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166 Cards in this Set

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  • Back
What two kinds of Amenorrhoea exist?
Primary - 16+ (or 2 years after breast development) RARE

Secondary - Absent menses 6+ months

Primary amenorrhea refers to the absence of the onset of menstruation by age 16 whether or not normal growth and secondary sexual characteristics are present, or the absence of menses after age 14 when normal growth and signs of secondary sexual characteristics are present. Secondary amenorrhea is the absence of menses for three cycles or six months in women who have previously menstruated.
How long is the normal cycle?
21 to 36 days
What does oligoamenorrhoea mean?
no menstruation for more than 36 days to 6 months
Define amenorrhoea.
>6 months
Define dysmenorrhoea.
painful periods
Define dysparenunia.
pain with intercourse
Define hypermenorrhoea.
Excessive flow - amount + duration
Define menorrhagia.
Heavy flow

Prolonged flow (often used for hypermenorrhoea)
Define Metrohagia.
Normal flow but irregular intervals.
Define Menometrorrhagia.
Frequent, excessive, prolonged & irregular
Define Polymenorrhoea.
frequent and regular <21 days
What are the causes of primary amenorrhoea?
Delayed puberty
- Growth rate and bone age

Hypothalamic - stress, exercise, LOW
- Decreased FSH/LH

Gonadal dysgenesis
- increased FSH/LSH

Congenital outflow obstruction
- Ultrasound

Other - e.g. androgen insensitivity (decreased axillary/pubic hair)
What are the causes of secondary amenorrhoea?
Hyperprolactinemia - adenoma, drgus
Hypothalamic - stress, exercise, dieting, anorexia
Endocrinopathies - thyrotoxicosis, Cushings, Addisons
Polycystic Ovarian syndrome - 6-9% population
Premature ovarian failure/menopause
Iatrogenic - long acting progestins
Endometrial pathology - rare
What are the investigations to be done with Amenorrhoea?
LH, FSH, Estroen
- Chromosomal analysis
- Pelvic ultrasound
- Androgens (hydroepiandrosterone etc)
- MRI/CT pituitary
What is the frequency of birth defects?
- 2% at birth
- 2% up to 5 years
- 1% perinatal death

= 5% total

Total birth defects due to drugs = 0.04% (1% of all birth defects)
Define perinatal.
Perinatal defines the period occurring around the time of birth (5 months before and 1 month after).

The perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth. (WHO - World Health Organization).
What does the birth defects register do?
- determine how often birth defects occur; identify changing health service needs
- respond to community concerns about perceived clusters or changes in frequency of birth defects
- provide statistics for provision of health care
- epidemiological research to increase knowlege of aetiology and preventability of birth defects
- assess effectiveness of primary prevention and screening programs
What are the top 10 defects?
Obstructive defects of renal pelvis (1/285)
Hypospadias (1/292)
Ventricular septal defect (1/307)
Trisomy 21 (1/355)
Congenital dislocation of hip (1/431)
Hydrocephalus (1/952)
Cleft palate (1/1266)
Cystic kidney (1/1471)
Transposition of great vessels (1/1613)
Renal agenesis/dysgenesis (1/1639)
Are multiple defects common?
Yes. Many babies have more than one defect.
What are causes of birth defects?
Teratogens: drugs/toxins, infections
Chromosomal abnormality
Single gene disorders
What is teratology?
Study of birth defects (terata=monster)

Thalidomide started understanding that drugs could cause birth defects

More recently means study birth defects produced by external agents that interfere with fetal development
What are the different kinds of teratogens?
- alcohol
- antiepileptics: valproate

Intrauterine infection
- Rubella, varicella
- Toxoplasmosis

- maternal phenylketonuria, maternal diabetes
- fetal glutaric aciduria
What happens with thalidomide embryopathy.
- Maternal exposure (1958-1962)

- limb reduction defects
- cardiac, urogenital defects
What is the alcohol intake in Australian women?
- 24.2% women don't drink
- 68% "low risk"
- 3.6% binge drinkers
- 3% potentially harmful levels consumed
- Intervention to address broad psychosocial issues and
- concerns about stigmatisation, blame/guilt
What factors influence the fetal alcohol syndrome/affect?
- Quantity and timing
- Binge drinking
- Nutrition
- Capacity to metabolise alcohol
- Potential interaction with other drugs
- Genetic susceptibility of the fetus
- Diagnosis: Dr's knowledge and P's access
What are the clinical features of fetal alcohol syndrome?
- 1:1000 live births
- <5% offspring of women with chronic alcohol intake (3-6 std drinks/day)

- small baby
- microcephaly
- distinctive appearance
- heart defect
- hearing loss
- variable intellectual function
3 points about teratogens.
- Identifying an association
- Timing (maximum risk 18-60 days - organogenesis)
- Dosage
> dosage exposure of the mother
> fetoplacental transfer, fetal dosage
What are the critical stages of development?
LIMB - 3.5 weeks - 7 weeks 6 days
BRAIN - 3 weeks - 5 weeks 2 days
HEART - 2.5 weeks to 5 weeks 4 days
- Note: all dates are from conception and not last menstrual period
What are the clinical features of Rubella embryopathy?
- Risk of infection
> 100% in first 8 weeks
> 80% < 13 weeks
> 54% 13-14 weeks
> 25% by end of 2nd trimester
> rare after 20 weeks (serology for clarification)
- Disseminated infection
- Deafness, cataracts
- heart defects
What are the clinical features of varicella embryopathy?
- 0.4% risk < 12 weeks
- 2.0% risk 13-20 weeks
- early exposure-rarely neurological, eye defect
- late exposure - cicatrial skin rash
What are the clinical features of congenital toxoplasmosis?
- Risk of embryopathy
> 61% at 13 weeks
> 25% at 24 weeks
> 9% at 36 weeks (amniocentesis to confirm)
- Brain: hydrocephaly
- MR, seizures
- Eye: microphthalmos, retinitis
What are the principles of teratology? (wilson)
1. Susceptibility depends on the genotype
2. Susceptibility depends on the developmental stage
3. Specific mechanisms occur: growth retardation, functional disorder
4. Access depends on nature of agent
5. Manifestations are dose-dependent
How has the evaluation of tertogenicity of new drugs been carried out?
- Animal studies
- Human observation: Is study methodology acceptable?
Apply the nine causation criteria
What clinical resources are there for teratology?
Australian Drug Evaluation Committee's categorisation of medicines in pregnancy
- Takes into account medical literature on human observation and gives a bottom line
What are category A drugs?
Drugs taken by a large number of women without harmful effects.

Doxylamine (Debendox)
What are category B drugs?
Drugs taken by a limited number of pregnant women without an increase in malformations

Animal studies:
B1 - no increase in abnormalities
B2 - few studies; no evidence of an increase in fetal damage (Hep B vaccine)
B3 - Some increase in abnormalities; unknown significance in humans (desferrioxamine)
What are category C drugs?
Drugs causing harmful effects

(Pharmacological and may be reversible)


tricyclic antidepressants
opiate analgesics
non steroidal anti-inflammatory drugs
What are category D drugs?
Drugs which have caused an increased incidence of human malformations

Usually relative risk < 5

warfarin, phenytoin, valproate, lithium
What are category X drugs - contraindicated?
Drugs that have such a high risk of permanent damage to the fetus that they should not be used

How is drug exposure in pregnancy assessed?
- Determine time of exposure (use LMP, cycle length, conception date if known, date of exposure)
- determine dose taken
- assess previous knowledge and experience of drug safety during pregnancy in humans:
> drugs in pregnancy categories
> database and literature search
- Assess data on drug safety in animal studies
- generate profile of risks to pregnancy
- assess which abnormalities may be visible on ultrasound
- counsel woman and partner regarding risks, attitude to disability, option of screening for abnormalities with ultrasound
What are the clinical features of an infant of a diabetic mother?
- 13% IDDM birth defects
- Hb A1c > 7%
- Macrosomia
- Hypoglycaemia
- Cardiac, renal limb defects
- caudal regression
What deformaties are associated with amniotic bands?
- Early rupture: NTD, body wall defects, facial clefts, malformations

- Late rupture: limb amputations, ring constrictions
What chromosome abnormalities are there?
- Aneuploidy, deletion, duplication
- Usually growth and mental retardation
- Distinctive appearance
- Specific pattern of birth defects
- May be identified antenataly on ultrasound markers
What are the clinical features of down syndrome?
- 1:700 of 65 000 births p.a. in victoria
- distinctive appearance
- congenital heart defect, duodenal atresia
- intellectual disability
- dementia
How do you make a syndrome diagnosis?
- Identifying the pattern of birth defects/dysmorphism
- Family history
- medical history
- examination
- investigation

- search database
What are the clinical features of Pitt-Rogers-Danks Syndrome?
diagnosis unknown in 1984
- postnatal short stature
- microcephaly
- mid face hypoplasia
- prominent eyes
- intellectual disability
What is the importance of appropriate fetal growth?
- neonatal survival/birthweight curve is J shaped.
- low birthweight may be due to prematurity or intrauterine growth retardation. ASsociated with poor neonatal oucome due to:
> birth injury
> immaturity (lungs, CNS, energy stores)
- high birthweight - often due to maternal diabetes, leading to fetal hyperglycaemia
What are the imputs to growth?
Endocrine regulation
What are the mechanisms of growth?
Matrix deposition
What are critical periods?
Some events must occur at specific times (critical periods) so that development proceeds in an orderly fashion.

Different organs/tissues have different critical periods e.g. most brain cells need to be formed before birth, but muscle cells can exhibit "catch-up" growth.
What are the sources of variation in birth weight?
Genetic - accounts for about 40% of observed variation. Maternal genotype more important than paternal. Maternal half-sibs BW correlates r=0.58 but paternal half-sibs r=0.10

Even under optimal nutritional conditions, differences in BW occur between populations

For exxample Luni (PNG) av BW = 24kg. Cheyenne 3.8kg

Maternal nutrition. Getus not a large burden on maternal resources until 3rd trimester. Fetal nutrient delivery maintained unless maternal intake <6.3MJ/day

Smoking 20 cgs/day reduces BW 200g

Attitude. Impaired )2 deliver

Temperature. Hyperthermia? IUGR in farm animals.

Maternal drugs


Ethanol-IUGR + craniofacial, limb, cardiac anomalies

Glucocorticoids. IUGR. Programs adult diseas?

Cytotoxics. Antimitotic

beta blockers. fetal hypotension.
What are discriminating features in a young child?
short palpebral fissures
flat midface
short nose
indistinct philtrum
thin upper lip

What are associated features in a child?
epicanthal folds
low nasal bridge
minor ear anomalies
How does the endocrine system control fetal growth with GH?
- growth hormone concentration v. high
- if [GH] low as in anencephaly or isolated GH deficiency, fetal size at birth is only slightly reduced.
- Experimental hypophysectomy --> small reduction in BW, asymmetrically distributed + obesity
- GH receptors lacking in liver relative to postnatal levels

Can result in anencephalic fetus or dwarf
How does the endocrine system control fetal growth with the thyroid?
- Hypothyroid infants normal BW & length
- T4 especially important for brain growth & development. Even if cretins receive T4 from birth, functional deficits persist.

can result in cretins
How does the endocrine system control fetal growth with insulin?
- maternal diabetes. fetal glucose & insulin elevated. ?large, fat "tomato faced" babies.
- pancreatic agenesis BW 1.2-2.0kg fatal

Can result in infant of a diabetic mother, infant born with no pancrease or leprechaunism - Insulin receptor defect
How does the endocrine system control fetal growth with glucocorticoids?
- glucocorticoids promote tissue differentiation
- mature organ systems, e.g. lung surfactant
- retard growth
- T4 --> T3 potentiated
- fetal GC concs increase in late gestation
- in many species provide the trigger for birth
What does stretch stimulate?
Define normal fetal growth.
Expression of genetic potential to grow which is neither excessively constrained not promoted by internal or external factors.
Define Intrauterine growth restriction.
Failure to attain genetic growth potential.
Define Macrosomia.
Fetal overgrowth.
Do the majority of small-for gestational age (SGA) fetuses have IUGR?
No. The majority of small-for-gestational age (SGA) fetuses do not have IUGR
Do a significant number of IUGR fetuses have a birth-weight within the "normal" range?
Yes. A significant number of IUGR fetuses have a birth-weight within the "normal" range.
What factors regulate fetal growth?
What are the percentages of contribution to fetal weight of different factors?
Maternal genotype - 20% contribution
Fetal genotype - 15%
Y chromosome - 2%
Maternal environment - 31%
Intrauterine environment - 31%
Describe the gentic factor in the regulation of fetal growth.
- maternal vs paternal gene
> shetland pony vs shire pony
> genetic imprinting
> uniparental disomy (UPD)
- ethnic influences
> customised growth charts
- chromosome abnormalities
> aneuploidy
Describe the endocrine factor in the regulation of fetal growth.
- thyroid
- pituitary
- growth hormone
- insulin/IGFs/IGF-BPs
Describe the environmental factor in the regulation of fetal growth.
- uterine size
- nutrition
> pre-pregnancy, pregnancy
- altitude
- drugs
> therapeutic
> social (smoking, alcohol, cocaine)
- Infection
> viral
Describe the placentation factor in the regulation of fetal growth.
- Primary
- Secondary
> Diabetes
> hypertension
List placental factors in fetal growth (i.e. mechanism of placental transport). Name the substances involved in each mechanism.
Mechanism of placental transport - Substance

Passive diffusion
- oxygen
- carbon dioxide
- fatty acid
- ketones
- fat-soluble vitamins

Facilitated diffusion
- sugars

Active transport
- amino acids

- proteins
What are two fetal growth abnormalities?
- 90th centile for gestaion

Fetal growth restriction (IUGR)
- symmetrical
- asymmetrical
What is the aetiology of IUGR?
Fetal anomaly
- chromosomal (approx 5%) e.g. trisomies 13, 18, 21; triploidy; CPM-UPD
- structural (approx 7%)

Infection (approx 5%)

- drugs (therapeutic, smoking, alcohol, cocaine etc)
- lifestyle (physical activity, nutrition)

- idiopathic
- hypertensive disorders (include treatment)
- antiphospholipid syndrome
- thrombophilias
- other medical disorders (diabetes, renal disease)
- being male
Describe the assessment of fetal growth.
Intrauterine fetal growth restriction (IUGR) is a concept defining the failure of a fetus to achieve its growth potential.

IUGR is associateed with an increased perinatal mortality and morbidity, including cerebral palsy.

The identification of the IUGR fetus allows appropriate surveillance, timely delivery resulting in improved outcomes.

The majority of small-for-gestational age (SGA) fetuses do not have IUGR.

A significant number of IUGR fetuses have a birth-weight within the "normal" range.
How is IUGR detected?

Clinical examination
- abodominal palpation
- symphysial-fundal height
- 50-75% detection rate; 30% specificity

Ultrasound biometry

Doppler studies
What are elements of fetal biometry?
Biparietal diameter
Abdominal circumference
Femur length
How is IUGR managed?

Fetal surveillance
- biophysical profile (rather than CTG)
- doppler FVW studies (UA, MCA, DV)
- (serial biometry)

Fetal preparation
- corticosteroids

Maternal surveillance
- risk of hypertension

Maternal (parental) preparation
- visit NIVU
- assess and discuss mode of delivery
What does the biophysical profile consist of?
Amniotic fluid volume
Fetal breathing
Fetal tone
Fetal movements
Fetal heart rate pattern
What are some future prospects for IUGR?
Key remaining problems

1. Efficiently discerning IUGR from healthy SGA
2. Identifying "normal sized" IUGR fetus
3. Predicting IUGR
What are the main conclusions of IUGR?
Clinical examination remains the key to identifying the "at risk" mother-fetus pair
- ultrasound biometry (AC) should be used to confirm/refute a diagnosis of SGA.

Doppler ultrasound of UA (<35 weeks) or UtA (>35 weeks) will assist in differntiating IUGR from SGA.

Careful anatomical survey and karyotyping should be offered for all fetuses <10th centile.

Fetal/maternal surveillance should be tailored to gestation/severity.

Delivery should be timed by careful surveillance, increasingly Doppler studies.
What are some statistics on birth defcts in victoria?
- In 1999-2000 there were 886 stillbirths in Victoria, 210 (23.7%) had a birth defect
- In 1999-2000 there were 416 neonatal deaths. 196 (47.1% had a birth defect)
- 31.2% of all perinatal deaths were associated with one or more defects
What are the trends in birth prevalence of defects?
Increasing prevalence
- better ascertainment
- "true" increases (what reasons?)

Increasing terminations
- (increased x100 over 20 years)
List three developmental anormalies.
Chromosomal anomalies
Structural anomalies
Single gene defects
What is the distribution of perinatal losses with congenital abnormalities in Victoria?
CNS - 21%
CVS - 10%

Chromosomal - 17%
Multiple - 30%
Describe the link between the detection rate and the screen positive rate in screening.
Th higher the detection rate, the higher the screen positive rate

The lower the screen positive rate, the lower teh detection rate
What are the screening approaches for down syndrome?
Maternal age
First trimester (serum and NT)
Second trimester serum
Describe amniocentesis. When is it done and what is the chance of a miscarriage?
A needle is guided into the amniotic fluid and a small amount of fluid is removed.

> 15 weeks gestation

0.2%-0.5% of miscarriage.
Desribe chorionic villus sampling. When is it done and what is the chance of a miscarriage?
A sample of chorionic villi is taken with a needle and syringe using the transabdominal approach.

10-14 weeks gestation

0.5%-1% of miscarriage
How useful is ultrasound for detection of fetal anomaly?
- The relative detection rate of all anomalies by routine ultrasound was 3.1(35% v 11%)

- Ultrasound screeening in low risk population did not significantly imrove perinatal outcome compared to selected use.

The relative detection rate of ultrasound screening before 24 weeks gestation in a tertiary v a non-tertiary facility was 2.7
What is done for single gene defects?
- usually a family history
- single gene mutation identified (e.g Cuchenne muscular dystrophy, cystic fibrosis)
- tissue collected by CVS or amniocentesis
- some screening programs established (thalassemia, CF)
What theraputic interventions are there for fetal anomalies?
Therapeutic interventions

Structural anomalies
> selective fetal surgery (research only)
> termination of pregnancy

Chromosomal anomalies
> termination

Single gene defects
> termination
What are some new horizons in realtion to fetal anomalies?
- better surgical interventions (informed by animal research)
- gene therapy
- preimplanation genetic diagnosis
- genome-wide screening
What doesn't a fetus need to do?
What does a fetus need to do?
- Mature its lungs - structurally and functionally
- Prepare its gut for feeding - "gut closure"
- Develop its ability to concentrate urine
- Generate heat for thermoregulation
- Change its Hb type
- Store energy substrates - Brown fat & glycogen
How are the functions a fetus needs to do accelerated?
All these functions are accelerated by glucocorticoids

- secreted by the fetal adrenal cortex
- concentration increases before birth
- prepartum "cortisol surge" - unlike any subsequent phenomenon
- promote differentiation
- slows growth
What is the HPA axis?



Cortisol feeds back to the hypothalamus and the pituitary gland
What are the connections of HPA axis and parturition?
- In 1933, Percy Malpas noted prolonged gestation in humans if fetus was anencephalic.
- sheep - no parturition if ewe ate Veratrum californicum on d14 after mating (implantation d 16). Fetal anterior pituitary was absent, adrenals small.
What is the influence of the Liggins hypothesis?
- The elegance of the ovine system for synchronizing fetal maturation with birth has led to many theories of human parturition that seek to incorporate features of the ovine system.
- These features include fetal autonomy and a role for the fetal HPA axis.
What are the caveats on application of Liggins Hypothesis to human parturition?
- Human cortisol surge is gradual
- fetuses lacking cortisol are born on time
- no decline in progesterone concentration
- no increase in estrogen concentration
- placental aromatase deficiency does not affect timing of labour
- exogenous estradiol does not induce labour
What are uterotrophic mechanism?
Same for all species

- These are mechanisms that prepare the uterus for contraction
- Contraction-associated proteins include:
> gap junction proteins-connexins
> oxytocin receptors
> prostaglandin synthases
What are uterotonic mechanisms?
Uterotonic mechanisms cause myometrial contraction
- Cytokines & inflammatory mediators leading to the production of:
> prostaglandins
> oxytocin
- The changes that take place in the uterus and birth canal strongly resemble inflammation
What is the role of prostaglandins in labour?
Thw two PGs implicated in labour contractions are:
- PGF 2 alpha
- PGF alpha

Both are synthesized locally in the uterus

Both directly activate the myometrium
What is the role of oxytocin in labour?
Secreted episodically from neurohypophysis

Secretio builds up over days

Secretion corretlates with Uterine Activity-Braxton-Hicks contractions

Involved in Ferguson reflex
What is the ferguson reflex?
1. Hypothalamus sends efferent impulses to posterior pituitary where oxytocin is stored.

2. Posterior pituitary releases oxytocin to blood; oxytocin targets mother's uterus muscle
3. Uterus responds by contracting more vigorously
4. Baby moves depper into mothers birth canal
5. Afferent impulses to hypothalamus
6. Pressorecptors (?) in cervix of uterus excited

Positive feedback mechanism contributes to cycle until interrupted by birth of the baby.
What happens to the cervix in labour?
- The cervix has a differnt composition from the uterus.
- At labour, it changes dramatically from a tight, cylindrical organ to a soft, compliant one.
- Pro-inflammatory changes and neutrophilic infiltrate fabour rapid tissue remodelling
- PGE2 gel can initiate this change
What are the stages of labour?
1. From the onset of contractions to full dilation of the cervis.
2. From full dilation to delivery of the neonate
3. Expulsion of the placenta
How is lactation regulated by the endocrine?
- During pregnancy, progesterone and estrogens promote growth of the ducts and alveoli in the breats. Prolactin contributes, but its action is inhibited by sex steroid action.
- Colostrum formed
- At birth, progesterone and estrogen concentrations fall dramatically
- Lactation established 2-3 days post partum
What is colostrum?
Colostrum (also known as beestings or first milk) is a form of milk produced by the mammary glands in late pregnancy and the few days after giving birth.
What are the main sturctures of the breast?
Lactiferous ducts
Subcutaneous fat
What is teh Mechanical regualtion of lactation?
- The let-down reflex
- suckling associated with spikes of Prolactin and oxytocin (Prl concs decline over a few weeks but the suckling response persists)
- Prl needed for galactopoiesis (pituitary tumours)
What are the functions of the placenta?
- to provide nutrients to the fetus (glucose, AAs, Lipids, minerals, O2)
- to remove wastes from the fetus (urea, heat, CO2)
- to synthesise and secrete hormones needed for the maintenance of pregnancy
- to synthesise and secrete hormones needed for the normal termination of pregnancy
What are the mechanisms of placental transport?
- passive diffusion e.g. water, gases, urea, FFAs, drugs
- faciliated diffusion e.g. glucose, lactate
- active transport e.g. amino acids (against conc gradient)
- receptor-mediated endocytosis - complex lipids, cholesterol
What hormones does the placenta secrete?
- Steroids
> progesterone (P4), estrogens & their precursors
- Prostaglandins
> PGE2 and PGF2alpha
- Proteins or peptides
> hCG, hPL, CRH, GH
Describe the placental synthesis of Chorionic Gonadotrophin (CG).
- The embryo must take control of the CL to ensure its own survival
- hCG secreted by blastocyst, then by the synctiotrophoblast
- maintains CL until the placenta takes over P4 secretion (approx. 8 weeks)
- excreted in urine from 2-3d post-implantation (pregnancy tests)
Describe the placental synthesis of Steroids "the feto-placental unit".
- Human placenta can't make estrogens from P4 (no 17-OHase) so makes them from fetal and maternal androgens.
- fetal adrenal makes DHEAS
- Fetal liver makes 16-OH DHEAS
- placenta converts 16-OH DHEAS to E3 &
- makes E1 & E2 from maternal androgens
What is DHEA?
Dehydroepiandrosterone (DHEA), is a natural steroid hormone produced from cholesterol by the adrenal glands, the gonads, adipose tissue and the brain. DHEA is the precursor of, androstenedione, testosterone and estrogen. It is the most abundant hormone in the human body.
What is the role of Progesterone (P4) in pregnancy?
- maintains electrical quiescence of myometrium (antagonises estrogens)
- promotes uterine growth (with estrogens)
- initial source is CL but the placenta takes over P4 synthesis
- The increase in P4 over gestation is 10x that of estrogens (P4 dominance)
- Actions include relaxation of smooth muscle in genital, vascular, urinary & GI tracts.
- May "tranquilize" or "anaesthetize" fetus
- Vasodilation esp in kidney & skin
- hyperventilation - lowers PCO2
- increase in body temperature
- increase in thirts, appetite, fat deposition
- breasts: growth of ducts, inhibition of Prl
What is the role of estrogens in pregnancy?
- until week 6, most comes from CL (estradiol-17 beta; E2 beta)
- E3 from fetal subtrate becomes more important (fetal adrenal makes 100-200mg steroid/day vs 20-30 in adult)
- 1 pregnancy produces 150 years worth of estrogens for a non-pregnant woman
- Actions include growth of myometrium, endometrium
- growth of alveoli & ducts of breasts
- angiogenesis esp in genital tract
- softening of ground substance, skin and cervix
What is the anatomy of trophoblast invasion?
- Invading trophoblasts leave placental cell columns - enter maternal space - penetrate endometrium and upper layers of myometrium
- Invading trophoblasts selectively surround maternal spiral arteries - modify muscular, high resistance channels into wide, low-resistance vessels
- Pijnenborg: '2-wave' hypothesis of trophoblast invasion
- First tirmester interstitial invasion (increased perfusion detectable between 8-12 weeks)
- second trimester endovascular invasion
- complete by mid-trimester (18-22 weeks)
What is a trophoblast?
The trophoblast (from Greek threphein: to feed) is considered to be the first of all embryonic annexes. It secretes hCG in order to maintain progesterone secretion and sustain a pregnancy. Trophoblasts are invasive, eroding, and metastasizing cells of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg.

The invasion of a specific type of trophoblast (extravillous trophoblast) into the maternal uterus is a vital stage in the establishment of pregnancy. Failure of the trophoblast to invade sufficiently may be important in the development of some cases of pre-eclampsia, while too firm an attachment may lead to placenta accreta.

Trophoblasts mediate the implantation of the fetus into the placenta, but they are never incorporated into the mother's body or the fetus. They are not "fetal" cells.

Trophoblasts become inert during pregnancy and are completely rejected by the fetus and mother at delivery. They can be seen as the thin membrane covering the fetus at birth, the caul.
The fetus requires successful invasion of spiral arteries.
What prevents invading tophoblasts from penetrating uterus, causing maternal haemorrhage?
Describe decidualisation.
- Following LH surge, under progesterone effect, endometrial cells enlarge, become eosinophillic
- endometrial stroma becomes a dense barrier (the decidua)
- the decidua acts as physical barrier against invasion
- also elaborates cytokines that promote attachment, inhibit invasion
What is maternal spiral artery conversion?
From high resistance circuit to low resistance utero-placental unit
What are the effects on uterine perfusion from the non-pregnant to the pregnant state?
- Uterine perfusion makes up <1% cardiac output in non-pregnant state
- Pregnancy increases cardiac output up to 35%
- uterine blood flow constitutes 25% of maternal cardiac output at term
What can the Uterine Artery Doppler do?
Uterine Artery Doppler: A measure of placental downstream resistance (maternal interface)
- Maternal Uterine Arteries can be interrogated at the apparent 'cross-over' with Ext. Iliac Arteries
- The spectral doppler waveform is determined by local (elastic recoil) and downstream factors (placental resistance)

Uterine Artery Doppler: Changes through gestation
- In non-pregnant state, Ut.Aa typically high resistance, reverse flow in early diastole - 'notching'
- First to second trimester increased flow in diastole, loss of prominence of 'notch'
- By mid-trimester, high diastolic flow, no early diastolic notching (10% persistence of notching at 23 weeks)
Describe mid-trimester Uterine Artery Doppler in the prediction of PET/FGR.
- Various criteria of screening have been used (>95% centile resistance +/- bilateral notching)
- Mid-trimester Uterine Artery Doppler has >80% sensitivity for early-onset/severe PET/FGR.
- Mid-trimester Uterine Artery Doppler has ~60% sensitivity of all PET, ~30% sensitivity for all SGA infants.
Describe villus ultrastructure in uncomplicated pregnancy.
- numerous terminal villi
- balanced longitudinal growth and branching of vessels
- sinusoid dilations in capillaries
Does the placenta demonstrate pathognomonic histological appearances in specific disease states?
What does pathognomic mean?
Pathognomonic (often misspelled as pathognomic) is a word, often used in medicine, which means diagnostic for a particular disease. A pathognomonic sign is a particular sign whose presence means, beyond any doubt, that a particular disease is present. It is derived from the Greek pathos (παθος, disease) and gnomon (γνωμον, "judge"). Labelling a sign or symptom "pathognomonic" represents a marked intensification of a "diagnostic" sign or symptom.
Describe villus ultrastructure in IUGR with Absent end-diastolic velocity
- longitudinal growth of villi and capillaries
- reduced number of terminal villi and capillary branching
- hyperoxia in intervillus space
- predominant PIGF expression
Describe villus ultrastructure in maternal anaemia, high altitude pregnancy, pre-eclampsia
- increased terminal villi number
- increased branching resulting in hypercapilarisation
- hypoxia in intervillus space
- predominant VEGF expression
Umbilical artery doppler can measure placental resistance (fetal interface)
Reduced number of terminal villi and capillary branching results in increased vascular impedance/resistance (in IUGR)
Describe the changes in umbilical artery doppler spectral waeform with increasing placental resistance.
- Increasing resistance/pulsatility indices as a rsult of decreasing diastolic flow
- forward flow absent in diastole
- forward flow reversed in diastole
What is pre-eclampsia?
A syndrome of many cuases, rather than a specific disease.
Descrive the evidence for the role of the placenta
- remission of signs and symptoms after termination of pregnancy
- the syndrome can occur without the context of a fetus (GTD/hyatidiform mole)
- pre-eclamptic placentae show abnormal integrin expression (needed for cell-cell, cell-matrix interactions) leading to deficient invasive trophoblast action and porr spiral artery conversion.
Poor spiral artery conversion: inadequate invasive trophoblast action.
What is the theory of 'oxidative stress'?
Abnormal placentation leads to relative hypoxia and characteristic histological changes at villus level.
- Placenta releases cytokines, lipid peroxidation products and other mediators into maternal circulation.
- These mediators act on maternal endothelium to affect flow-mediated vasodilation.
What is the role of genetics in abnormal placenta?
- Significant association between genetically abnormal trophoblasts and increased risk of pre-eclampsia or IUGR
- examples: gestational trophoblastic disease, diandric triploidy, trisomy 13 and PET; digynic triploidy and IUGR
- Mechanism: Abnormal vascular trophoblast remodelling of spiral arteries seen on histology
- ? aberrant gene expression resulting in abnormal trophoblast invasion
- also issue of maternal susceptibility
What are the principles of screening as applied to antenatal population?
- Identification of asymptomatic individuals at risk
- Condition in its preclinical stage (unborn)
- condition is well-understood
- condition is significant public-health problem
- sceening test that is reliable, repeatable, acceptable, known sensitivity/specificity
- the diagnostic test/treatment is effective and available with clear policies on who to test/treat
What are two diagnostic tests for fetal abnormality?
Chorionic Villus Sampling (CVS)

What is down's syndrome?
- the most frequent form of mental retardation
- caused by a demonstratable chromosomal aberration [triplicate state (trisomy) of all or a critical portion of chromosome 21]
- is characterised by well-defined and distinctive phenotypic features and natural history
What are the clinical features of down's syndrome?
- Incidence: In an unscreened population, 1 in 700 live births
- Phenotype: characteristic facies
- Low IQ - wide range
- Cardiac (40%) - atrio-ventricular canal defects, pulmonary hypertension
- Early Alzheimer's (characteristic plaques and neurofibrillary tangles at mean age 40 years)
Describe 'free trisomy 21'.
- 95% of down's syndrome have 3 copies of chromosome 21 ('free trisomy 21')

Cytogenetic mechanism:
- non-disjunction at meiosis I or meiosis II
- maternal in origin
- increased incidence with advancing maternal age (incidence @ birth 1:1000 at 30 years, 1:100 at 40 years)

2-4% recognisable mosaicism

5% due to non-disjunction at spermatogenesis (not age related)
Decribe translocation trisomy 21.
- constitutes 5% of cases
- t(21,21), t(21,22) or t(14,21)

Cytogenetics: Robertsonian translocation [t(14,21)] or isocentric translocation [t(21,21), (dup21q)]

Unrelated to maternal age
Source may be maternal or paternal
What is Edward's syndrome (trisomy 18)?
- A multiple malformation syndrome
- Trisomy of all or part of chromosome 18
- Mechanism: non-disjunction (translocation rare), with maternal age effect
- Prevalence: 3/10000 pregnancies
- Prognosis - high lethality, 2/3 diagnosed in-utero die before delivery, >90% liveborn die in first month, few survive to 1 year and have profound mental retardation
What are the associated anomalies with Trisomy 18?
- CNS - myelomeningocele, Arnold-Chiari malformation
- Face/neck/skull - low-set ears, micrognathia, microcephaly
- CVS - VSD, poly-valvular dysplasia
- GIT - omphalocele, diaphragmatic hernia
- GU - horseshoe kidney, renal dysplasia
- Skeletal - overlapping fingers, rocker-bottom feet
- General - growth restriction, polyhydramnios
Describe Patau's syndrome (trisomy 13).
- A multiple malformation syndrome
- Trisomy of all or part of chromosome 13
- Mechanism: non-disjunction (translocation uncommon - t(13,14) or t(13,15) parental or denovo with matternal age effect
- Incidence: 2/10000 pregnancies
- Prognosis - high lethality - intrauterine death/stillbirth, few born alive do not survive past 6 months
- Screening by ultrasound
What are the associated anomalies with Trisomy 13?
- CNS - hydrocephaly, holoprosencephaly
- Skull/face/neck - cleft lip/palate, persistent nucal fold
- GIT - omphalocele, diaphragmatic hernia
- Skeletal - Club hand, ulnar deviation
- GU - pyelectasis, cystic kidneys
- General - growth restriction
Describe the effect of maternal age.
- On trisomy 21, 18, 13: risk increases with maternal age
- On Turner's Syndrome (XO), Tiploidy and XXX/XXY/XYY: risk unchanged with maternal age
How does gestation-related risk (relative to risk at 10 weeks) change over time?
- On trisomy 21, 18, 13: risk increases with maternal age
- On Turner's Syndrome (XO), Tiploidy and XXX/XXY/XYY: risk unchanged with maternal age
Describe gestation-related lethality.
- The earlier the gestation, the higher the risk of aneuploidy
- Between 12 weeks (gest for NT screening) and 40 weeks, 30% loss-rate for T21
- Between 16 weeks (gest for midtrimester screening) and 40 weeks, 20% loss-rate for T21
- Between 12 and 40 weeks, loss-rate for T18, 13 and 45XO is 85%
What are neural tube defects?
- Include spina bifida and anencephaly
- pattern of biochemical abnormality: increased AFP (open NTD)
- AFP > 2 MoM is indication for tertiary level ultrasound (diagnosis)
What is myelomeningocele?
Spina bifida (Latin: "split spine") describes birth defects caused by an incomplete closure (an opening) of one or more vertebral arches of the spine, resulting in malformations of the spinal cord. The spinal membranes and spinal cord may protrude through the absence of vertebral arches (called clefts). These malformations fall into three categories: spina bifida occulta, spina bifida cystica (myelomeningocele), and meningocele.
What are two points about myelomeningocele?
- Arnold-Chiari malformation type II in cranial examination
- spinal survey in 3 planes
Describe anencephaly.
- Defective closure of anterior portion of neural tube
- Absence of cranium, cerebral hemispheres
- May have some brainstem tissue - may have some cardiorespiratory function first few hours, ultimately incompatible with life
- Detectable at first trimester U/S.
Define Nuchal translucency.
The sonographic appearance of the subcutaneous accumulation of fluid behind the fetal neck in the first trimester of pregnancy
What is NT Assessment?
- Window of assessment; CRL 45mm-84mm (11 weeks to 13+6 weeks)
- Increased of NT is associated with Trisomy 21 and other chromosomal abnormalities, as well as structural malformations (e.g. cardiac, skeletal) and genetic syndromes.
- Increase NT in first trimester may resolve by second trimester, or persist as nuchal oedema or develop into hydrops.
Why 11 to 13+6 weeks?
- The option of first trimester termination
- The incidence of increased NT in chromosomally abnormal fetuses between 14-18 weeks is lower than that <14 weeks (reduced sensitivity, the increased NT may be transient)
- Technical aspects - 98% successful images 11-13+6 weeks, 90% success after 14 weeks (fetus vertical)
Describe first trimester serum screening.
Window: 11-14 weeks

The analytes: free beta hCG (increased) + PAPP-A (decreased)

True nature of 'PAPP-A'
Describe mid-trimester serum screening.
Various analytes have been used ('double' test, 'triple' test, 'quadruple' test)
What are the current screening models for down's syndrome?
Combined test:
- first trimester
- NT + free beta hCG + PAPP-A + maternal age

Integrated test:
- first (NT + PAPP-A) + second trimester (quadruple test)

Quadruple test
- second trimester
- alpha-fetoprotein + unconjugated oestriol + fee/total beta hCG + Inhibin A + mat. age

Serum integrated test:
- first (PAPP-A) + second trimester (quadruple test)
What are some principles of testing?
- 'A priori' risk/background risk
- lieklihod ratios
- independence of each test
- sensitivity and specificity of each test does not vary with populations
- positive and negative predictive value of each test varies with the prevalence of condition within population under test
How to interpret detection rates?
- Caution: Detection rates at mid-trimester and at term are materially different (re: gestation-related loss)
- When assessing tests, consider if tests are done at comparable gestations (i.e. is fetal bias relecant?)
- 'Marker related fetal loss bias': markers (increased NT, hCG) themselves may be related to miscarriage, as well as to Down's syndrome - in practice, this difference is small when comparing first & second trimester tests.
What tests have a detection rate > 75%, FP <3%, cut-off 1:250 at term?
From 11 to 14 weeks:
- the combined test (NT, hCG and PAPP-A)

From 14-20 weeks
- the quadruple test (hCG, AFP, uE3, inhibin A)

From 11 to 14 weeks AND 14 to 20 weeks:
- the integrated test (NT, PAPP-A + hCG, AFP, uE, inhibin A)
- the serum integrated test (PAPP-A + hCG, AFP, uE3, inhibin A)
What are the structural malformations that can be seen in an ultrasound from 18-20 weeks?
- Single-system malformations
- Malformations constituting a 'syndrome'
- Malformations associated with aneuploidy (e.g. AVSD and Trisomy 21)
What are the 'soft markers' seen in an 18-20 week ultrasound?
Definition: minor defects or ultrasound appearances that are themselves not associated with handicap, but have varying degrees of association with aneuploidy

Examples: short femur/humerus, echogenic bowel, (cardiac) echogenic focus
- Each has a 'strength of association' or 'likelihood ratio' that alters the background risk
What is the link between counselling and screening and diagnosis of fetal abnormalities?
- Is there an understanding of a problem screened for?
- Screening ('risk' information) vs Diagnosis (definite answers)
- An understanding of the limitations of the test' (concept of 'false negatives' vs 'false positives')
- 'Opting-in' - an active decision to be screened.