Disorders of Early Development

Question 1

What fraction of fertilised eggs are estimated to spontaneously miscarry in the early stages of pregnancy?

Answer 1

Before implantation: 30-75%
Before 6 weeks: 50%, 70%, 80%
Before 8 weeks: 75%
First trimester: 70%
Between fertilisation and birth: 46-90%

Question 2

What proportion of those are lost after a pregnancy has been biochemically confirmed?

Answer 2

10% of all clinically-recognised pregnancies lost

80% of those losses occur in the first trimester

Question 3

How does maternal age affect the chance of miscarriage?

Answer 3

Risk is lowest between 25-29 (10% risk of it happening)

Miscarriage risk mirror increase in aneuploidy risk

Primary driver of age-related miscarriage is aneuploidy

Loss of cohesion between homologous chromosomes in oocyte with increasing age

Question 4

What is recurrent miscarriage?

Answer 4

Loss of three or more consecutive pregnancies, affects 1% of couples trying to conceive

Question 5

What is recurrent implantation failure?

Answer 5

Refers to cases in which women have had three

failed in vitro fertilisation (IVF) attempts with good-quality embryos

Question 6

What is the difference between recurrent miscarriage and recurrent implantation failure?

Answer 6

Failure to implant or sustain pregnancy by natural conception
(recurrent miscarriage) versus failure of transferred embryo to implant/sustain
pregnancy (RIF)

Question 7

What potential common/overlapping causes would you explore

in the first instance for patients experiencing these conditions?

Answer 7

Check for uterine anatomical defects or presence of fibroids/polyps that might
disrupt implantation

Determine the presence of auto-immune antibodies (anti-nuclear or antiphospholipid antibodies)

Test for paternal DNA sperm integrity or fragmentation

Question 8

What signalling pathway(s) might underpin recurrent

miscarriage or RIF?

Answer 8

LIF: leukaemia inhibitory factor (cytokine)

It was found that there was normal embryo development but failed implantation in LIF-deficient mouse models.

LIF promotes the decidualisation of human endometrial stromal cells in
cultures

Reduced LIF in the uterine secretions of subfertile women would cause recurrent miscarriage/implantation failure

OR progesterone/corpus luteum signalling failure

Question 9

What is endometrial scratching and how might it help a patient
experiencing RIF?

Answer 9

This is the use of pipette or hysteroscope to damage endometrial mucosa before
embryo transfer in IVF.

The mechanism is unknown but thought to stimulate immune cell infiltration
and wound healing cytokine production.

Evidence in support of is variable but there is possible benefit in selected
groups (e.g. RIF).

Large NZ study suggests no benefit in any group.

Question 10

What are ectopic pregnancies?

Answer 10

Ectopic pregnancies arise from the implantation of the embryo at a site other than
the uterine endometrium.

Question 11

Where do ectopic pregnancies usually occur?

Answer 11

98% of these implantation events occur in the fallopian

tube.

Question 12

What percentage of pregnancies are ectopic?

Answer 12

Around 1-1.5% of pregnancies are ectopic

Question 13

What is the treatments for ectopic pregnancies?

Answer 13

ranges from

chemotherapy (methotrexate) to surgery to remove the affected tube

Question 14

What can rupture of ectopic pregnancy lead to?

Answer 14

Rupture of an

ectopic pregnancy can lead to severe internal bleeding.

Question 15

Histologically, how is the fallopian tube adapted to support

transit of the fertilised embryo to the uterus?

Answer 15

Smooth muscle - contractions drive the embryo along the fallopian tube

Epithelium - coated in cilia (microvilli) promote fluid movement

Question 16

What happens if a fertilised egg moves up the peritoneum?

Answer 16

leads to placenta attaching to

the peritoneum and is impossible to remove without severe fatal bleeding

Question 17

How might this help explain how cigarette smoking increases

the risk of ectopic pregnancy?

Answer 17

Continine is a component of cigarette smoke and has been shown to regulate
the expression of PROKR1

This is a regulator of fallopian tube smooth muscle contractility

Cotinine increases expression of pro-apopotic proteins the fallopian tube explants

Tobacco smoke also likely to inhibit ciliary function, reducing transit fo the
embryo through the fallopian tube

Question 18

At the molecular level, how might cannabis use elevate the risk
of tubal pregnancy?

Answer 18

Fallopian tube expressed CB1 and CB2 cannabinoid receptor.

CB1 reduced in ectopic pregnancy patients and CB1 KO in mice causes embryo
retention in the fallopian tubes.

THC can get through to the fallopian tubes and affect there

Levels of endocannabinoids elevated in ectopic pregnancy fallopian tubes

Components such as THC in cannabis may act directly on the fallopian tube to
perturb transit or alter the balance of endocannabinoids in the fallopian tube
leading to a disrupted embryo environment

Question 19

What is the monthly probability of conception?

Answer 19

15-25%

So very high estimates of foetal loss are unlikely