The goal of prenatal diagnosis to help parents learn what they need to know about the health of their unborn child, to help them make informed decisions for themselves and their family within the context of their own ethical value system. Obstetrician can use a wide variety of screening and diagnostic tests to assess health of a fetus to  manage the pregnancy, to determine potential outcomes, to plan for complications at birth, to decide whether to continue the pregnancy and to discover conditions that may impact future pregnancies. Use of non-judgmental,non-directive genetic counselling is important in helping families make the best choice for them. The obstetrician and geneticist have also to provide risk assessment for other family members. The decision to terminate or continue a pregnancy is based on prenatal diagnostic findings& is not an easy decision because we need to address ethical, Legal, Social issues.In last four decades availability of biochemical and sonography screening and explosion of laboratory techniques has revolutionized the approach altogether.

Complexity of genetic information has generated huge scope but frontline obstetrician or fetal medicine expert has no time to explain nuances of emerging science of prenatal diagnosis hence need for genetic counselor is more relevant in current scenario and it is observed that counselor some time know better than treating clinician about genetic disorders.

Ultimately benefit from prenatal diagnosis is observed in Advanced maternal age  (> 35 years) couple, Ethnicity at increased risk for genetic disease, known family history of genetic disease or multifactorial disorders, history of multiple pregnancy losses, exposure of teratogen  during early pregnancy, abnormal ultrasound findings, abnormal maternal serum screen results.

Obstetrician’s duty is to explain about types of birth defects such as structural defects, genetic syndromes, chromosomal disorder to the couple. Experience has shown that the care and prevention of birth defects is feasible and cost-effective and requires comprehensive approach about maternal and child health programs and also provision of basic medical genetic services to ensure that people with birth defects or at reproductive risk of having children with birth defects can reproduce as normally as possible.

Established prenatal diagnosis techniques are maternal serum screening tests, visualization of the fetus by Ultrasound (2D and 3D) and by fetoscopy,genetic and biochemical studies of fetal cells by chorionic villus sampling / amniocentesis/ fetal blood sample (percutaneous umbilical sample) / circulating fetal cells or cell free fetal DNA in maternal blood. Therefore obstetrician must familiarise to these prenatal diagnostic procedures to discharge his obligationin proper way. Therefore goal of healthy baby requires an integrated team approach involving the patient, obstetrician, genetic professional, genetic laboratory, fetal medicine specialists and pediatrician to ensure maximum options and appropriate care and that will create Positive impact on public health by reducing burden of abnormal children

Birth defect:

Birth defects are defined as abnormalities of structure or function, including metabolism, which are present from birth. Serious birth defects are life threatening or have the potential to result in disability which may be physical, intellectual, visual or hearing impairment or epilepsy. More than 7000different birth defects have been identified to date. Some birth defects are clinically obvious at birth and others may only be diagnosed later in life. The spina Bifida is one example of a structural defect that is obvious at birth whereas hemophilia is a functional defect usually not clinically obvious until infancy or childhood.

Challenges of Prenatal Diagnosis:

All couple want a healthy baby, but 2 - 3 % of children is born with a birth defect is universal fact. Two basic questions are required to be answered:

Can we offer prenatal diagnosis to all pregnant women?

  • 90%of structural and chromosomal abnormal fetus are born to “Low risk women”
  • Maternal age alone  is “poor screening tool”(detects ~ 30% of Down Syndrome cases)
  • “Acceptance& tolerance of genetic risk” differ between elderly primigravida&multigravida
  • Birthing trend in society (1-2 child Norm)
  • 1970 - ~5% birth to women over 35years
  • 1990 - ~10% birth to women over 35years
  • 2015 - ~15% birth to women over 35years

If Abnormality is detected by screening test then what?

 Further confirmatory testing required (CVS/Amniocentesis)

 Referral to tertiary care center

 Genetic counseling and altered obstetric management (MTP/NICU care)

 Preparation for special needs for neonatal or child management

Window of opportunities during Preconception period:

  • Balanced diet with adequate micronutrient and Folic acid 400 microgram (FIGO recommendation) + B12 + B6 combination  (for prevention of NTD & Hemocysteinaemia)
  • Rubella  status of woman and vaccination (for prevention of structural defects)
  • Torch panel (to know Toxoplasmosis and Rubella and Syphilis status )
  • Diabetes control is essential (HB1AC<6.0) (for prevention of structural defects)
  • Minimize or avoid Teratogenic drugs (Isotretinoin, Phenytoin, Thalidomide, Valproic acid, Streptomycin, Lithium)
  • Screening for abnormal hemaglobinopathies (Sickle cell, Thalassemia trait)
  • Ethnicity for increased risk for genetic disease (Pan ethnic screening program)
  • Review of past obstetric record (POC report in cases of RPL)
  • Educate the public about birth defects (what steps to be taken by couple to maximize the chances of a healthy pregnancy)

Problems with Pan ethnic program are required to be answered:

 Are public policies catching up with technological reality?

• Is there any connection between high risk and actual risk after screening?

 An Ashkenazi panel 1-3 tests in ‘1970’ has went up to 18 tests ‘currently’ as routine test offerings. Is it cost effective to offer screening for everything to everyone?

 Nowadays patient come in clinic tells us that they tested for everything. Is it true in real sense?

Window of opportunities in the ART/IVF clinic:

Maintenance of genomic integrity during gametogenesis, fertilization and embryo cleavage is essential for normal human embryogenesis.

Various ART Clinics scenario where opportunity arises:

 Male partner with severe oligospermia or obstructive azoospermia, there is role ofcyto-genetics & Y-microdeletion study and Molecular genetics.

 Female partner with unexplained low ovarian reserve may have Mosiac turner XX/XO andFragile X syndrome-FMR-1 mutation carrier status and that to be investigated.

 All Elderly couple (female >35 years) is usually asked to undergo first trimester screening.

 Donor of gemetes are screened for Pan Ethnic panel and infectious diseases as perICMR guidelines of India.

Pre-implantation genetic screening:

 Biopsy of embryos and molecular cytogenetic genetic analysis (spectral karyotyping) offered to couple having translocation, XXY problems, cystic fibrosis, Taysachs disease.

Window of opportunities during 1st month ofGestation:

Dating, Viability & Chorionicityscan (TVS):The purpose of the dating scan is to

 How many week pregnancy and to workout due date (EDD).

 Check whether twins or multiple pregnancy.

 Check for Intrauterine orExtrauterine pregnancy.

 Check for fetal development.

Give attention to multiple pregnancy especially monozygotic twins:

 ~3% of all birth is twin and ~1% are monozygotic in USA

 Risk of abnormal child is increased approximately twice in MZT than age related risk

 Diagnosing vanishing twin (Mosiacism on CVS kayotyping report create confusion)

Window of opportunities during 2nd month ofGestation:

Non-Invasive Prenatal screening with cell free fetal DNA (cffDNA) (NIPT test):

 1997, Introduction of  NIPT as routine antenatal care thus need for invasive diagnostic test for aneuploidy can be avoided

 Test prices for NIPT screening test is varied from $US 350 to $US 900.

 Presently high test prices limits or restricts widespread use of NIPT  

 In India, PC -PNDT ACT restricted use of this technique especially in Maharashtra state

Couple having family H/ocongenital anomalies (e.g. Retinitis Pigmentosa):

Importance of History taking & Pedigree chart

The incidence of primary RP is approximately 1 in 4000. To date, more than 70 different genetic defects have been identified.

Following are the defects:


 Autosomal recessive (~16%)

 Autosomal dominant (~22%)

 Remaining cases (~53%) are primary RP or RP simplex

Early referral to geneticist is of paramount importance to know inheritance pattern and advice for prenatal diagnosis.

Window of opportunities during 3rd month of Gestation:

· NT scan with nasal bone visualization between11-14 weeks

· Neuro-Sonogram or structural defect scanning

 Anencephaly (Frog eye appearance)

 Holoprosencephaly (Trisomy 13)

 Cystic hygroma, (abnormal outcome in ~86% of fetuses) (45XO, trisomy18)

 Distended bladder (Trisomy 18)

· Dual screening test (PAPP-A and free B-HCG levelin maternal serum)

· Opportunity to carryout CVS procedure (FISH/structural karyotyping)

· Fetal reduction offered for multiple pregnancy

· Send Product of conception if miscarriage forcytogenetic and FISH study to explain the cause for abortion to bereaved couple

Neuro-Sonogram (Anencephaly):

Anencephaly is the most severe form of cranial neural tube defect (NTD) and is characterised by absence of cortical tissue (brainstem and cerebellum may be variably present) as well as absence of the cranial vault.  Incidence is around 1:1000 and female predilection with a F:M of ~4:1. Anencephaly may be sonographically detectable as early as 11 weeks and has an accuracy of approximating 100%at 14 weeks. Anencephaly is incompatible with life. Folic acid therapy may reduce risk of recurrence. There is a slight risk ~2.5% in recurrence of a neural tube defect in future pregnancies.

Neuro-sonogram (Acrania):

Acrania isa rare congenital disorder that occurs in the human fetus in which the flat bones in the cranial vault are either completely or partially absent. The cerebral hemispheres develop completely but abnormally. The condition is frequently, though not always, associated with anencephaly. Fetalacrania can be diagnosed from 11 weeks onward. At 11–14 weeks gestation, no vault ossification is visible in the midline on a perfect mid-sagittal image.

Summary of First trimester opportunities:

95% of high risk & 80% of low risk women preferred first trimester screening. EarlyRisk Assessment between 11 and 14 weeks by sonography for structural defects (an abnormality of the formation of a specific organ or body part) such as:

 Hydrocephalus/anencephaly/acrania / Spina bifida

 Several kidney abnormalities

 Clubbed foot /Cleft lip / Various types of heart defects

Offering carrier testing based on ethnicity and to identify genetic syndromes prenatally by family history of both parents and by drawing pedigree chart to know type of pattern of inheritance.

 Autosomal dominant disorders ( Vertical pattern of inheritance)

 Autosomal recessive disorders  (Horizontal pattern of inheritance)

 X-linked disorders  (knights move pattern of inheritance)

Genetic abnormalities mostly results in miscarriage therefore POC study is useful for counseling.

App. half of recognized miscarriages are due to chromosome abnormalities of these 2% have unbalanced translocations. The balanced translocation carriers may be interested in fetal chromosome analysis by CVS procedure during future pregnancies (Gardner and Sutherland, 1996). Some abnormal fetus is carried to term & can have varying degrees of problems after birth such as Trisomy 21,13,18, X, Y, hence early diagnosis by CVS orNIPT is indicated in elderly female.The karyotypes may also reveal other structural chromosome abnormalities such as translocations, inversions, insertions, deletions or rings.

Window of opportunities during 4th month of Gestation:
Anomaly scan:

Ultrasound may suggest the presence of chromosomal aneuploidies such as Down syndrome, genetic syndromes such as dwarfism,hereditary renal disorders or isolated birth defects.The abnormal ultrasound findings may prompt “Amniocentesis” if fetal structural abnormalities or markers associated with chromosome conditions are identified.

Some common conditions detected by ultrasound (anomaly scan) such as:

 Neuraltube defects/ventriculomegaly

 Body wall defects/diaphragmatic hernia

 Majororgan abnormalities

 Oligoor polyhydramnios

 Major limb abnormalities

 Growth disturbances


Amniocentesis is carried out between 14 - 18 weeks of pregnancy. Amniotic fluid sent to a genetic diagnostic lab for high resolution karyotyping. This procedure requires no anesthesia and Lab result is usually obtained in about 3 to 4 weeks.When the test is carried out by experienced obstetrician, the risk of a miscarriage related to the test is about1 %. Potential disadvantages of techniques include maternal cell contamination, placental mosaicism and failure to obtain an adequate specimen which may result in the need for a repeat amniocentesis.

Window of opportunities during 5th month of gestation:

Repeat Anomalies scan for:


Normal sonographic studies during the first half of pregnancy do not exclude the subsequent development of congenital diaphragmatichernia, therefore advisable of repeat USG examinations at 22 weeks.

 Cardiac scan

Fetal cardiac anomalies are common, with half of them being lethal or requiring complex surgeries.

Early detection of these anomalies enables early referral to tertiary care centers with adequate expertise. A routine antenatal ultrasound performed between 18 - 22 weeks enables detection of most of these malformations. Further comprehensive evaluation can be performed with adedicated Fetal Echo-Cardiography.

Window of opportunities during 6th month of Gestation:

Rule out renal anomalies and urogenital sinus abnormalities by USG between 24-28 weeks. The persistent urogenital sinus and associated renal anomalies are usually diagnosed prenatally between 25- 30 weeks gestation. Itis important to diagnose type of IUGR and its relevance to genetic abnormalities. Congenital hydrocephalus is another condition which to be looked for.

Developmental renal defects include:

1. Bilateral/unilateral renal agenesis

2. Renal hypodysplasia with or without cysts

3. Multi cystic dysplastic kidney

Prenatal diagnostic studies of genetic syndrome involving renal abnormalities are:

1. Meckel syndrome

2. Roberts syndrome

3. Bilateral renal agenesis

Looking for sign of IUGR /oligohydramnios:

Oligohydramnios is inadequate volume of amniotic fluid(amniotic fluid index < or = 5 cm). Oligohydramnios results in poor development of the lung tissue and can lead to fetal death and commonly observe in renal anomalies, fetal demise, trisomy 13/18/triploidy, premature rupture of membrane.

Congenital Hydrocephalus:

Hydrocephalus is one of the most common congenital anomalies affecting the nervous system, and incidence of 0.3 to 2.5per 1,000 live births.  Common causes are Aqueductal Stenosis, Dandy Walker syndrome, spina bifida, Chiari IImalformation.

Classic X-linked recessive aqueduct stenosis hydrocephalus (Bickers-Adam syndrome) represents ~ 7 % of male hydrocephalus.Hydrocephalus may also be present in a number of major and minor chromosomal aberrations affecting chromosome 8, 9, 13, 15, 18 or 21.

Prenatal diagnosis is carried out by using sonographic measurements of the enlarged ventricles. Ratio of LVH/HW had the highest diagnostic accuracy of 97.1% bet 19-21 wks and 100% bet 22-24wks. Fetal MRI is a more anatomically precise modality for prenatal neuroimaging. Amniocentesis is offered for viral cultures, chromosomal analysis and alpha-fetoprotein levels.(Reece EA, et al., Early prenatal diagnosis of hydrocephalus.,Am J.Perinatol. 1997 Feb;14(2):69-73.)

Window of opportunities during Third trimester:

Skeleton dysplasia:

Ultrasound examination during third trimestercan demonstrate the osteo-chondro-dysplasias or skeletal dysplasias, which area genetically heterogeneous group of over 350 distinct disorders. It isessential to differentiating “lethal” skeletal dysplasias (by appearance of thechest) from   “non-lethal” disorders and todetermine post-delivery management plans.The skeletal dysplasias can beinherited as autosomal dominant, autosomal recessive, or X-linked disorders,and occasionally from imprinting errors, somatic mosaicism, and teratogenexposure.

The molecular defect has been identified inalmost half of the well-recognized skeletal dysplasias. However, theapplication of these findings to direct patient care is not yet possible formany of these disorders.The mothers who themselves have skeletal dysplasiasneed consultation with obstetricians and anesthetistregarding optimalmanagement, including mode of delivery

Fetal Middle cerebral arterydoppler assessment for:

 Fetal cardiovascular distress



 Intra-uterine growth restriction(IUGR)

 Twin to twin transfusion syndrome (TTTS) and Twin anaemiapolycythaemia sequence(TAPS)

Thereare a variety of non-invasive and invasive techniques available for prenataldiagnosis andeach of them can be applied only during specific time periodsduring the pregnancy for maximum utility. Knowingabout problems before the neonate is born may help parents make decisions abouthealth care for their neonate and some problems can be treated before the fetusis born, while other problems may need special treatment right after deliverybut in some cases intending couple may decide not to continue the pregnancy.


1. Tanya Milachich, New advances of preimplantation and prenatal genetic screening and noninvasive testing as a potential predictor of health status of babies., Biomed Res Int: 2014, 2014;306505 PubMed 24783200 

2. Peter Benn, Kirsten J Curnow, Steven Chapman, Steven NMichalopoulos, John Hornberger, Matthew Rabinowitz., An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing inthe US General Pregnancy Population. PLoS ONE:2015, 10(7);e0132313 PubMed 26158465 

3. Feichtinger M, Stopp T, Göbl C, Feichtinger E, Vaccari E, MädelU, et al. (2015) Increasing Live Birth Rateby Preimplantation Genetic Screening of Pooled Polar Bodies Using ArrayComparative Genomic Hybridization.

4. Errol RNorwitz, Brynn Levy Noninvasive prenatal testing: the future is now. Rev ObstetGynecol: 2013, 6(2);48-62 PubMed 24466384

5. Jacob O Kitzman, Matthew W Snyder, Mario Ventura, Alexandra PLewis, RuolanQiu, Lavone E Simmons, Hilary S Gammill, Craig E Rubens, Donna ASantillan, Jeffrey C Murray, Holly K Tabor, Michael J Bamshad, Evan E Eichler,Jay Shendure Noninvasive whole-genome sequencing ofa human fetus. SciTransl Med: 2012, 4(137);137ra76 PubMed 22674554

6. XinGuo, Philip Bayliss, Marian Damewood, John Varney, Emily Ma,Brett Vallecillo, RavinderDhallan A noninvasive test to determine paternity in pregnancy. N. Engl. J.Med.: 2012, 366(18);1743-5 PubMed 22551147

7. MollieAMinear, Celine Lewis, SubarnaPradhan, Subhashini Chandrasekharan Global perspectives on clinical adoption of NIPT. Prenat.Diagn.: 2015; PubMed 26085345

  1. Guedj F, BianchiDW.,PrenatDiagn., Noninvasive prenataltesting creates an opportunity for antenatal treatment of Down syndrome.2013Jun;33(6):614-8.
  • Antepartum and Intrapartumconsensus guideline. JObstetGynaecol Can: 2007, 29(9 Suppl 4); S3-56 PubMed 17845745
  1. AbruzzoMA and Hassold TJ (1995) The etiology of nondisjunction in humans.Environmental and Molecular Mutagenesis 25 (supplement 2): 38–47.
  2. BurtonBK, Schulz CJ and Burd LI (1992) Limb anomalies associated with chorionicvillus sampling. Obstetrics and Gynecology 79: 726–730.
  3. Ferguson-Smithand Yates RW (1984) Maternal age specific rates for chromosome aberrations andfactors influencing them: report of a collaborative European study on 52 965amniocenteses. Prenatal Diagnosis 4 (Spec. No.): 5–44.
  4. FirthHV, Boyd PA, Chamberlain P et al. (1991) Severe limb abnormalities afterchorionic villus sampling at 56–66 days’ gestation. Lancet 337: 762–763.
  5. GardnerRJM and Sutherland GR (1996) Chromosome Abnormalities and Genetic Counseling,2nd edn. Oxford: Oxford University Press.
  6. HookEB (1981) Rates of chromosomal abnormalities of different maternal ages.Obstetrics and Gynecology 58: 282.
  7. HookEB (1990) Chromosome abnormalities in older women by maternal age: evaluationof regression-derived rates in chorionic villus biopsy specimens. American Journalof Medical Genetics 35: 184–187.
  8. HookEB and Chamber GM (1977) Estimated rates of Down syndrome in live births by oneyear maternal age intervals for mothers aged 20–49 in a New York State study:implications of the risk figures for genetic counselling and cost–benefitanalysis of prenatal diagnosis programs. Birth Defects Original Article Series13(3A): 123–141.
  9. JonesKL (1997) Smith’s Recognizable Patterns of Human Malformation, 5th edn. London:WB Saunders.
  10. MooreKL and Persaud TVN (1998) The Developing Human: Clinically Oriented Embryology,6th edn. London: WB Saunders.
  11. ReedS (1955) Counselling in Medical Genetics. London: WB Saunders.
  12. ShermanSL, Petersen MB, Freeman SB et al. (1994) Nondisjunction of chromosome 21 inmaternal meiosis I: evidence for a maternal-age dependent mechanism involvingreduced recombination. Human Molecular Genetics 3: 1529–1535.
  13. Tongsong T,Wanapirak C, Kunavikatikul C et al. (2000) Cordocentesis at 16–24 weeks ofgestation: experience of 1320 cases. Prenatal Diagnosis 20: 224–228.