factors of an ectopic pregnancy?

Answer 31

→ smoking
→ cannabis
→ age > 35
→ history of infertility
→ use of assisted reproductive technology, such as IVF

Question 32

What is the impact of smoking of the fallopian tube?

Answer 32

→ 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?

Question 33

How might cannabis affect the fallopian tube?

Answer 33

→ 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