Week 8 Flashcards
History Anti-D
In 1932 the three most characteristic clinical signs of Rh haemolytic disease of the fetus and newborn HDFN hydrops fetalis, severe neonatal jaundice and delayed anaemia of the newborn were identified as being caused by the same process
In the early 1940s Philip Levine identified that the cause of HDFN was antibodies to the D antigen
In 1969 postnatal anti-D immunoglobulin was first introduced
Between 1976 and 1991 this guidance was extended to include anti-D immunoglobulin administration following potentially sensitising events PSE
The 2002 guidance further extended the previous guidance to include routine antenatal anti-D prophylaxis RAADP
The widespread intro of anti-D immunoglobulin prophylaxis saw a dramatic fall in deaths attributed to RhD HDFN between 1977 and 1989. This fall in the death rate from RhD HDFN is mainly due to the introduction of anti-D immunoglobulin prophylaxis
Anti-D prophylaxis administered postnatally and following potentially sensitising events during pregnancy has reduced the UK maternal RhD sensitisation rate to 1.0-1.5%
Anti-D immunoglobulin prophylaxis
The anti-D immunoglobulin prophylaxis policy has been so successful that it is hailed as one of the major achievements in obstetrics in the twentieth century
It’s predicted that the universal introduction of RAADP will prevent a further 17 late fetal and neonatal deaths in the UK each year
Blood groups
A+
A-
B+
B-
AB+ can receive from everyone
AB-
O+
O- can be donor to everyone
RhD factor and pregnancy
Blood types can be categorised as either RhD positive or RhD negative
Being RhD negative is usually only of consequence during pregnancy
If a RhD negative woman is pregnant with a RhD positive fetus she maybe have a potentially harmful immune response resulting in the formation of anti-D antibodies
Genetic determinants of blood RhD factor
The RhD positive gene is more common than the RhD negative gene and is more dominant
If one of the two genes is RhD positive and the other RhD negative your blood type is RhD positive
It takes a pair of RhD negative genes to make your blood type RhD
Anti-D formation
If fetal red cells cross the placenta and enter the maternal blood stream the spleen is activated by the fetal RhD positive red blood cells to produce anti-D antibodies
The presence RhD positive fetal red blood cells in maternal circulation stimulates the production of anti-D antibodies
Anti-D
Anti-D immunoglobulin prophylaxis is administered to prevent maternal sensitisation with anti-D antibodies
If anti-D is not given
Anti-D antibodies can cross the placenta and bind to the fetal RhD positive red cells
If this happens without the anti-D immunoglobulin injection the maternal anti-D antibodies will become permanent and irreversible. This is known as maternal sensitisation
It’s unlikely that the first pregnancy will be affected
However in a future pregnancy if the baby is RhD positive the maternal immune response will be greater
The maternal anti-D antibodies will cross to the fetal circulation and destroy fetal red blood cells. This leads to haemolytic disease of the fetus and newborn HDFN
Maternal sensitisation
A woman is considered sensitised if she develops antibodies such as anti-D in her blood
Once sensitisation occurs its irreversible
The antibodies which are formed as a result of the sensitisation do not affect the mothers health
And only rarely affect first pregnancy
However they could affect future pregnancies where the baby is RhD positive
Impact of sensitisation on pregnancy
During the pregnancy that results in a woman becoming sensitised the anti-D antibody is rarely produced at a high enough level to cause haemolytic disease of the fetus and newborn HDFN
Any future pregnancies may however be at risk of developing HDFN if the baby is RhD positive
The anti-D antibody which resulted from the earlier sensitisation can cross the placenta and attach and destroy RhD positive fetal red cells causing HDFN
The anti-D antibody resulting from maternal sensitisation will only attack RhD positive fetal red blood cells
Fetomaternal haemorrhage
During pregnancy the placenta normally prevents maternal and fetal blood mixing
Fetomaternal haemorrhage FMH is the term used to describe any bleed from the fetus into maternal circulation
It’s the most common in the third trimester and around the time for birth
It’s often occurs with a potentially sensitising event such as vaginal bleeding but may also happen in the absence of any obvious potentially sensitising event
Sensitised
The timing, rate and severity of the maternal immune response will vary between individuals
The level of antibody present can be detected by laboratory tests on maternal blood samples
The higher the levels the greater the significance for a pregnancy
If a women is sensitised anti-D immunoglobulin will have no effect
It should therefore not be given to a women with immune anti-D in their blood even if they experience a potentially sensitising event
How maternal sensitisation occurs
Certain events during pregnancy are known to increase the risk of fetal maternal haemorrhage and maternal sensitisation these are known as potentially sensitising events PSEs
Gestation is an important factor for determining how a potentially sensitising event is managed
If anti-D immunoglobulin is required it should be given within 72hours of a potentially sensitising event occurring
The decision to give anti-D immunoglobulin in response to a potentially sensitising event should not affect or be affected by routine ante or post natal anti-D immunoglobulin prophylaxis
Potentially sensitising events
Any vaginal bleeding
Blunt abdominal trauma
Invasive antenatal testing (amniocentesis, CVS)
External cephalic version
Miscarriage or termination of pregnancy
Ectopic pregnancy
Intrauterine death
Stillbirth and birth of a RhD positive baby
Management of potentially sensitising events
The management of a potentially sensitising even varies according to gestation
Prior to 12 weeks gestation anti-D immunoglobulin is only occasionally indicated following a potentially sensitising event
Between 12 and 20 weeks gestation a minimum dose of anti-D immunoglobulin 1500iu is recommended
At 20 weeks gestation and onwards a minimum dose of anti-D 1500iu is also required however more anti-D immunoglobulin may be required depending upon the size of FMH this will be determined by laboratory tests
management of potentially sensitising events 2
Anti-D immunoglobulin is most effective if given within 72 hours of a potentially sensitising event. However if a woman has not received anti-D immunoglobulin within this time it may still offer some protection if given up to 10 days after the potentially sensitising event occurred
Before the 12 weeks gestation, anti-D immunoglobulin should be considered if PV bleeding is heavy or persistent and/or associated with severe pain, particularly when approaching 12 weeks gestation
Anti-D immunoglobulin is always indicated following surgical intervention to remove products of conception (miscarriage and termination of pregnancy)
Anti-D immunoglobulin should always be given in cases of termination of pregnancy whether by surgical or medical means. In some cases anti-D immunoglobulin is also offered if early pregnancy loss, due to miscarriage or ectopic pregnancy if managed medically
Sensitisation
Is irreversible there’s no treatment for it
Anti-D immunoglobulin should not be given to sensitised woman in the event that it is inadvertently administered the only consequence is the unnecessary exposure of the woman to a blood product
Sensitisation is only likely to cause problems for a women should she become pregnant with a RhD positive baby or require blood transfusion. It may be difficult to cross match blood and transfusion reactions could occur if RhD positive blood is given inadvertently eg during an emergency
This will usually mean regular monitoring of the anti-D antibody level in the woman’s blood. Usually the higher the antibody level the greater the risk of harm to the baby
There is no effective treatment that can change the levels of antibody produced and levels are likely to rise during the pregnancy if the fetus is RhD positive
Management of pregnancies at increased risk due to maternal sensitisation
Some RhD negative women will be known to be sensitised before their first visit or it will be discovered during pregnancy. Although this does not affect woman’s health the baby is at risk of developing HDFN
Sensitised women require specialised care during pregnancy to monitor the health of their baby. They should be referred to a consultant obstetrician/fetal medicine department and have a haematologist or transfusion specialist involved in planning their care
Specialist investigations such as serial ultrasound including middle cerebral artery Doppler scanning can be used to monitor the health of the developing baby. Repeated testing of the woman’s antibody levels during pregnancy can help to predict the risk to the baby from HDFN
Babies of women known to have anti-D antibodies should be delivered in a hospital with neonatal care facilities it should be recognised that a future pregnancy with a RhD positive baby is likely to be at even greater risk of HDFN
Management continued
Middle cerebral artery:
-measurement of Doppler flow through MCA can help identify babies with anaemia. Babies with anaemia have increased blood flow and should be referred to a fetal medicine unit
Fetal medicine unit:
-in the most serious cases intrauterine blood sampling may be indicated to determine the fetal haemoglobin level. If a fetus is found to be very anaemia a intrauterine blood transfusion may be required
Neonatal care:
-babies born to sensitised women are at risk of HDFN. They need to be assessed at birth by a paediatrician and may require treatment
Future pregnancies:
-women should be counselled about the likely risk of HDFN. In future pregnancies this should include follow up appointments with an obstetrician and/or haematologist/transfusion specialised and liaison with their general practitioner
Booking visit
A maternal blood sample should be taken early in pregnancy ideally at the first antenatal clinic visit and before 16 weeks of gestation. This is to establish ABO and RhD type of the woman and to screen for the presence of red cell antibodies
If known the gestation of the fetus and any transfusion or anti-D administration history should be included on the request form to assist the effective interpretation of results
Fetal DNA testing
We can now test whether the fetus of a women who is Rh negative is Rh positive or Rh negative
This test can be done from 11+2 weeks up to 24 weeks
The test is sent in a normal group and save bottle, the bottle must be handwritten.
The form can have a sticker on it but there must be a EDD from a scan on the form otherwise the sample will. Be rejected
The results will be put as an alert of Badgernet and a copy sent to woman
If the fetus is predicted Rh negative then the woman doesn’t need to have any antenatal or post natal anti-D—A cord sample needs to be sent at delivery for confirmation of blood group
If the fetus is predicted Rh positive then antenatal and post natal anti-D must be continued- A cord sample and Kleihauer must be sent at delivery
Routine antenatal care
At the 28 week antenatal clinic visit a maternal blood test must be taken to recheck the ABO and RhD type and to screen for presence of any clinically significant antibodies the woman should then be offered routine antenatal anti-D prophylaxis RAADP
RAADP is given as a single dose at 28 weeks
The blood test must be taken before the woman is given RAADP
If anti-D immunoglobulin has previously been given for a potentially sensitising event, antibody screening should still be undertaken and the 28 week dose of RADDAP should still be given
Routine postnatal care
Women who do not receive RAADP at 28 weeks eg. As a result of a missed appointment may still benefit from treatment at a later stage of gestation
The individual circumstances should be discussed with medical staff
Should the woman decline RAADP this should be recorded in her case notes
Postnatal care:
-at birth a cord blood sample should be taken from the baby to check for:
—the ABO and RhD type
A maternal blood sample should be taken no sooner than 30-45 minutes after the placenta has separated. Anti-D immunoglobulin is never administered to a baby
Anti-D informed decision making
Health care professionals have a responsibility to support RhD negative women to make a fully informed decision about the use of anti-D immunoglobulin in pregnancy
Administration of anti-D immunoglobulin and RAADP in particular will benefit a small number of women and may carry some risks. Both health care professionals and the woman herself should be aware that the decision to accept or reject anti-D is hers
Notes
Fit for purpose
Information provided should use readily understandable language and include:
-the reason anti-D immunoglobulin is offered
-the potential benefits
-the potential risks
-the option to decline anti-D immunoglobulin
-a list of potentially sensitising even and action to be taken in relation to them
-sources of further information about anti-D immunoglobulin
-a statement offering the opportunity to discuss anti-D immunoglobulin prophylaxis further
Potential benefits of anti-D immunoglobulin
Although there are some theoretical concerns about anti-D immunoglobulin crossing the placenta entering the fetal circulation and causing harm to the unborn baby this has never been observed clinically
Known side effects of anti-D immunoglobulin occur infrequently and include: localised pain at the injection site, fever and/or malaise and allergic reaction
There are some RhD negative women who do not need or will not benefit from receiving anti-D immunoglobulin. However for these women the decision to decline anti-D immunoglobulin maybe difficult
Examples of such circumstances:
-women who are certain that the father is also RhD negative
-women who are certain this will be their final pregancy
Level of information
HCP should ensure that all women understand the information they have been given.some women will require more detailed info. Provision of this information is the responsibility of the healthcare professional
The overall chance of a woman benefitting from RAADP is around 1 in 5790 this represents the risk of her becoming sensitised and going on to have a pregnancy affected by HDFN
The chance of benefitting through avoiding sensitisation alone is around 1 in 228
In most sensitised pregnancies the baby will not develop clinically significant HDFN. However HDFN can be very serious and in around 10-12% of sensitised pregnancies the fetus will require one or more intrauterine blood transfusions. At present RhD HDFN causes about 37 fetal and neonatal deaths each year in the UK and around same number babies are born with developmental problems caused by HDFN
Level of information continues
All human plasma use in the manufacture of anti-D immunoglobulin is screened for viruses known to be transmitted by blood. Anti-D immunoglobulin is only manufactured from plasma donated in countries outside the UK. This is to minimise any potential risk of vCJD. The risk of viral transmission by anti-D immunoglobulin is considered to be exceptionally low
Transmission of Hep C via contaminated anti-D immunoglobulin is known to have occurred in the Republic of Ireland and in Germany between 1977 and 1979 prior to the introduction of hep c screening of blood donors and following intravenous administration of the product
Level of information 3
Severe allergic reactions caused by anti-D immunoglobulin are rare
Paternal RhD blood group testing is not usually offered routinely but if requested must be determined by formal lab tests
If father is RhD negative all babies born to couple will be RhD- and woman cannot become sensitised to the RhD antigen. Sensitive counselling may be required to establish that women is certain of identity of this babies father prior to paternal RhD blood group testing
Sensitisation is only likely to impact on future pregnancy women who seem certain that this will be their last pregnancy should be counselled on the risk should an unplanned pregnancy occur
For those who will be sterilised at birth or soon afterwards anti-D immunoglobulin is of no benefit
Ordering and administration of anti-D
Anti-D immunoglobulin is given as a standard dose
It’s requested from blood bank on a named patient basis
To request anti-D you must send a pink transfusion request form and tick the box for anti-D
If the request is urgent hand the form to biomedical scientist and state that its urgent and patient is waiting and they’ll issue anti-d soon as
Before administering anti-D it’s imperative to ensure the women has been confirmed as RhD-
Anti-D made from human plasma and is subject to same ID checks and stringent documentation that are applied to the administration of other blood products
In order to be effective it must be given as intramuscular injection
Late administration, omission or administration of anti-D to wrong patient must all be reported via DATIX and the SHOT reporting system
Management continued
Decline RAADP
Some women may not accept RAADP:
-personal choice
-women who choose to be sterilised following delivery
-women sure that father is RhD negative
-where women is sure she wont have another child
Difficult for women to be certain about these factors and the decision to decline should only be made after careful consideration and counselling
Adverse reactions and drug interactions
As with any blood product occasional undesirable effects may occur all adverse effect must be recorded and the patients GP informed
If anti-D given in community setting it’s recommended that where practicable the woman should be observed for 20 mins after admin
Passively acquired antibody (present in anti-D preparation) can interfere with the maternal responses to live virus vaccines such as MMR
Live vaccines such as MMR should not be given within 3 months of injection
In postpartum period MMR may be given with anti-D provided that separate syringes are used and products are administered to separate limbs
If not given simultaneously MMR given 3 months after
Notes 2
Any muscle can be used for administration , care when injecting gluteal area and to women with higher BMI to ensure its intramuscular not subcutaneous
Muscle more vascular so it’s absorbed more effectively
Record must include:
-first and last name women, DOB, unique ID/hospital number and whether consent was given
-name of product, dose, batch number, route, site , time and date of admin
-name and signature of staff who administered it
Accurate documentation important to enable clinicians to plan future treatment. It also allow s lab staff to accurately interpret test results to help determine whether any anti-D present is passive or active
Adverse events relating to anti-D administration
SHOT (serious hazards of transfusion) advise that improving HCP knowledge and understanding of guidance on anti-D immunoglobulin is key to changing practise and improving patient outcomes
SHOT data shows a steady increase over the last 10 years in reported incidence involving anti-D immunoglobulin administration
There is evidence to suggest that poor compliance with guidelines for anti-D immunoglobulin administration is a contributing factor to maternal sensitisation in the UK
Evidence shows a consistent failure to recognise potentially sensitising events in pregnancy and a failure to manage them appropriately when they do occur
For RAADP to be effective it must be administered in the third trimester of pregnancy
The fetal period
Growth and physiological maturation of the structures created during the embryonic period
Period involving preparation for the transition to independent life after birth
From fertilisation to birth
Preembryonic period- 1-2 weeks
Embryonic period- 3-8 weeks
Fetal period 9 to 38 weeks
Pregnancy weeks calculated from date of LMP. I.e conception weeks +2 so term is pregnancy 40 weeks
Respiratory system
The lungs develop relatively late
Embryonic development creates only the bronchopulmonary tree
Functional specialisation occurs in the fetal period
Important implications for pre term survival
Lung development in the foetal period
Weeks 8-16: pseudoglandular stage bronchioles
Weeks 16-26: canalicular stage respiratory bronchioles
Weeks 26-term: terminal sac stage. Alveoli type I and type II cells. Surfactant
The lungs during T2 and T3
Gas exchange conducted at placenta but lungs must be prepared to assume full burden at birth
“Breathing” movements: conditioning of the respiratory musculature
Fluid filled: crucial for normal lung development
Respiratory distress syndrome
Often affects infants born prematurely
Insufficient surfactant production
If preterm delivery is unavoidable or inevitable
-glucocorticoid treatment (of the mother)
-increases surfactant production in fetus
Developmental disorders/birth defects
Present at birth
Structural/functioal/metabolic
Wide range of causes
Single gene defects, chromosomal, polygenic, teratogenic, unknown
Teratogens
Congenital infection: TORCH, rubella, Zika virus, CMV
Drugs and environmental pollutants/insecticides
-vit A, pesticides, medications (sodium valproate for epilepsy), alcohol, recreational drugs
Maternal metabolic disease. DM
Radiation exposure
Classify by timing
Preembryonic (pre wk2): lethal or no effect
Early effects (2-4 weeks): scattered pattern
Later effects (4-8 weeks): localised defect
Fetal period (>9weeks): organ growth and functional maturation affected)
Terminology congenital anomalies occur when normal development is disrupted
Deformation: late changes in previously normal structures (mechanical effect) eg talipes
Disruption: secondary disturbance due to early influence of external factors eg amniotic bands
Sequence: primary defect leads to a cascade of further anomalies eg potter sequence
Malformation: primary disturbance of embryogenesis
Antenatal screening and diagnostic tests
Screening:
-Noninvasive
-Blood tests and obstetric ultrasound scanning
Chance of condition
Diagnostic:
-invasive
-amniocentesis/chorionic villus sampling CVS
Definitive result
Combined test and quadruple test
Combined:
-needs to be done before 14 weeks
-maternal age + nuchal translucency (measure amount fluid in nuchal fold)+serum free betahCG and PAPP-A
-reports chance of T21 and T18/T13
Quadruple:
-maternal age, betahCG, unconjugated E3, inhibin A and AFP
-tests for T21 only
Non invasive prenatal test NIPT
Fetal DNA fragments extracted from maternal plasma
DNA technology sequences the fragments and mapped to the genome
Number of reads from the chromosomes of interest undergo statistical analysis
Genetics
Single gene: mutation, deletion
Chromosomes: translocation, duplications, microdeletions
Trisomy 21
Non-disjunction 94%: at meiosis so at fertilisation true aneuploidy trisomy 21. One embryo not viable no chromosomes because of the non disjunction at meiosis
Robertsonian translocation 5%: bit of 21 on 14 , some offspring not viable, some translocation carrier, some translocation Down’s syndrome (2 chromosome21 , chromosme 14 and chromosome 21+14)
Di George syndrome
Deletion of a section of chromosome 22, 22q11.2
Characterised by a range of anomalies involving a range of structures
-craniofacial and pharyngeal region
Includes failure of development of 3rd and 4th pharyngeal (branchial) pouches during embryonic development
CHARGE syndrome
CHD7 (chromodomain helicase DNA-binding domain, ATP dependent chromatin remodeller)
CHARGE syndrome: CHD7 heterozygous mutation
CHD7 expression essential for the production of Multipotent neural crest cells
-coloboma: part eye tissue missing
-heart defects
-choanal atresia- nasal choanae occluded
-growth and developmental retardation
-genital hypoplasia
-ear defects
20 week screening scan
Screening for 11 conditions that
-benefit from treatment before or after birth
-need treatment in a specialist setting after birth
-could mean the baby may die shortly after birth
-lead to a discussion about pregnancy options
Assessment of craniofacial development, femur, spine and abdominal circumference plus cardiac development
Spina bifida and anencephaly
The CNS is derived from the neural tube
The neural tube fuses along its length
Defects in closure of the neuropores underlie serious and common birth defects of the central nervous system
Caudal NT defect results in spina bifida
Cranial NT defect results in anencephaly
Spina bifida
Can occur anywhere along the length most common in lumbosacral region
Neurological defects can occur
Hydrocephalus nearly always occurs
Multifactorial:
-genetic, environmental, maternal, nutritional status
-folic acid supplementation prevents NTDs
Meningocele and myelomeningocele
Cleft lip and palate
Difficulty feeding
Hearing problems
Dental problems
Speech problems
Can be an isolated finding but often associated with trisomies 13 and 18 (and often rarer symptoms)
Development of nose and upper lip
3 different tissue types
Maxillary prominences grow medially pushing the nasal prominences closer together in the midline
Maxillary prominences fuse with medial nasal prominences
Medial nasal prominences then fuse in midline
Cleft lip and palates
Primary palate: intermaxillary segment
Secondary palate: palatal shelves
Lateral cleft lip- primary palate
Cleft lip and palate- 1 and 2 palates
Gastroschisis
Anterior body wall closure defect, lateral to umbilicus
Normal development of GIT
Incidence increasing
Associated with younger mothers, smoking and recreational drug use
Omphalocoele
Persistence of physiological herniation of midgut
Normal developmental process doesn’t complete, not normal development GIT
Commonly associated with other abnormalities
20% chromosomal abnormalities eg Edward’s T18
Congenital heart defects
Occur when there is a structural defect of the chambers, great vessels. Theres an obstruction, there’s a communication between pulmonary and systemic circulation
Additional complexity in embryonic development due to the differing circulatory needs of the fetus as compared to the newborn (mature)
Congenital heart defects are the most common birth defect
Often associated with chromsomal abnormalities
Worldwide incidence 1%
90% survival to adulthood
Compared to just 20% in the 1950s
Importance of congenital anomaly
Affect 3% liveborn infants
Causing perinatal and neonatal death and disability
Lifelong impact to child/family
-20-30% admissions to tertiary care emotional and physical wellbeing financial cost
Prevention
Removal of risk factors and addition of protective factors
Good diet and nutrition
-folic acid/iodine supplementation
Avoidance of teratogenic drugs/substances/agents
Vaccinations. Rubella
Screening for infections eg syphilis
Maternal age- increased age a significant risk factor
Urinary system
Fetal kidney function begins in week 10
Fetal urine is a major contributor to amniotic fluid volume
Fetal kidney function is not necessary for survival in utero but without it there is oligohydramnios
Amniotic fluid is important for stimulating lung development
Importance of amniotic fluid volume
Oligohydramnios- too little, placental insufficiency, fetal renal impairment, abnormality
Polyhydramnios- too much, fetal abnormality eg inability to swallow
Nervous system
Nervous system is first to begin development and last to finish
Corticospinal tracts required for coordinated voluntary movement begin to form in the 4th month
Myelination of brain only begins in 9th month
-eg corticospinal tract myelination incomplete at birth as evidence by increasing infant mortality in the 1st year
Sensory and motor systems
No movement until 8th week
Thereafter a large repertoire of movements develop
“Practising” for post natal life suckling, breathing
Implications “quickening”
Maternal awareness of fetal movements from 17 weeks onwards
Low cost, simple method of antepartum fetal surveillance
Development of lungs and brain
9 weeks: lungs begin functional adaptation
16 weeks: cerebellar development, corticospinal tracts begin to form
20 weeks: myelination begins in spinal cords
24 weeks: terminal air sacs appears; some surfactant production
28 weeks: characteristic gyri and sulci appear as cerebellar hemispheres grow larger than skull
36 weeks: greatly increased surfactant production, myelination begins in brain
Deformation
Talipes: club foot
Congenital hip dislocation
Disruption
Amniotic bands- strips of amniotic membrane
Poland anomaly- absent pectoral muscle interruption of the subclavian artery
Sequence
Potter sequence:
-bilateral renal agenesis or bilateral multicystic dysplastic kidneys
-reduced fetal urine excretion
-oligohydramnios causing fetal compression
Potter facies: low set ears, beaked nose, prominent epicanthic folds and downward slant to eyes, pulmonary hypoplasia causing respiratory failure, limb deformities
Pierre robin sequence:
-mechanical theory
-begins with mandibular hypoplasia
-tongue cannot drop
-impacts on development of palate
Fetal alcohol syndrome
There is no known safe level of alcohol consumption during pregnancy
Facial Skeleton derived from neural crest cells populating the pharyngeal arches
Neural crest migration as well as development of the brain are known to be extremely sensitive to alcohol
Incidence of FAS and alcohol related neuro developmental delay= 1/100 births
Features: small head, low nasal bridge, epicanthal folds, small eye openings, flat midface, short nose, thin upper lip, smooth philtrum, underdeveloped Jaw
Congenital rubella syndrome
Infection of the fetus with rubella virus
Viral infection affects development of organs of special senses, heart plus a range of others
Microcephaly, patent ductus arteriosud PDA, cataracts
Normal growth
Three phases of fetal growth and development:
-first: 4-20 weeks: increases in fetal weight, protein content and DNA content (cellular hyperplasia)
-second: 20-28 weeks: increased in protein and weight and lesser increases in fetal DNA content (hyperplasia and concomitant hypertrophy)
-Third: 28 weeks to term: continued increases in fetal protein and weight but no increase in DNA (hypertrophy)
Fetal growth- definitions
Fetal growth restrictions (FGR)
-failure of a fetus to achieve his or her growth potential
Small for gestational age (SGA)
-birth weight <10th centile for gestational age
-centiles are based on local populations
-can be adjusted for sex, parity, race, maternal weight and height
Large for gestational age LGA:
-birth weight >90th centile
Low birth weight LBW:
-birth weight less than a certain threshold eg 2500g
Neonatal indices:
-ponderal index, skin fold thickness, MAC/HC ratio
Fetal growth restrictions- consequences
3-10% all births
Significant cause of perinatal mortality and morbidity
-still birth or neonatal death within 7 days birth
85% of unexplained stillbirths may be due to FGR
LBW infants are more likely:
-to die within first year of life
-suffer from neonatal problems (birth asphyxia, hypoglycaemia, hypothermia)
-fetal origin of adult disease
Fetal programming “barker hypothesis”
Most show catch-up growth in childhood though may have smaller size in adulthood
However IUGR can have lifelong impact
Evidence to suggest curves are u shaped
Babies born to GDM mothers in adulthood are at increased risk of IGT, diabetes and obesity
Early exposure to increased insulin levels leads to metabolic and epigenetic differences
Fetal programming 2
Good evidence that increased risk in adult life of:
-obesity
-type 2 diabetes
-BP, stroke, heart disease
-secondary to changes in growth, metabolism and vasculature
-however postnatal factors are also important
Due to “thrifty phenotype” programming:
-evolved to offer advantage in a “famine environment” but problems in industrialised society
Intergenerational effects
Mothers who were small for gestational age SGA themselves are more likely to have
-SGA babies
-increase perinatal mortality
Rodent models:
-maternal undernutrition F0 increase adiposity, glucose intolerance and cardiovascular risk in F1 and F2 generations
-after undernutrition for 12 generations, takes 3 generations of normal diet to restore normal foetal growth and development
Mechanisms for transgenerational effects
Epigenetics: heritable changes in gene expression by mechanisms other than underlying DNA sequences
-DNA methylation
-histone modification
-micro RNA
Maternal mitochondria: food restriction can alter number and function. Directly passed onto to offspring through ova
LGA definition and causes
Definitions:
-large for gestational age (LGA) birth weight >90th centile
-macrosomia -birth weight>4500g
Causes:
-gestational age: pregnancies that go beyond 40 weeks increase incidence
-Fetal sex; male infants tend to weigh more than female
-excessive maternal weight gain and obesity
-multiparity (have 2-3x vs primaparas)
-erythroblastosis fetalis -hydrops fetalis
-genetic disorder of overgrowth (eg Beckwith-Wiedemann syndrome, Sotos syndrome)
-maternal diabetes (pre existing or gestational)
Pathophysiology:
-increased maternal glucose concentrations
-increased fetal insulin concentrations
-increased fetal growth factors
Growth regulation
Genetic and environmental
Environmental complex with multiple levels:
-maternal
-fetal
-placental
Successful placentation required for regulation
Placental and fetal growth regulated by combination of substrate availability and endocrine or paracrine signalling
-IGF1 and IGF2 major stimulus
Maternal factors
Ethnicity
Maternal stature/BMI
-maternal v paternal influence
Drugs
-cigarettes, alcohol, drugs of abuse
Nutrition
Maternal hypoxia
-cyanotic heart disease, chronic respiratory disease, altitude
Maternal undernutrition
Dutch famine 1940s
-late gestation —> decreased birthweight (started pregnancy at normal nutritional status)
-early gestation—> not growth restricted
But prenatal programming: when these babies become adults they are more likely to deliver growth restricted babies
Developing world- IUGR major cause of perinatal mortality/morbidity:
-maternal undernutrition
-synergistic with low age, maternal anaemia, chronic disease/HIV and placental malaria
Fetal factors
Genome
-chromosomal disorders
Growth factors:
-insulin like growth factors, thyroxine
Congenital infection: cytomegalovirus CMV, toxoplasmosis, rubella
Placental factors
Primary placental problems
-abnormality of placenta structure/function
Secondary placental problems:
-hypertension, chronic renal disease, vasculitis, pro-thrombotic disorders
Multiple gestation: growth discordance less SA available for growth
Malplacentation in IUGR
Majority of blood flow to uterus is supplied by uterine arteries (supplying Arcuate and spinal arteries)
Shape of uterine artery waveform is unique and changes with gestation: early-high vascular impedance and low flow. Mid- high flow low resistance
Poor trophoblast invasion of maternal spiral arteries:
-increased impedance to flow and decreased placental perfusion
-change in Doppler indices- diastolic notch etc
Preeclampsia
Asymmetrical v symmetrical patterns of IUGR
Asymmetrical:
-uteroplacental insufficiency- decreased glycogen stores so decreased abdominal circumference
Symmetrical:
-early growth insult, chromosomal viral infection-disrupted regulation of growth processes or disruption at cell hyperplasia stage
Patterns are seen but generally not helpful in predicting cause or outcome thus need to distinguish between small and healthy- small and not well IUGR
IUGR is a combination of reducing growth velocity and placental insufficiency (abnormal uterine and/or raised umbilical artery PI)
How do we manage foetal growth clinically
Antenatal visit
Fetal growth assessment: symphsio-fundal height
Ultrasound: fetal head circumference, abdominal circumference, femur length
Fetal wellbeing assessment:
-short term wellbeing- cardiotocograph CTG foetal HR
-long term wellbeing- resistance to flow in arteries. Umbilical artery Doppler, middle cerebral artery Doppler, ductus venosus Doppler, liquor volume
Risk factors for SGA
History:
-age, parity, BMI, maternal substance exposure, exercise, weight gain, diet, SGA, hypertension, diabetes, renal disease
Current pregnancy:
-threatened miscarriage, fetal anomaly, pre eclampsia, pregnancy induced hypertension, placental abruption
Monitoring babies that have estimated foetal weight <10th centile
Monitoring throughout pregnancy with umbilical artery Doppler and if they are <10th centile with normal umbilical artery Dopplers then push to have delivery at term
If evidence of increased flow in umbilical artery Doppler then they are monitored more frequently to try and deliver at 37 weeks
More significant abnormalities in umbilical artery Doppler eg have absence or reversed end diastolic flow then frequency of monitoring is increased and monitored closely with intent to deliver at 30-32 weeks
Gestational diabetes
GDM is defined as any degree of glucose intolerance with its onset (or first recognition) during pregnancy
5% pregnancies
Pre-existing risk: pancreatic Beta cell dysfunction (deficient insulin production) on background chronic insulin resistance (deficient receptors/altered insulin signalling pathway) present before pregnancy
Pregnancy is a state of insulin resistance- hormonal, inflammatory, cytokines, adipokines changes (eg hPL, TNFa, resistin and others). Resistance increases with advancing gestation
Screening
Screen from early pregnancy 16-18 weeks if:
-past history of GDM or glucose intolerance
Screen from 24-26 weeks if:
-family history of diabetes (first degree relative)
-PCOS
-BMI>30
-ethnicity:Asian, black, Middle Eastern
-previous macrosomia >4500g
-previous unexplained stillbirth
-on steroids (eg prednisolone)
Screen urgently if arises in current pregnancy:
-significant glycosuria (3+ at any time or 2+ on two or more occasions)
-polyhydramnios and macrosomia
Screen via:
-OGTT (overnight fast then 75g glucose load, test at 2 hrs)
-random blood glucose profile >36 weeks
Complications of GDM- maternal
Pre eclampsia
Pre term labour
Instrumental delivery- C section
Diabetes in later life
Complications- foetal
Macrosomia
Shoulder dystocia: anterior foetal shoulder stuck on maternal pubic symphysis delaying birth compromised blood flow to heart
Polyhydramnios
Perinatal mortality and morbidity:
-neonatal hypoglycaemia, jaundice, polycythemia, hypocalcaemia
Fetal programming and increased risks of adult diseases
Management GDM
Multidisciplinary:
-obstetrician
-diabetologist
-diabetic nurse
-dietician
Regular monitoring and strict control:
-blood sugars up to 7 times a day
Medical management:
-diet
-oral agents eg metformin
-insulin
Tight glucose control reduces risk of
Obstetric management GDM
Regular growth scans
Regular BM monitoring
Deliver around 38 weeks- placenta wont work as well for as long
Offer GTT 6 weeks postnatal: glucose tolerance test assess future risk diabetes
