Antenatal

Question 1

Drugs and substance use in pregnancy

Answer 1

Drug exposure accounts for 2-3% of birth defects

Normal physiological changes in pregnancy change pharmacokinetics of drugs

• Increase plasma volume
• Reduced gastric emptying
• Increased eGFR
• Increased body fat for lipophilic drugs

Most defects occur in embryonic period (2-8 weeks post conception)

MEDICATIONS:

• Antiepileptics - associated with NTD, oral clefts, cardiac anomalies, urinary tract malformations (carbemazepine or lamotrigine preferred, not valproate or phenytoin)
• ACE-I - cardiac and CNS abnormalities, disrupt fetal renal system
• NSAIDs - 80% risk of miscarriage, premature closure of ductus arteriosus, risk of NEC
• Antibiotics - avoid tetracyclines (doxycycline), quinolones (ciprofloxacin), trimethprim
• Antivirals - avoid ribavirin
• Psych meds - antidepressants safe, lithium associated with Ebstein’s anomaly, neonatal goitre and hypothyroidism
• Thyroid - usually use PTU in 1st trimester then carbimazole after
• Anticoagulants - heparin does not cross placenta so preferred

SUBSTANCE USE:

Antenatal

• Identify drugs and length of use
• Screen for HIV, hep B, hep C
• Urine drug test
• MDT - dietician, D&A, social work, paeds
• Morph scan +/- growth US

Intrapartum:

• Continuous CTG
• IVC
• Alert paeds

Postpartum:

• Observe for withdrawal in baby
• Encourage breastfeeding unless HIV pos
• Contraception

Complications:

• Miscarriage
• IUGR
• Anomalies
• Stillbirth
• Preterm birth
• Perinatal infections - hepatitis, HIV, syphillus
• Withdrawal in neonate
• Longterm effects on neurodevelopment and growth

ALCOHOL:

• No known safe amount
• Fetal: fetal alcohol syndrome disorder (includes FAS), stillbirth, miscarriage, neonatal withdrawal
• Maternal: poor nutrition, other drug use, domestic violence, withdrawal, violent behaviour, reduce fertility in men and women
• Fetal alcohol syndrome (FAS) - intellectual disability, dysmorphic facial features, growth impairment, CNS abnormalities, behavioural issues, poor memory, impaired language, poor impulse control, social delays
• Prevent with education/awareness, screening with 5 A’s (ask, assess, advise, assist, arrange), discuss other drug use/smoking/DV/psych issues
• AUDIT-C (alcohol use disorders identification test - consumption) - 3 questions to estimate alcohol use
• T-ace (tolerance, annoyance, cut down, eye-opener)
• Alcohol enters breastmilk and stays for a few hours

SMOKING:

• 17% in pregnancy
• Fetal: miscarriage, ectopic, stillbirth, IUGR, abruption, preterm birth, PPROM, cardiac/MSK/GIT anomalies, praevia
• Maternal: VTE, respiratory issues, anaesthetic issues, PET
• Child: SIDS, asthma, learning difficulties
• Treat with education, CBT, quitline, NRT (intermittent use > continuous use patches)
• Even if ceased in pregnancy, 50-70% restart postpartum

AMPHETAMINES & COCAINE:

• Fetal: miscarriage, IUGR, stillbirth, preterm, abruption, neonatal withdrawal
• Maternal: PET
• Need growth US and monitor BP

CANNABIS:

• Commonest ilicit drug in pregnancy
• Not teratogenic but causes neonatal withdrawal with irritability, jittery

HEROIN & METHADONE:

• Can develop neonatal abstinence syndrome in baby with withdrawal (methadone > heroin) - CNS hyperritability, GIT disturbance; resolve in a few days; supportive care and opioids
• Fetal: miscarriage, IUGR, stillbirth, preterm, abruption, neonatal withdrawal
• Maternal: PET
• Child: SIDS

RANZCOG: substance use in pregnancy and smoking in pregnancy

Question 2

Prenatal testing and carrier screening

Answer 2

All women should be offered aneuploidy screening in early pregnancy and have option of invasive diagnostic testing (once aware of risks, benefits, costs, limitations)

Risk factors:

• Age
• Previous Hx or FHx of trisomy

During counselling:

• Voluntary to screen
• Description of the conditions screened for
• Explain the difference between screening and diagnostic test
• Types of screening and diagnostic tests including sensitivity for trisomies
• Specific gestation for each screening test
• Consequences of prenatal screening
• Costs
• Risks of diagnostic testing
• If trisomy high risk, information about diagnostic testing, the condition itself, prognosis, abnormalities, option of TOP
• Offer genetics counselling if high risk
• Risk of fetal demise with T18 (highest) then T13 then T21

Diagnostic screening if:

• High risk screening test - can offer cfDNA test or straight to diagnostic test; no need to repeat biochemical marker screening
• Previous trisomy
• One major or two minor structural anomalies
• Known parental chromosomal issue

SCREENING TESTS
cFTS:
- US + biomarkers (PAPP-A, bhCG)
- 11-13+6 weeks
- Singletons: 85% sensitivity, 95% specificity, 7-10% PPV, 5% false positive rate
- Twins: similar sensitivity, but higher false positive rate of 9%; perform separate NT for each twin but biomarkers are for overall pregnancy not each twin
- Recommended for twins and higher order pregnancies with nasal bone assessment and NT

Second trimester maternal serum screening:

• 14-20+6wks
• AFP + free bHCG + unconjugated estriol +/- inhibin A
• Combine with age, weight and gestation to give result
• But no ultrasound and is later in pregnancy
• 70-75% sensitivity, 93% specificity, 2-3% PPV

Cell free DNA:

• > 10wks for adequate fetal fraction
• Detection rate 99% for T21
• 99% sensitivity, 99% specificity, 45% PPV
• Low false positive rate but can be due to mosaicism, demised co-twin, large maternal copy variants, maternal malignancy
• Higher failure rate in twins
• Still recommend US in 1st trimester, but do not need serum markers (bHCG + AFP) as it increases false positive rate but not detection rate
• Expensive (no rebate)
• If unable to provide result (1-6% of cases) do ultrasound, repeat test (successful 50%), offer alternative screening or offer diagnostic testing
• Factors affecting result = obesity, twins or higher order multiples, fetal anomaly, ART, maternal organ transplants, women on biological treatment, placental mosaicism, maternal mosaicism, enoxaparin
• Can detect 22q11.2 deletion (DiGeorge syndrome)

DIAGNOSTIC TESTS
- CVS - 1st trimester, from 11wks, if done before risk of transverse limb reduction defects
- Amniocentesis - 2nd trimester >15wks, if done <14wks risk of talipes
- Can use FISH (only detects 13,18,21,X, Y aneuploidies) or QF-PCR (faster) or CMA (can find deletions or duplications) or karyotype (all 46 chromosomes)
- Recommend prior to definitive management (e.g. TOP)
- Miscarriage quoted 0.5-1% but with experienced operators, as low as 1 in 900, twins is 1%
- Risks: miscarriage, PPROM, preterm birth, infection, bleeding, sample failure, bloodstained sample, if serology positive transmission of infection
(higher with high viral load)

T21:

• Risk 1:300 age 35, 1:100 age 40
• Risk of cardiac anomalies (ASD, PDA, VSD, TOF, AVSD) , duodenal atresia, duodenal stenosis, imperforate anus, tracheo-oesophageal fistula, Hirschsprung disease, intellectual impairment, dysmorphic features, behavioural and psychiatric disorders, seizures

CARRIER SCREENING

• For those without known history - refer to genetics if known or suspected genetic disorder
• All women should be offered screening for thalassemia, CF, spinal muscular atrophy, fragile X
• Expanded carrier screening can be for many disorders (most autosomal recessive, some X linked or autosomal dominant) but varies between labs
• Need to be for conditions that have well defined genotype/phenotype, childhood onset, high carrier frequency, cause cognitive disability, need surgical/medical intervention, poor quality of life or prenatal diagnosis could lead to prenatal intervention to optimise outcomes - not to screen to extremely rare or adult onset conditions
• Usually test female first and if carrier, test partner rather than test both simultaneously
• Can do expanded carrier screening for other conditions (not those above)
• Adv of expanded carrier screening = identify carriers regardless of race/ethinicity and screen for many disorders in a single test
• Disadv of expanded carrier screening = cost, no uniform process to screen, may not improve reproductive outcome, panels offered differ between labs, may find conditions with unknown significance
• Screen all women for thalassemia with FBC and HbEPG if low Hb/MCV or high risk population

CYSTIC FIBROSIS SCREENING

• Up to 1 in 35 can be carriers
• Offered to ALL couples regardless of history
• Higher risk if family history present, caucasian, Ashkenazi Jews; also if echogenic bowel or unable to see gallbladder at morph present
• Uses full genomic sequencing to identify CF mutations
• Can screen mother then if positive to screen partner (serial screening) or couple screening (screen both simultaneously, provides combined risk so will change if partners change, more expensive but more accurate and efficient)
• Adv of screening: identify condition, be educated and prepare for birth
• Disadv of screening: multiple mutations for CF, may not change whether to continue pregnancy, increased anxiety knowing they are carriers

FRAGILE X SCREENING

• Most common inherited cause of intellectual disability
• X linked recessive
• Males affected more than females
• FMR1 mutation causing CGG repeats- test with PCR and southern blot
• Screen in family Hx of fragile X, intellectual disability of unknown origin, POI, elevated FSH, FHx of movement disorders - these are females at increased risk of mutation
• Do not usually test males as if they have male child will be unaffected, if they have female child they will be carriers
• In females, risk of expansion of CGG mutation in offspring (not in males as not carried in sperm)
• If carrier, refer to genetics

OPTIONS FOR CARRIERS

• IVF + PGD
• Prenatal diagnostic testing (amnio/CVS)
• Newborn screening
• Donor egg or sperm
• Adoption
• Not having children

Resources:

• Uptodate
• RANZCOG guidelines
• RCOG guidelines

Question 3

Prenatal testing question

Answer 3

July 2014 – Question 2

A 28 year old G2P0 is seeing you at 12 weeks gestation for her first visit and asks for advice regarding prenatal chromosome testing. She had a termination for Trisomy 21 in her first pregnancy. She has no other relevant medical or family history.

a) What is her additional risk of Trisomy 21 in this pregnancy? (1 mark)
- 1% above baseline risk determined by maternal age; RR = 2.2

b) Explain the underlying principles of the currently available non-invasive prenatal tests (NIPT) used to detect Trisomy 21. (5 marks - NIPT uses cell-free fetal DNA of placental origin in maternal serum to screen for fetal aneuploidies
- Cell free DNA fragments released from trophoblast
- Comprise ~10% of the total cell-free DNA in maternal blood
- A portion of each DNA fragment (maternal and fetal) in maternal plasma is sequenced… each DNA sequence is mapped to a reference genome to determine its chromosome of origin… the number of fragments arising from each chromosome is counted
- If number of fragments for a particular chromosome is observed to be greater than expected -> suggests aneuploidy
- Blood test of maternal serum to look for fetal cells and abnormalities in these cells – cell free DNA
- Cannot get test result if fetal fraction <4%
- Needs to be >10wks gestation (less than this gestation is too early and not enough fetal cells)
- False results with placental or maternal mosaicism, malignancy, enoxaparin use, obesity, twins, fetal anomaly
- Screening test not diagnostic
- High sensitivity and specificity for T21 (>99% for each)
- Option for first trimester screening instead of cFTS
- However, would still recommend first trimester ultrasound to look for structural abnormalities but do not need to do biochemical serum screening (bHCG, PAPP-A)
- Expensive $450, out of pocket, not covered by medicare or private health insurance

c. Outline the benefits and limitations of NIPT compared with combined first trimester screening (FTS) in this woman.
i) Benefits (3 marks)
ii) Limitations (3 marks)

i) Benefits – can do after first trimester (>10wks), very high sensitivity and specificity for trisomy 21 more than cFTS, low false positive rate
ii) Limitations – expensive (not covered by medicare or private health insurance), 1-9% test failure rate commonly due to low fetal fracture, does not provide information on structural abnormalities/placental localisation/dating, still requires diagnostic test if high risk, cFTS screens for more conditions than NIPT

Following your counselling, she elects to have a prenatal diagnosis with chorionic villus sampling (CVS) instead of NIPT.

d. Discuss the risks associated with this test. (3 marks)
- Invasive testing of placenta to diagnose chromosomal anomaly
- Done from 11-14wks
- Risk of miscarriage, PPROM, bleeding, pain, infection, false result with placental mosaicism, cannot do after 14weeks (would recommend amniocentesis), not performed everywhere – need to find high risk tertiary centres, need anti D, failure to obtain sample, risk of vertical transmission of hep B/C/HIV, if done <11wks there is risk of transverse limb reduction defects

January 2020
Cystic Fibrosis

Patient has cousin with CF

a) Explain important factors for this couple; factors in history that increase suspicion for risk (2)
- Is it a first cousin
- Are parents related
- Other first degree relatives that are affected by CF
- History of parents having multiple infection, lung problems
- High risk background – Caucasian, Ashkenazi Jews

b) Explain inheritance of CF (2)
- Autosomal recessive inheritance
- Affected only if both recessive genes are inherited
- If both parents carriers, 25% risk of affected child and 50% risk of child being a carrier

c) 3 x advantages and disadvantages in this couple for couple screening vs. sequential screening (6 marks)
- Couple screening is screening both parents at the same time
- Sequential screening is screen one parent first (usually mother), and if they are a carrier then to screen other parent

Adv of couple screening:

• Efficient
• More accurate
• Less time consuming then screening one after another

Disadv of couple screening:

• Expensive
• If couple separates and have new partners, need to repeat screening
• May not be necessary if only one is carrier

Show both carriers and at risk to passing on

d) Options for her to be pregnant with non-affected child
- IVF + PGD
- Spontaneous pregnancy and have diagnostic testing during pregnancy with CVS or amniocentesis
- Test child after birth with newborn screening
- Donated ovum or sperm with IVF
- Adopted child
- Not have children