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F E T A L M E D I C I N E

N O T E S F O R M R C O G

Fetal Medicine Notes by Dr Alina Shirazi, MRCOG, FCPS, EFOG, MRCPi

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Fetal Abnormalities and Genetics Birth defects are common, with 2–3% of neonates having a major abnormality and up to 10% having minor abnormalities.

Fetal abnormalities and genetics table

Type Description

Malformation Resulting from inherent abnormality in early embryonic life, for example congenital heart disease

Disruption As a result of external pressure on the fetus, for example talipes in oligohydramnios

Deformation Abnormal developments as a result of external interference, for example teratogens, maternal infection or trauma, for example from amniotic bands

Dysplasia Resulting from abnormal tissue development, e.g. osteogenesis imperfecta.

Syndrome This refers to a collection of abnormalities whose pathogenesis is linked, for example Down syndrome resulting from a chromosomal abnormality,

Sequence A single defect can have a cascading effect on other defects, for example Potters sequence resulting from oligohydramnios, which then causes talipes, hip dislocation and lung hypoplasia


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Inheritance

Multifactorial Many common diseases and malformations show a familial tendency but do

not follow the simple Mendelian patterns of inheritance – these conditions are

said to be multifactorial in origin. They are more common than single gene or

chromosomal abnormalities and include cleft lip and palate, talipes, congenital

heart disease and neural tube defectsi.

Autosomal dominant inheritance In autosomal dominant conditions the trait is demonstrated in heterozygotes,

The offspring of an individual with an autosomal dominant condition has a one

in two (50%) chance of being affected.

Autosomal dominant conditions include:

Achondroplasia

Adult polycystic kidney disease

Ehlers-danlos syndrome

Familial adenomatous polyposis coli

Familial hypercholesterolemia

Gilbert's syndrome

Huntington's chorea

Von hippel-lindau disease

Marfan syndrome

Myotonic dystrophy

Neurofibromatosis types 1 and 2

Tuberous sclerosis

Von willebrand's disease

Breast/ovarian cancer susceptibility (brca1/brca2)


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Family tree

Autosomal dominant conditions affect both sexes equally and there can be transmission between the sexes in every combination: male-to-male, male-to-female, female-to-male and female-to-female.

Autosomal Recessive Inheritance Autosomal recessive conditions are only manifest as the full phenotype when

the individual is homozygous for the mutant allele. Individuals who are

heterozygous for the condition often show no features and are completely

healthy (carriers).


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Autosomal recessive conditions include:

Alkaptonuria

Α1-antitrypsin deficiency

Ataxia telangiectasia

Β-thalassaemia

Congenital adrenal hyperplasia

Cystic fibrosis

Dubin-johnson syndrome

Fanconi's anaemia

Galactosaemia

Glycogen storage diseases

Homocystinuria

Haemochromatosis

Oculocutaneous albinism

Phenylketonuria

Sickle cell anaemia

Spinal muscular atrophy

Tay-sachs disease

Wilson's disease.

Autosomal Recessive Family Tree Three possibilities

1. There is a one in four chance that both mutated alleles will be passed on, resulting in a homozygous and, therefore, affected individual

2. There is a one in four chance that both parents will pass on their normal alleles resulting in an unaffected individual

3. The final possibility is that one of the mutant alleles would be passed on and the other parent would pass on the normal allele. This could occur from either the maternal or paternal side, resulting in a one in two


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chance of the resulting offspring being a carrier similar to each of the parent.

Note that:

It is not possible to trace autosomal recessive conditions through the family tree in contrast to the family tree of autosomal dominant conditions.

In this example, only two siblings are affected

These conditions also affect males and females in equal proportions.

Sex-Linked Inheritance X-linked recessive conditions

X-linked dominant conditions

Y-linked conditions

X-linked recessive conditions

The mutant gene is carried on the X chromosome and the condition is usually only manifest in males. Healthy heterozygous females transmit the condition to one in two of their sons, and one in two of their daughters become carriers.


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X-linked recessive conditions include:

Becker muscular dystrophy

Duchenne's muscular dystrophy

Fabry's disease

Fragile X syndrome

Haemophilias A and B

Hunter's syndrome

Ocular albinism

Red–green colour blindness

Testicular feminisation syndrome

Wiskott-Aldrich's syndrome.

X-Linked Recessive Family Tree The disease is transmitted from healthy heterozygote female carriers to affected males, and from affected males to all their daughters who become obligate carriers.

Therefore, any male grandchildren of the affected male would be at risk.


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X-Linked Dominant Conditions X-linked dominant conditions are uncommon. The conditions are manifest in both male and heterozygote females.

The pattern of inheritance resembles that of an autosomal dominant condition with an important exception in that affected males transmit the condition to all their daughters but none of their sons.

Examples of this uncommon mode of inheritance are:

Vitamin D-resistant rickets

Incontinentia pigmenti

Rett syndrome

Y-Linked Conditions

There is little genetic information on the Y chromosome other than that for gender determination. One gene that codes for hairy ears has been identified on the Y chromosome.

This will be passed from a father to all of his sons, but to none of his daughters


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CHROMOSOMAL ABNORMALITIES:

Down syndrome/trisomy 21:

Down syndrome is a genetic disorder caused when abnormal cell division results in an extra full or partial copy of chromosome 21 total 47 chromosomes.

The overall incidence of Down syndrome is one in 700 live births. The incidence is higher at conception, but 60% of cases are miscarried

and 20% are stillborn. The incidence of Down syndrome increases with maternal age.

Genetics of Down Syndrome:

The majority (96%) of trisomy 21 arises from non-dysjunction in meiosis. This arises from the maternal cell line in 85% of cases and from the

father in 15% of cases. Two to three percent of cases arise from a parental balanced

translocation involving chromosome 21 or as a result of a de novo translocation.

The final 1% are mosaics


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Clinical Features:

This extra genetic material causes the developmental changes and physical features of Down syndrome

Complications

There is a significant chance of congenital heart disease in Down syndrome, with 40% of children being affected ( the most common is atrioventricular septal defects AVSD)

If an AVSD is diagnosed antenatally, the couple should be counselled about the chance of Down syndrome (which is in the order of 15%) and offered further investigation.

Other cardiac lesions can be associated with Down syndrome including

ventricular septal defects (VSD), and tetralogy of Fallot.

Other complications include duodenal atresia, cataracts (2%), epilepsy (10%), acute leukaemia (1%) and early-onset dementia (in 50% by the age of 50 years).


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Intellectual disability is another complication associated with people with Down syndrome. Children and adults with Down syndrome are now achieving far more than in the past.

Chance of Recurrence The chance of recurrence of trisomy 21 or other major chromosomal

abnormalities at birth is 0.56–0.75% above the background risk. This means that for a younger woman with previous baby down syndrome , this

has a significant impact on the chance of recurrence, whereas for an older woman this does not significantly increase her background chance.

Downs Syndrome Recurrence Risk Table.

Age Background risk

Additional chance of having had a child with Down syndrome

New risk

18 1:1500 (i.e. 0.067%)

0.56–0.75% 0.56–0.76%

41 1:100 (i.e. 1%) 0.56–0.75% 1.56–1.75%

Screening for Down Syndrome:

Combined test

Performed from 11–14 weeks of gestation: the combined test reviews nuchal translucency measurement human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein-A (PAPP-A). In Down Syndrome NT increase>35mm, PAPPA reduced and B-HCG increased.


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Non-invasive prenatal testing (NIPT)

Performed at approximately 10 weeks of gestation. At present NIPT is available on the NHS in England and Wales only, and not in Scotland.

This test analyses the cell-free fetal DNA (cffDNA) in maternal plasma and has an overall test accuracy for detection of T21, T13 and T18 of greater than 98%.

There are THREE possible results following NIPT for T21:

1. Positive: the fetus is predicted to be affected by Down syndrome. An invasive test should be offered to confirm the result

2. Negative: the fetus is highly unlikely to be affected by Down syndrome

3. Inconclusive: this occurs in up to 4% of cases. This is usually because the proportion of fetal DNA present in the sample is not high enough to give an accurate result. NIPT may be repeated with the hope that the cffDNA levels will increase with gestation.

The integrated test ( not a first line)

The „integrated test‟ is based on a nuchal translucency ultrasound scan measurement, together with two blood tests - one taken at 10 weeks and another at 15 weeks.

The serum integrated test – PAPP-A in first trimester with hCG, α-FP, uE3 and inhibin A in the second trimester (hCG reduced, α-FP reduced, uE3 reduced and inhibin levels elevated in Down syndrome)

Invasive testing Amniocentesis.

Amniocentesis is an invasive procedure that is carried out under ultrasound guidance and involves taking a sample of amniotic fluid using a fine needle, which is analysed by FISH, QF-PCR or culture and karyotype.

http://www.rcm.org.uk/news-views/rcm-opinion/rolling-out-nipt/


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The miscarriage rate with amniocentesis is 1% above that expected in women who had not undergone amniocentesis.

Chorionic villus sampling (CVS)

CVS involves taking a small placental biopsy and can be performed transabdominally or, less commonly, transvaginally.

This procedure is associated with a higher risk of miscarriage than amniocentesis but has the advantage that it can be performed earlier in pregnancy (after 10 completed weeks of gestation).

Edward syndrome/trisomy 18

Abnormality

Head Strawberry skull

Choroid plexus cysts

Enlarged cisterna magna

Face/neck Micrognathia

Low-set ears

Cleft lip and palate

Hands/feet Flexed/overlapping fingers

Rocker-bottom/club-foot

Heart VSD, AVSD, double outlet right ventricle


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The overall

incidence of Edward syndrome is one in 3000 live births. The incidence at conception is much higher, but 95% miscarry. Over 90% of fetuses have abnormalities detectable by ultrasound in the second trimester.

Trisomy 18 ultrasound and clinical features

The prognosis for children born with trisomy 18 is poor, with the majority of neonates dying within the first few days of life..

Genetics

Trisomy 18 usually results from maternal non-dysjunction (95%). More rarely, paternal non-dysjunction occurs (5%) and, occasionally, mosaicism is seen with a milder phenotype.

Abdomen Exomphalos

Thorax Diaphragmatic hernia

General Growth restriction

Polyhydramnios


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Chance of recurrence

The recurrence chance is approximately 0.75–1%.

Patau’s Syndrome/Trisomy 13 The overall birth incidence of Patau's syndrome is slightly less than that of Edward syndrome at about one in 5000. As with Edward syndrome and Down syndrome, there is an association with increasing maternal age.

Clinical features of trisomy 13

Trisomy 13 is associated with multiple complications and a very poor prognosis. Fifty percent of affected babies die within the first month of life, 75% within six months and less than 5% survive to one year of age. The main features of trisomy 13 that are detectable by mid-trimester screening are shown in the table below.

Abnormality

Head Holoprosencephaly

Agenesis of corpus callosum

Dandy-Walker syndrome

Face Cleft lip and palate

Hands/feet Polydactyly

Heart AVSD/VSD/hypoplastic left heart

Kidney Renal cysts/hydronephrosis

General Growth restriction


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Genetics

This usually reveals a straightforward trisomy. There is increasing incidence with maternal age. Approximately 10% of cases are due to mosaicism or unbalanced translocations.


The chance of recurrence is approximately 0.75–1% on top of incidence related to maternal age.


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Turner Syndrome (45, XO) This condition, which only affects women, is common at conception but the majority of affected fetuses miscarry, to give an incidence at birth of approximately 1:2500.

The condition can be suspected antenatally in the second trimester with the finding of oedema, which can be generalised (hydrops) or localised to the back of the fetal neck (cystic hygroma).

Genetics

The most common finding on chromosome analysis is 45XO. Other less common findings include mosaicism, e.g. 45XO/46XX. .

Clinical features:

Complications: There is associated congenital heart disease in up to 20% of cases – typically coarctation of the aorta and atrial septal defect.( Intelligence and lifespan are normal).

Risk of early ovarian failure


17 Treatment: Sex hormone therapy is used to allow development of secondary sexual characteristics and treatment with growth hormone also allows for an increase in the girl‟s final height by 3–5 cm. Women with Turner syndrome can have normal pregnancies following IVF using donor oocytes.


The chance of recurrence is not increased above the general population, so women with a previous affected pregnancy can be reassured and do not require any additional screening in subsequent pregnancies.

Kleinefelter’s Syndrome (47, XXY) The incidence of Kleinefelter‟s syndrome is relatively common, with one in 1000 males affected. The condition can be suspected in childhood in boys presenting with clumsiness or mild learning difficulties.

Genetics

The extra X chromosome is maternally derived usually so total is 47xxy chromosome.

physical characteristics:


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The IQ is approximately 10–20 points below unaffected siblings. Adults tend to be taller than average, with long lower limbs. It is the most common cause of

hypogonadism and infertility in men. 40% of affected men have gynaecomastia. The incidence of breast cancer in men with Kleinefelter's syndrome is similar to

that in women. Boys can be treated with testosterone therapy in adolescence, which improves

the secondary sexual characteristics but does not improve fertility.


This is not increased above the incidence in the general population.

Neural Tube Defects:

Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen

in the first month of pregnancy, often before a woman even knows that she is pregnant.

Types of NTDS


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Anencephaly: anencephaly is incompatible with life offer termination

Encephalocele treatment: Encephalocele is treated with surgery to place the

protruding part of the brain and the membranes covering it back into the skull and close

the opening in the skull. However, neurologic problems caused by the encephalocele

will still be present.

Consequences of spina bifida:

Weakness or total paralysis of the legs

Bowel incontinence and urinary incontinence

Loss of skin sensation in the legs and around the bottom – the child is unable to

feel hot or cold, which can lead to accidental injury

Many babies will have or develop hydrocephalus (a build-up of fluid on the brain),

which can further damage the brain.

Most people with spina bifida have normal intelligence, but some have learning

difficulties.

Causes of spina bifida

The cause of spina bifida is unknown, but a number of factors can increase the risk of a

baby developing the condition, including:

Low folic acid intake during pregnancy

Obesity

Having a family history of spina bifida

Medication – taking certain medications during pregnancy like anti-epileptics has

been linked to an increased risk of having a baby with spina bifida

Diagnosing spina bifida

Most cases of spina bifida are detected during the mid-pregnancy anomaly scan, which is

offered to all pregnant women between 18 and 21 weeks of pregnancy..

Treating spina bifida

Treatments for the symptoms or conditions associated with spina bifida include:

Surgery soon after birth to close the opening in the spine and treat

hydrocephalus

Therapies to help make day-to-day life easier and improve independence, such

as physiotherapy and occupational therapy

Assistive devices and mobility equipment, such as a wheelchair, or walking aids


20 Treatments for bowel and urinary problems.

Initial surgery to repair the spine in babies with spina bifida, nerves and

membranes can push out of an opening in the spine and form a sack. This

damages the nerves and can lead to serious infections, so your baby will usually

have surgery to repair the spine within 48 hours of birth.

Preventing spina bifida with folic acid:

The best way to prevent spina bifida is to take folic acid supplements before and during

pregnancy.

Every patient should take a 400 microgram folic acid tablet every day while you're trying

to get pregnant and until you're 12 weeks pregnant..

Recommendations for women at higher risk of spina bifida

Women thought to be at higher risk of having a child with spina bifida need to be

prescribed a higher (5 milligram) dose of folic acid by their GP.

Women at higher risk include those:

1. With a family history of neural tube defects

2. With a partner with a family history of neural tube defects

3. Who've had a previous pregnancy affected by a neural tube defect

4. With diabetes

5. With high BMI

Head and neck anomalies:

Cleft lip and palate Cleft lip and cleft palate are openings or splits in the upper lip, the roof of the mouth (palate) or both. Cleft lip and cleft palate result when facial structures that are developing in an unborn baby don't close completely. The incidence of cleft lip and palate is about 1 per 1000.


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More common in males than females – 2:1

The risk of recurrence is about 4% if a parent or previous child is affected

Associated with chromosomal abnormality – particularly if midline or bilateral

o Trisomy: 13–65% have facial clefting

o Triploidy: – 30% have facial clefting

Associated with genetic syndromes, particularly when other abnormalities are seen

Particularly difficult to diagnose isolated posterior cleft palate on ultrasound

If facial clefting is seen, you should determine whether it is midline, bilateral or unilateral

Check for other abnormalities

If midline, bilateral or other abnormalities present, then offer karyotype refer to fetal medicine unit

3d ultrasound is increasingly being utilised to allow better visualisation for parents prenatally

Hydrocephalus

Definition: Hydrocephalus is a condition in which excess cerebrospinal fluid (CSF) builds up within

the fluid-containing cavities or ventricles of the brain.

This increased size in the ventricles may be referred to as ventriculomegaly.

Ventriculomegaly occurs when the two lateral ventricles are greater than 10mm in width.

The ventricles can fill to such an extent that the fetus‟s head size becomes enlarged.

1. Mild hydrocephalus: Size of lateral ventricular diameter>10mm but < 12mm : 1%

risk of anomalies

2. Moderate hydrocephalus: Size of lateral ventricular diameter >12mm but < 15

mm : 25-30% risk of anomalies


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3. Severe hydrocephalus: size of lateral ventricular diameter >15mm: 50% risk of

anomalies

Types of hydrocephalus

Communicating Hydrocephalus: This type of hydrocephalus occurs when there is no obstruction to the flow of CSF within the ventricular system. The condition arises either due to inadequate absorption or due to an abnormal increase in the quantity of CSF produced.

Non-communication (Obstructive) Hydrocephalus: It occurs when the flow of CSF is blocked along one of more of the passages connecting the ventricles, causing enlargement of the pathways upstream of the block and leading to an increase in pressure within the skull.

Prenatal diagnosis of hydrocephalus

Ultrasound: Hydrocephalus usually diagnosed on a routine ultrasound. The ventricles

within the head will measure larger than normal. Fetal medicine unit expert will perform

a targeted ultrasound to examine the anatomy of the brain to confirm ventriculomegaly.

He or she will also look for any associated anomalies.

Amniocentesis: Hydrocephalus is occasionally associated with chromosomal

abnormalities. Your fetal medicine unit specialist will typically offer an amniocentesis to

look for chromosomal issues and fetal infections.

MRI: . Fetal MRI is a non-invasive diagnostic test that produces better images of soft

tissue, and bone or dense tissue does not interfere with the image. The biggest

limitation of fetal MRI is that the best images are obtained when the fetus stays still,

which can be difficult.


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Mode of delivery. The method of delivery will be determined by baby's head size and

his or her well-being at the time of labor and delivery, as with any pregnancy.

Hydrocephalus does not, by itself, necessitate a Caesarian section delivery.

Clinical Manifestation At Birth

Unusually large head size Rapidly increasing head circumference Bulging and tense fontanelle or soft spot Prominent scalp veins Downward deviation of eyes or sunset sign Vomiting Sleepiness Irritability Seizures

Post-natal treatment:

Hydrocephalus can be treated in a variety of ways. Based on the underlying etiology, the condition may be treated directly by removing the cause of CSF obstruction or indirectly by diverting the excess fluid.

Hydrocephalus is most commonly treated indirectly by implanting a device known as a “shunt” to divert the excess CSF away from the brain. The shunt is a flexible tube which, along with a catheter and a valve, is placed under the skin to drain excess CSF from a ventricle inside the brain to another body cavity such as the peritoneal cavity (the area surrounding the abdominal organs).

Once inserted, the shunt system usually remains in place for the duration of a patient's life.


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Anterior abdominal wall anomalies:

Hydrops Fetalis: Hydrops is the presence of excess fluid in more than one body cavity – subcutaneous oedema, pleural effusions, pericardial effusion or ascites. There may often be associated polyhydramnios.


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Hydrops may be due to a variety of causes:

Isoimmunisation from blood group antibodies

Chromosomal trisomy 21, turner syndrome xo, or other trisomies

Genetic causes

Infection – parvovirus b19, cytomegalovirus, syphilis, coxsackie

Anaemia – alpha thalassaemia, chronic fetomaternal haemorrhage

Cardiovascular – structural or tachyarrhthmias causing a rise in central venous pressure

Pulmonary, e.g. Cam lung, congenital diaphragmatic hernia

Cystic hygroma

Fetal akinesia

Treatment Of Hydrops

The treatment depends on the underlying diagnosis. Management options include:

Intrauterine transfusion can be offered for isoimmunisation and parvovirus infection – can have a good long-term prognosis

Syphilis – mother should be treated with high dose penicillin and the hydrops will gradually resolve

Coxsackie – may resolve spontaneously

Cmv – poor long term outlook in view of association with cns damage

Tachyarrhythmias can be treated with antiarrhythmic agents

Termination of pregnancy may also be offered as an option if the long term outlook is considered poor, if other abnormalities are seen or if an abnormal karyotype is found.


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Parvovirus B19 Infection:

Parvovirus is a virus that causes a common childhood illness, also called "fifth disease" or "erythema infectiosum." Fetal infection by parvovirus B19 is a common cause of fetal anemia, nonimmune hydrops fetalis, and spontaneous abortion, and it can result in fetal death.

Management: fetal medicine unit monitor parvovirus positive fetus with MCA-PSF and consider IUT if there are signs of hydrops in ultrasound or MSA-PSF >1.5 mom


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Fetal medical conditions:

Fetal hyperthyroidism Fetal hypothyroidism

Occur secondary to maternal Grave‟s disease due the passage of TRAbs which stimulate fetal thyroid from 20 weeks.

Features: fetal tachycardia, IUGR, accelerated bone maturation, cardiomegaly, cardiac failure and hydrops.

A large goiter can cause fetal neck hyperextension resulting in malpresentation.

Goiter cause esophageal compression which result in polyhyroamnios which is associated with preterm labour.

Result in neonatal thyrotoxicosis 2%

Management: ultrasound and color Doppler can detect hyper or hyperthyroidism in the fetus. Monthly ultrasound is recommended from 20 weeks to assess thyroid size ( fetal effect from 20 weeks)

Treatment: maternal administration of antithyroid drug (propylthiouracil is the drug of choice.

Iron deficiency is the leading cause. Fetal causes are: TSH receptor mutation, thyroid dyshormonogenesis and TSH receptor mutations. Maternal causes are maternal thyroid disease with thyroid autoantibodies (effect in 3rd trimester), anti-thyroid drugs and radioactive iodine( effect from 10-12 weeks).

Features: IUGR, goiter, reduced fetal movements, complete heart block, cardiomegaly and delayed skeletal maturation can occur.

Cause neonatal cretinism: a condition

characterized by physical deformity and learning difficulties that is caused by congenital thyroid deficiency.

Management: If due to maternal anti-thyroid medication then reduce dose with aim to keep maternal T4 level in upper normal limits. Ultrasound fortnightly to monitor size reduction. Intra- amniotic 200-500ug of t4 7-10 days is proposed regime (as transplacental fetal transfer of T4 in inadequate).

Cordocentesis is reserved for refractory cases.


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Congenital adrenal hyperplasiaii:

Congenital adrenal hyperplasia (CAH) is the most common cause of

ambiguous genitalia and is an autosomal recessive disorder. It occurs in

approximately 1 in 14000 births in the UK.

Pathogenesis: It is due to deficiency of 21- hydroxylase deficiency in which cholesterol

will not convert to cortisol and there will be androgenic excess which result in virilization of a female fetus( male will not affect), its severe form results in salt losing syndrome secondary to aldosterone deficiency.

The risk of effected fetus is ¼ and a virilized female fetus is 1/8.

Management:

Confirm female gender by CFFDNA in high risk patients at 6 weeks. And commence dexamethasone from 7 weeks after the confirmation of

a female fetus. Offer CVS at 11-12 weeks to identify an effected fetus, discontinue dexa

if fetus unaffected.

i StratOG 2020 ii Dewhurst‟s text book of obstetrics and gynecology

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