Problems in Pregnancy Flashcards
How common is implantation failure?
• 4/5 menstrual cycles during unprotected intercourse fail to produce a pregnancy of which the mother is away (20% pregnancy rate) due to:
− Failed fertilization
− Pre-implantation developmental arrest
− Failed implantation
• Now 5 million IVF babies worldwide. European 2010 data suggest:
− Single embryo transfer occurs in 26% cycles (the rest are multiple)
− Delivery rate is 21%
− Risk of preterm delivery of twins is 11%
− So even though the majority of transfers are multiple embryos, delivery rate is still low
− Now been suggested you need a single good embryo rather than multiple embryos
• Failed implantation remains a major barrier of ART
• Implantation rates have remained the same for around 20 years
• However, humans produce many abnormal embryos → if you force embryos to implant, increases the chance an abnormal one will implant
What are rough statistics for chromosomal abnormalities
- Abnormal oocytes: >20% (mostly before of errors at meiosis (>70% women over 40))
- Abnormal sperm: 7%
- ~40% all human zygotes
- Rates of abnormality higher in women after induced ovulation in ART
- ~50% blastocysts abnormal
What are typical outcomes of certain karyotypes
Karyotype and outcome
• Majority karyotypically abnormal pregnancies that implant miscarry in the first trimester
• About 60% all first trimester miscarriages have chromosomal abnormalities – you would expect these to be miscarried. The only 40% would have made it to term if it wasn’t for some other factor.
• Majority of karyotypically normal pregnancies continue
Progressive elimination of karyotypically abnormal pregnancies: • Week 1 → 30% rate of anormality • Week 4-5 → 15% • Week 8-9 → 3% • Week 16 → 1-2% • Term → 0.6%
Outcomes of pregnancies with abnormal karyotype vary:
• Monosomy and trisomy caused by errors in meiosis are common
• Monosomies and trisomy 1 fail before implantation → never see monosomies in products of miscarriage. Cant seem to invade.
• Other trisomic embryos can develop to normal looking blastocysts and implant
− Some then quickly show signs of impending failure
− Others survive
− Selection at implantation is efficient, 30% can be abnormal
Survival rates :
• Trisomy 13 and 18 → 1%
• Trisomy 16 → aborts
• Trisomy 21 → 80%
How do we do preimplantation genetic testing?
• Blastomeres removed from 8 cell cleavage embryo
• Embryo senses loss of cells and replaces them → idea this may actually compromise the embryo
• Removed cells used for FISH and CGH
• Newer technologies are coming in:
− Karyomapping of SNPs → may reveal genetic alterations of unknown outcome – do you tell them?
− Next generation sequencing
FISH (outdated)
• Fluorescent nucleotide probe hybridizes with target sequence and is visualized by fluorescene microscopy
• This tests for chromosome number
• Mutiprobe methodology can show different chromsomes in same cell
• Chromosomes show as fluorescent dots, eg) 3 dots may indicate trisomy
CGH
• Oligonucleotide probes representing the whole genome on a glass slide
• Fluorscently labeled patient DNA hybridses onto the slide, and is compared with reference DNA
• Comparative ratios can detect gain or loss of material
- FISH and CGH both confirm high rates of chromosomal abnormality in humans
- Allow embryos with normal karyotype (or with new tech, those lacking specific disase mutations) to be selected and transferred into recipients
- If we didn’t do this, would be transplanting embryos destined to fail
What is the link with maternal age and aneuploidy?
• Rate of miscarriage increases
• Not due to uterine ageing → when oocytes are donated by younger women, rate of miscarriage is low
• Due to declining oocyte quality
− Rate of trisomy increases with maternal age over 35
− Risk reduced by using oocytes from younger donors
• There are now many donor pregnancies in older women having ART
− Oocyte donation accounts for 5% births after IVF
− Pregnancy rate increases
− ~50,000 babies born so far after oocyte donation
− Women who go through IVF may be willing to donate unused eggs
How is the endocrine switch linked with miscarriage?
The endocrine switch:
• At 7-9 weeks, placenta takes over production of E and P from the corpus luteum
• Trophoblast produces hCG
• Some evidence that hCG might contribute to stimulating increased blood flow to the uterus
→ At this stage, we are down to 3% chromosomally abnormal pregnancies
→ The rest of them fail to produce a placental capable of undergoing the endocrine switch
How is the oxygen switch linked with problems in pregnancy?
Extravillous trophoblast:
• Distinct population of CT
• Anchoring vili attach to decidue → at the anchoring sites, CT columns form
• Invasive CTs break off and invade the stroma → form aggregates that plug spiral arterioles
→ There is an oxygen switch at this time
The oxygen switch
• Lack of normal trophoblast development in late 1st trimester may lead to oxidative stress as a result of failed plugging of spiral arterioles → they are exposed to more oxygen
− Seen in pre-eclampsia
• Arterial blood gains access to the intervillous space too early, and at an abnormally high pressure
• This could cause pregnancy failure, or trigger pre-eclampsia later on
What are the features of pre-eclampsia?
• Multi-system disease
• Affects potentially all organ systems and different people in different ways
• Therefore seen as a syndrome → spectrum of clinical signs and symptoms accompanying microvascular changes in multiple organ systems.
− Complex heterogenous syndrome
− Multifactorial
− No prediction
− No preventative treatment
• Involves the placenta, and seems to reflect the systemic affects of stress responses in the placenta appearing later in pregnancy as a result of early defects in development.
• It is a maternal syndrome → complication for the mother
• Symptoms appear in the 3rd trimester:
− Hypertension
− Proteinuria
− Fluid retention
− Sometimes FGR
− If left untreated, leads to eclampsia → fitting
• Only treatment option is delivery
How does aberrant spiral artery remodelling lead to pre-eclampsia?
- Where the villous trophoblast is directly bathed in maternal blood
- The late fetoplacental unit depends on high volume, low resistance uteroplacental blood supply
- During weeks 2-20 of pregnancy, in the distal segments of spiral arteries, loss of VSM renders them insensitive to vasoconstriction and ensures delivery at low pressure
- In pre-eclampsia, remodeling fails in the myometrial segments of the spiral arerties
- Trophoblast invasion is not as deep
- As a result, perfusion of the placenta occurs at higher pressure, as the spiral arteries are narrower
- This leads to mechanical damage and oxidative stress
How can altered uterine and radial artery flow charactestics be linked with pre-eclampsia?
Uterine Artery Flow
Normal
• Big difference between systolic and diastolic – because of more resistance
• You lose the peak as you get less resistance
• Impedence is influenced by:
− Trophoblast invasion
− Hormonal influences on the elastic artery
Impaired Placental Blood Flow
• In placental blood flow, deoxygenated blood travels through umbilical artery, picks up oxygen in the placenta and then oxygenated blood travels back in the umbilical vein
• Low resistance arteries gives unimpeded blood flow
Abnormal:
• Early diastolic notch
• Absent end diastolic flow
− No diastolic peak
− Reflects the fact the resistance is so high, in between fetal heart beat the blood flow stops
− Sign the baby is in dange
• Reverse end diastolic flow
− Resistance is so high, the blood flow is moving backwards
− Very serious – impairing any supply of oxygen and nutrients to the baby
Radial Artery Flow Characteristics
• The contribution of different endothelial-derived vasodilators to radial artery relaxation changes in pre-eclampsia.
• Shown experimentally upon exposure to bradykinin
• Non pregnant → about half the response controlled by NO and half EDHF
• Pregnant → balance has shifted to much more control by EDHF – NO response is attenuated
• Pre-eclampsia → the NO system is still very dominant, as inhibition of NO production only gives around 20% relaxation. So pre-eclampsia is much more NO dependent rather than EDHF
• There is also a change in the anatomical architecture of the radial artery
• Increased wall:lumen ratio
• Smooth muscle layer is thicker
• Because of all this, blood supply to the placenta is limited compared to normal pregnancy
− Less relaxation of the radial artery
− Thicker walls
− Less remodelling of spiral arterioles
➢ Gives less blood being supplied, but the blood supply is at higher pressure.
How does these placenta effects affect the mother systemically?
• Damage/abnormal development of the placenta seems to cause the release of factors that leads to a disseminated compromise in maternal vascular endothelial cell function
− The kidney endothelium is particularly susceptible -→ proteinuria
• Factors released from pre-eclamptic placentas reduce ATP in maternal VECs in vitro
• So blood from the placenta is toxic to the maternal endothelium, causing:
− Oedema
− Vasoconstriction
− Proteinuria
− Cerebral artery spasm and oedema
− Platelet activation and clumping
• This is when you get the onset of maternal syndrome and multi-system response
What are the risks and risk factors of pre-eclampsia?
- IN the UK, 18 women died 2003-2005
- Worldwide, estimated 50,000 to 70,000 deaths per year
- Risk of pre-eclampsia recurring increases with the severity of the disease
- 1.9x increased relative risk of later CVD
Harskamp and Zeeman, 2007:
• Population based studies relate pre-eclampsia to an increased risk of later chronic hypertension (RR 2 to 8) and cardiovascular mortality (1.3 to 3.07) compared with normotensive pregnancy.
• Women who develop PE before 36 weeks or have multiple hypertensive pregnancies are at highest risk (3.4 to 8.12)
• Many risk factors shared by CVD and PE → endothelial dyfunction, obesity, hypertension, hyperglycaemia, insulin resistance, dyslipidemia.
Clinical Risk Factors: • Chronic hypertension → 20-24% • Obesity → 10% • Previous pre-eclampsia → 23% • Twin or triplet → 11% • Diabetes → 18% • Chronic renal disease → 30% • Abnormal uterine artery Doppler → 24%
