An Introduction to Genetics and Fetal Medicine Deepika Deka, Narendra Malhotra
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1Understanding Genetics
  • An Introduction to Fetal Medicine
  • Genetic Counseling for Obstetricians
  • Periconceptional Care
  • Recurrent Pregnancy Loss
    • Chromosomal Factor
    • Male Factor
  • Teratogens and Radiation Exposure

An Introduction to Fetal MedicineChapter 1

Deepika Deka,
Narendra Malhotra
The aim of obstetric care is to see that the baby is born in the best of mental, physical and social health. With control of communicable and infectious diseases, Congenital malformations and Genetic Disorders are becoming more common and important causes of Perinatal Mortality and Morbidity. Prenatal Diagnosis (PND)—the art and science of diagnosing abnormalities of the fetus/baby in utero of more than 4000 diseases can now be made. The goal of fetal medicine and genetics is to identify the 3–5% of women who are at high-risk of carrying a fetus with a congenital or genetic abnormality, who need specific genetic counseling, diagnostic tests, and/or referral. Hence, it is important that obstetricians keep their knowledge updated, and give the best evidence based care to the pregnant woman and her baby, mainly to assure the couple that their baby is normal. Also, medicolegal problems for obstetricians are increasing, and the obstetrician is liable to be prosecuted if a baby with anencephaly, thalassemia or any other condition is delivered.
The prenatal diagnosis of fetal genetic disease has become a part of routine obstetric care. Pregnancies at risk are identified by a number of factors, including maternal age, positive serum screening, a history of a previous affected child, a parental chromosome rearrangement or an ultrasound-identified anomaly.
Ultrasonography has expanded the capabilities of perinatologists to examine, test, and treat the fetus. By providing guidance for all of these procedures, real-time ultrasonography has revolutionized prenatal diagnosis and therapy; it will continue to be a crucial component in evaluating and treating complicated pregnancies.
The birth of a baby with handicap is a great social and economic burden to the family, society and the nation. Magnitude of problems of congenital and genetic disorders in India are shown in Table 1.1.1
Table 1.1   Magnitude of problems of congenital and genetic disorders
at birth
in stillbirths
in NN deaths
(1:50, 6 lacs/year)
(DS – 1:916, 22,000/year)
Single Gene
(B-thal – 1:2700, 9000/year;
SCD – 5,200/year;
DMD + SMA – 4,500/year)
Courtesy: IC Verma, Preventive Genetics, 2006.
Awareness among Obstetricians and Gynecologists of congenital/genetic diseases and their prevention is poor. There is need for education about prenatal screening as they play a key role, they are expected to have a working knowledge of common congenital and genetic diseases, ultrasound and biochemical screening, interpretation of laboratory tests-estimation of risk-odds (e.g. 1:25, 1:270) of having disorders like Down's syndrome, neural tube defect, etc. They must be able to inform couples of specific genetic disease, prognosis, options, need for confirmatory prenatal diagnostic test and therapeutic procedures-risk, cost.
Obstetricians should be familiar with Genetic Counseling: 3 generation family history taking, emphasis on common disorders likely to be encountered, screen pregnancies at risk of fetal congenital and genetic. Maternity/nursing homes can use structured forms for antenatal screening by history taking at booking, training on risk factors. In primary care settings, multigenerational history of chronic diseases/genetic disorder, ethnicity can be taken.2 They should be able also to 4identify indications for genetic testing and for timely referral to Maternal Fetal Medicine specialists where necessary, and also be competent to counsel for follow-up—monitoring and care.
Abnormalities of various body organs can occur, such as of the heart, gastrointestinal tract (gastroscisis, duodenal atresia), renal tract (posterior urethral valve, hydronephrosis), skeletal system, etc. Various syndromes such as Down's sydrome, Dandy Walker syndrome, Meckel Grueber syndrome-which have various patterns of inheritance, may occur.
Common Preventable Congenital Disorders
Polygenic-Cleft Lip and Palate, Lethal Malformations
CNS-anencephaly, skeletal dysplasia
Autosomal aneuploidies
  • 47, XX or XY + 21: Trisomy 21 (Down's syndrome)
  • 47, XX or XY + 13: Trisomy 13 (Patau's syndrome)
  • 47, XX or XY + 18: Trisomy 18 (Edward's syndrome)
Sex chromosome aneuploidies
  • 45, X Monosomy X (Turner's syndrome)
  • 47, XXY Klinefelter syndrome
  • 45, X/46, XX Mosaic (Turner's syndrome)
  • 69, XXY Triploidy
  • 46, XX or XY, del (18) (q21)
  • 46, XX or XY del (17) (p13)
  • 46, XX or XY, t(2;12)
  • (p 14; p13)
Mother's age and risk of having a baby with a chromosomal abnormality are shown in Table 1.2.
Mendelian Inheritance
Single gene disorders are:
Autosomal recessive: Thalassemia major-patients need blood transfusion at least once a month. Thalassemia (Mediterrenean anemia) carries a 25% fetal risk, if both partners are traits. Screening, marital counseling, prenatal testing has reduced incidence of new cases by 80% in Mediterranean countries.3
Table 1.2   Mother's age and risk of having a baby with a chromosomal abnormality
Age of mother
Risk of Down's syndrome
Risk of any chromosomal abnormality
1 in 1667
1 in 526
1 in 1250
1 in 476
1 in 952
1 in 384
1 in 385
1 in 192
1 in 106
1 in 66
1 in 30
1 in 21
1 in 11
1 in 8
  • The carrier state has no disadvantage.
  • Homozygous state is very severe and fatal.
  • Prenatal diagnosis is available and safe.
Other common recessively inherited disorders are Congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease. Lethal skin disorders like Harlequin ichthyosis, epidermolysis bullosa dystrophica; nonlethal albinism.
Autosomal dominant disorders, e.g. achondroplasia, adult polycystic kidney disease.
X-linked disorders: Hemophilia A and B, Duchenne muscular dystrophy (DMD), Fragile X syndrome.
Maternal diseases and drugs can affect the fetus and newborn, may cause fetal alcohol syndrome, cretinism, fetal warfarin syndrome, cephalhematoma (if mother has idiopathic thrombocytopenic purpura), congenital syphilis, macrosomic infant if diabetic mother, congenital fetal infection like congenital Rubella.
Rapid advances have been made in the field of prenatal diagnosis and therapy (Table 1.3). Ultrasound has revolutionized the practice of maternal fetal care, not only with 2, 3 and 4 dimension ultrasound for diagnosis of malformations and subtle markers of chromosomal anomalies, but also by enabling several sophisticated ultrasound guided procedures. The suspected “ill” fetus can now be treated as a “patient” accessible to diagnosis (Prenatal Diagnosis) and even therapy (Fetal Therapy).
Investigations for fetal chromosomes, DNA studies, congenital infection, hemogram, etc. can be performed by ultrasound guided prenatal diagnostic procedures of amniocentesis, chorionic villus sampling, cordocentesis, fetal tissue biopsy.
Table 1.3   Milestones in the history of prenatal diagnosis
X-ray-anencephaly, hydrocephalus; fluoroscopy IUT (Liley)4
Ultrasound imaging (Ian Donald)57
Amniocentesis for cytogenetic studies (Jacobson and Barter)8,9
First ultrasound diagnosis of fetal structural defect (anencephaly) and termination of pregnancy (Campbell)10
AF AFP in anencephaly, spina bifida (Brock and Sutcliffe)11,12
Maternal biochemical serum screening for Down's syndrome (Wald)13,14
Fetal nuchal translucency as a first trimester screening test for chromosomal abnormalities (Nicolaides)1518
Genetic Screening Test versus Prenatal Diagnostic Test
Screening Test is one that can be offered to all pregnant women (low and high-risk). It should be simple, inexpensive, noninvasive, and sensitive with a less than 5% false positive result, e.g. for Down's syndrome, neural tube defect, structural malformation. Assessment of maternal—fetal risk is a continuous process beginning before, during and after pregnancy. It is performed prepregnancy with counseling and care by family doctor, obstetrician or if needed by geneticist. Screening program requires an excellent interdisciplinary support among obstetrician, geneticist, ultrasonographer, besides an efficient laboratory and follow-up services program.
Preconception Care
Folate 0.36 mgm has been found to reduce the more common malformation—NTD by seven fold in women with previous NTD.19,20 Medical Research Council Vitamin Study Research Group (1991) recommends 4 mgm folic acid/day in women with previous NTD 1 month before conception, through 3 months of pregnancy and 0.4 mgm/day folic acid to all women planning pregnancy 1 month preconceptionally. This also reduces ‘a priori risk’ of first occurrence of NTD.21
Pregnancy Care
This starts with the search for any high-risk factor; on history taking:
  • Maternal age 35 years or more at expected date of delivery.
  • Previous child with chromosomal abnormality or malformations.
  • Existence of a chromosomal abnormality in either parent.
  • History of Down's syndrome or other chromosomal abnormality in a family member.
  • History of two or more spontaneous abortions.
  • Family history of DMD, hemophilia, or other genetic disease.
  • Pregnancies in couples at risk for inborn errors of metabolism, neural tube defects, sickle cell disease.
Prenatal Genetic Screening Investigations
  • Rh Group.
  • Syphilis.
  • Hb, MCV, MCHC, HbA2.
  • Blood sugar, HbA1C.
  • Biochemical screening.
  • Fundal height.
  • Ultrasound 1st trimester.
  • Ultrasound 2nd trimester, fetal echo.
At Risk Pregnancies Identifiable During Pregnancy
  • Abnormal ultrasound findings
  • Abnormal maternal serum screening
  • Maternal infection
  • Teratogen exposure
  • Abnormal investigative finding—MCHC, HBA2, HBE, HIV, HBsAg, VDRL, BS
    • Thalassemia carrier - north/central India 4 – 8% (ICMR)22
    • HBE (East), Sickle cell disease (Central India, tribal areas).
The suggested protocol for biochemical and ultrasound screening is shown in Table 1.4.
Table 1.4   Protocol for biochemical and ultrasound screening
Period of gestation
First trimester
10–13+6 weeks
Biochemical screen PAPP-A, free B-hCG
11–13+6 weeks
Ultrasound for fetal size, nuchal translucency, nasal bone, congenital malformations
Second trimester
16–18 weeks
Biochemical Screen: MSAFP, Free hCG, UE3
18–20 weeks
Ultrasound for congenital malformations/fetal echo
Late second/third trimester
Clinical features of polydramnios/oligo hydramnios/growth restriction: Ultrasound for congenital malformations
However, these are not guidelines by the Government, but considered in India to be extremely useful for timely patient management.
First trimester ultrasound for congenital malformations, complete fetal survey is possible by 11–12 weeks in 72 % by TAS, 82% by TVS, 95% TAS+TVS23 (Figs 1.1A and B).
Increased nuchal translucency can detect 77% of DS, 81% of Trisomy 18, 80% Turner's syndrome and 63% of Triploidy fetuses; 80% of these would result in IUD (Pandya, US Obstet Gynecol, 1996). Majority fetuses with Trisomy 21 have an NT < 4.5 mm, Tris 13/18-NT 4.5–8.4, Turner's syndrome > 8.5 mm.24
Sensitivity of first trimester screening for 5% false positive rate is appreciably high:25
  • 30% for maternal age (MA) alone.
  • 77% for MA and fetal nuchal translucency (NT).
  • 87% for MA, NT, serum biochemistry at 11–14 weeks.
  • 97% MA, NT, nasal bone, maternal serum biochemical tests.
By second trimester ultrasound—2D, 3D, 4D is now routine.26 However, a large number of patients are still referred with the first ultrasound scan finding of a lethal or nonlethal malformation of vital organ after 20 weeks of pregnancy, when termination of pregnancy is not possible in India due to the MTP Act (Figs 1.2 A to D).
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Figs 1.1A and B: First trimester ultrasound showing fetal anatomy
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Figs 1.2 A to C: (A) Intestinal atresia (bowel), (B) Fetal ascitis, (C) Hyperechoic bowel respectively
Table 1.5   Ultrasound findings suggestive of chromosomal anomalies
Trisomy 13
Trisomy 18
Trisomy 21
Enlarged cisterna magna Hydrocephalus choroid plexus cysts
  • Brachycephaly
  • BPD|FL > 1.8
  • Nuchal skin thickening
Midline deformity cleft lip/palate
Mild maxillary hypoplasia
Neural tube defects
VSD, AV canal
AV canal, VSD
  • Omphalocele
  • Polycystic or horseshoe kidneys
Diaphragmatic hernia Omphalocele
  • Duodenal atresia
  • Mild renal pyelectasis
Reduction deformities Club/rocker bottom feet Clenched fist with overlapping of index finger
  • Short femur
  • Hypoplasia or middle phalanx of 5th digit
  • MFL/EFL < 0.91 ‘Sandal gap’
  • Single umbilical artery
  • Severe IUGR
  • Polyhydramnios
zoom view
Fig. 1.2D: Multiple anomalies at 20 weeks
Genetic Scan for the diagnosis of chromosomal anomaly27 is recommended as a routine when an ultrasound is performed, increases the pick-up rate of aneuploidy fetuses (Table 1.5). Ultrasound ‘soft’ markers of karyotype anomaly are increased nuchal fold thickness, nonimmune hydrops—ascitis, pleural effusion, echogenic bowel, intracardiac echogenic focus, pyelectasis, sandal foot, teacup hand. Fetal karyotype is indicated if there are more than 2 soft markers; for 1 marker—risk of aneuploidy is minimal (Fig. 1.3).
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Fig. 1.3: Ultrasound of fetal head showing choroid plexus cyst
Invasive diagnostic testing can be performed in the first trimester by chorionic villus sampling or in the second trimester by amniocentesis. Amniocentesis and chorionic villus sampling have been the two most common prenatal diagnostic procedures for decades; Cordocentesis has fewer indications, but allows direct 8laboratory testing of fetal blood. Both procedures are safe, with an equivalent 0.5% risk of procedure-induced pregnancy loss. When performed prior to the routine sampling window of 15 weeks, amniocentesis may increase the risk of talipes equinovarus, the highest risk being encountered prior to 13 weeks' gestation. When chorionic villus sampling is performed prior to 9 weeks' gestation, there may be an increased risk of limb reduction defects.28 There are wide variations in utilization, operator skills, quoted procedure risks, actual observed risks, and patient choices that come from highly variable counseling as to those risks. The laboratory analysis of both procedures is reliable. Chorionic villus sampling has a 1–2% incidence of confined placental mosaicism, requiring additional evaluation in some cases. Most studies comparing CVS to amniocentesis in skilled hands have found equivalency of risks. No well controlled studies support claims of amniocentesis risk at 1/1000 or lower. There is no increased risks of limb reduction defects following CVS at 10 weeks or greater, but there is an increase in Talipes from “Early Amniocentesis.” In the first trimester CVS is the safer procedure. All invasive procedures should be performed under continuous ultrasound guidance by experienced operators. Within this context, mid-trimester amniocentesis remains the safest invasive procedure. There is also a 10-fold increase in the risk of mosaicism with CVS compared to amniocentesis. Patient counseling should include an evaluation of the risk associated with each individual procedure but also the operator's personal complication rate.
Common Indications
  • Chromosomal analysis: Advanced maternal age, positive biochemical/ultrasound screen, family history of chromosomal abnormality, parental chromosomal abnormalities)
  • Rh-isoimmunization for spectrophotometry, Rh group
  • Sex determination in X-linked diseases: CAH, DMD)
  • Biochemical/metabolic disorders (Gaucher's disease/Hurler's syndrome)
  • Intrauterine infections (TORCH)—PCR (Fig. 1.4).
Common Indications
  • Hematological Disorders—Thalassemia major, Hemophilia, Factor IX, X deficiency.
  • Karyotype—Positive first trimester ultrasound or biochemical screen, increased maternal age, parental chromosomal anomalies, family history of DS/fragile X/ataxia).
  • Duchenne muscular dystrophy/congenital adrenal hyperplasia/cystic fibrosis.
  • Biochemical, metabolic, amino acid disorders.
  • Skin disorders: Epidermolysis bullosa dystrophica, albinism, ichthyosis (Figs 1.5 and 1.6).
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Fig. 1.4: Procedure of amniocentesis
zoom view
Fig. 1.5: Transabdominal chorionic villus sampling (CVS)
zoom view
Fig. 1.6: Chorionic villi in Petri dish
Common Indications
  • Rh immunization—Hb, Blood group, Intrauterine transfusion
  • Rapid fetal karyotype (late pregnancy)
  • Hematology—Hb, Factor VIII, IX deficiency, platelets
  • Congenital infections—PCR, IgM (TORCH), parvovirus.
Indications are decreasing as prenatal diagnosis for these conditions can now be done by CVS or by amniocentesis.
For lethal structural abnormalities and genetic diseases, medical termination of pregnancy is the best option. Avoidance of cesarean section if diagnosed after 20 weeks appears reasonable to prevent a uterine scar, after adequate counseling. For conditions treatable at birth with baby in reasonably good condition, the best option is planned delivery and neonatal surgery at a center with ECMO facilities. However, for the few conditions likely to have deterioration of organ function during pregnancy, fetal therapy is now possible—medical and surgical.40,41
Fetal blood transfusion is an important tool in the treatment of Rh isoimmunization, some other forms of fetal anemia. Amnioreduction is a commonly used procedure for the treatment of polyhydramnios and TTTS. Multifetal reduction and selective termination offer previously unavailable options to patients carrying multiple gestations. Fetal shunts can reduce perinatal morbidity and mortality in cases of bladder outlet obstruction and hydrothorax.
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Fig. 1.7: Needle inserted into free loop of cord for intrauterime transfusion
Medical Fetal Therapy
  • Rh isoimmunization, non-immune hydrops due to anemia-fetal red blood cell transfusion (IUT).
  • Toxoplasmosis - Maternal spiramycin; Fetal infection: Pyrimethamine + Sulphadiazine.
  • Parvovirus B19 - Intrauterine transfusion.
  • Herpes Simplex II: Acyclovir.
  • Fetal hyperthyroidism - Maternal PTU, methimazol.
  • Fetal hypothyroidism - Thyroxine.42,43
  • Congenital Adrenal Hyperplasia (CAH)—Dexamethasone 0.25 mgm QID from 7–9 weeks till amniocentesis/CVS, continued if fetus is affected.
  • Fetal Cardiac Arrythmias Ectopic beats, SVT, Atrial flutter, atrioventricular block - avoid caffeine/sympathomimetic drugs, maternal IV digitalis, direct fetal digoxin, amiodarone, fleccainide, sotalol, postnatal electrical cardioversion, pacemaker implantation.44
Surgical Fetal Therapy4548
The biochemical screen report needs to be checked for risk of chromosomal anomaly in the presence of structural anomaly. The precise abnormality should be defined, type, severity of abnormality, other associated abnormalities should be looked for. Karyotype should be done if required. Assess fetal status, prognosis in consultation with pediatric surgeon, neonatologist, geneticist.
Table 1.6   Conditions which may benefit from fetal surgery
Fetal structural defect
Fetal outcome
Recommended treatment
Urinary obstruction (urethral valves)
Renal failure
Pulmonary hypoplasia
Vesicoamniotic shunt
Fetoscopic vesicostomy
Cystic adenomatoid malformation
Pulmonary hypoplasia
Hydrops fetalis
Pleuroamniotic shunt
Open pulmonary lobectomy
Laser ablation
Diaphragmatic hernia
Pulmonary hypoplasia
Open complete repair
Temporary tracheal occlusion
Band, Clip or Plug
Sacrococcygeal teratoma
Hydrops fetalis
Resection of tumor
Ablation of tumor
Fetoscopic vascular occlusion
Twin-twin transfusion syndrome
Hydrops fetalis
Laser ablation, Cord ligation/occlusion
Aqueductal stenosis
Brain damage
Ventriculoamniotic shunt
Open ventriculoperi-toneal shunt
Isolated pleural effusions
Lung hypoplasia
Serial thoracocentesis
Pleuroamniotic shunt
Cleft lip and palate
Fetoscopic coverage
Open repair
Counsel parents on risk, prognosis, interventions, cost, hospital stay (Table 1.6).49
Open fetal surgery by hysterotomy have been done for sacrococcygeal teratoma, CCAM.
Fetal Image Guided Surgery (FIGS) are:
  • Amnioreduction
  • Fetal reduction
  • Vesico/pleuroamniotic shunts
  • Fetal vesicocentesis.
Fetoscopic Surgery ‘FETENDO’ has developed with improvements in endoscopy especially pediatric surgery, and development of finer instruments.50 Examples are:
  • Balloon occlusion of trachea (for CDH)
  • Selective fetoscopic laser photocoagulation of arterio -venous anstomosis laser ablation of vessels (for TTTS)
  • Cord ligation/division
  • Cystoscopic ablation valves
  • Amniotic bands division
Fetal Therapy or Surgery
In pregnancy continuing, serial monitoring of fetal organ function by real time ultrasound and Doppler echo, fetal growth and fetal wellbeing by NST, BBP, Doppler.
Planned Delivery
Delivery should be planned in center with appropriate obstetrical, pediatric, pediatric surgical, cardiology and genetic facilities; may consider elective delivery at 38 weeks where intensive Neonatal Medical, Surgical care required after birth. Stabilize the neonate, confirm diagnosis, plan subsequent management (Fig. 1.8).
Postmortem exam/fetal autopsy if lethal is a must, as it is very useful to establish cause and counsel for future.51
In conclusion, prenatal diagnostic procedures are relatively safe, accurate. There is a need for improved screening methods to identify women with risk of fetus with congenital or genetic disease to minimize number of women requiring PND procedures Fetal therapeutic procedures are gradually advancing. Obstericians play a key role in fetal medicine, genetic screening, prenatal diagnostic and genetic services, by counseling, timely referral. Thus, for true “Perinatology”, the “New Obstetrics”.
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Fig. 1.8: Autopsy of fetus showing anomalies
Maternal: Fetal medicine must be recognized and incorporated into teaching, research, patient care service. Obstetricians should take advantage of CMEs, workshops, training in prenatal diagnosis and therapy.
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