Dr. Anil B. Jalan
Introdution :- Hydrops Fetalis is a diagnosis that in the past , was made after delivery and was described as excess collection of fluid in several neonatal body cavities .
Ballantyne described the first case of Hydrops Fetalis 100 yrs. ago , and 50 yrs. later ,Potter described nonimmune hydrops fetalis .
Nonimmune Hydrops Fetalis is responsible for 3 % of overall perinatal mortality .
In 1970 , MaCaffe et.al. reported that 82 % of hydrops cases were caused by immune diseases ; by 1992 , 87 % were caused by nonimmune conditions.
Definition :- The presence of excess extracellular fluid in two or more sites without any identifiable circulating antibody to red blood cell antigens .
Incidence :- Most of the large serieses have reported an incidence of 1 : 2000 to 1 : 3000. Almost 85 - 90 % of these hydrops fetalis incidents are due to nonimuune causes .
Since the advent of ultrasonography more and more cases of fetal hydrops are being detected by gynecologists & sonologists. At times it becomes diffcult to predict the outcome of such hydropic fetuses . The causes of hydrops fetalis are many , but few common ones must be remembered at the time of sonography , so that we look for other evidence which will give support to our provisional diagnosis .
Several large serieses have suggested that cardiac malformations are amongst the most common causes , because they are often found in hydropic fetuses . Yet , cardiac malformations are one of the most common defects and only seldom are associated with nonimmune hydrops fetalis . Thus , the presence of a heart defect doesnot prove that hydrops results from heart failure .
At present three main hypotheses have been proposed for the pathophysiological mechanisms underlying hydrops :-
1 ] Inadequate cardiac output due mainly to
a. Obstructive out-flow
b. Diverted blood flow
c. Inadequate blood return
d. Inadequate ventricualr filling
e. Inadequate inotropic force
f. Regurgitation of blood across Cardiac valves .
g. Reversal of blood flow in I.V.C.
All the above mechanisms lead to cardiac failure , cardiomegaly , and elevated umbilical venous pressure , also seen in Rh immune hydrops , due to portal hypertension .
Portal hypertension in immune hydrops is due to hypertrophy of Hepatic Erythropoeitic tissue .
2 ] Lymphatic Abnormalities Found in association with :-
a. Cystic hygroma
b. Noonan syndrome
c. Turner's syndrome
d. Pulmonary or peritoneal lymphangiectasia .
e. Lymphatic venous anastomosis .
f. Connective tissue malformation e.g. - skeletal dysplasia .
g. S.O.L. in thorax e.g. -Cystic adenamatoid malformation of lung & Diaphragmatic hernia .
Please note that in the above situation the umbilical venous pressure is normal .
3 ] Reduced osmotic pressure :- Hypoproteinemia .
The fetal outcome & the genetic counselling entierly depends upon the exact etiology of such hydrops . Without repeated USG & colour doppler it is impossible to judge the progress of the anasarca . It is quite evident in our cases . Over a period of 4 wks. we could demonstrate progressive anasarca & suspicion of chromosomal anomaly . This helped tremendously to gynecologists & parents in decision making , which was MTP . However in certain cases especially in the immune hydrops cases , in-utero intervention is possible but the decision of undertaking such heroic measures in the yet unborn patient entirely depends on the parental willingness . The causes of hydrops fetalis are given below .
Following is a list of few common causes of hydrops fetalis .
Causes of hydrops fetalis :-
a. Rhesus hemolytic anemia
b. Alfa thalassemia
c. Fetal erythro - leukemia
b. CMV infection
e. Other fetal infections .
a. Anagioma of palcenta or fetus
b. Renal or umbilical vein thrombosis
c. Cardiovascular malformation .
d. Fetal tachycardia
e. Cardiac rhabdomyoma ( Tuberous sclerosis )
a. Fetal haemorrhage
b. Twin to twin tranfussion syndrome
a. Fetal red cell enzyme defects
b. Lysosomal enzyme defects
a. Cystic adenomatoid malformation of the lung
b. Extralobar pulmonary sequestration
c. Pulmonary hypoplasia
d. Pulmonary lymphangiectasia
e. Tracheal atresia
f. Diaphragmatic hernia
a. Hepatitis or hepatic necrosis
8 . Lower urinary tract abnormalities
9 . Congenital neuroblastoma , teratoma, glioma
10. Some types of short limbed dwarfism
11. Noonan syndrome
12. Nuchal bleb syndrome
13. Optiz frias syndrome
14. Turner syndrome
15. Trisomy 18 and 21
17. Maternal nephrotic syndrome
Suggested investigations :-
Maternal tests with live fetus inutero :
1. BL.Gr. Serology and typing including titre for anti-d antibodies.
2 . Serum tests for Syphilis ( VDRL ) & TORCH titre .
3 . Kleihauer test for feto maternal haemorrhage .
4 . Fetal USG for cardiac anomalies and tumours .
5 . U.S.G. for placental hemangioma
Cord blood at delivery - irrespective of outcome .
1 . Blood Group Serology and tying
2 . Chromosome analysis.
3 . Total protein and albumin
4 . TORCH titre
5 . Hb and Hb - EPP . ( H.P.L.C. )
6 . Vacuolated lymphocytes
7 . Enzymology ( red cell and lysosomal enzyme ).
In the event of infant death detailed antopsy and H.P. is indicated especially to look for anomalies :-
1 . Cardiovascular system .
2 . Kidneys .
3 . Central nervous system .
Tissues from all usual organs must be taken for H.P.
If possible viral culture and chromosome analysis is indicated .
From the above discussion it appears that the list of causes is extensive . However it will be helpful to know that hydrops fetalis is common in certain conditions and only occasionally seen in others .
Hydrops fetalis is frequent in :-
1 ) Achondrogenesis , type I .
2 ) Fibro chondro genesis .
3 ) Monozygotic twinning and structural defects .
4 ) Osteogenesis Imperfecta syndrome type II .
5 ) XO - syndrome ( Turner syndrome ).
Occasional in :-
1 . Achondrogenesis - Hypochandrogeneis , type II
2 . Chondrodysplasia punctata - X Linked Dominant type .
3 . Down - syndrome .
4 . Generalised gangliosidosis , type I & severe infantile type .
5 . Lethal Multiple Pterygium syndrome .
6 . Morquio syndrome .
7 . Mucopolysacchroidosis type VII
8 . Short Rib Polydactyly syndrome type II ( Majewski type SRP )
It is impossible to discuss all the causes and pathologies of hydrops fetalis but we would like to highlight few conditions of clinical interest , especially syphilis and parvo - virus infection .
Hydrops Fetalis in Turner?Syndrome :- The Turner?syndrome is one of the commonest cause for fetal hydrops especially in the Indian situation . The frequency of Turner?syndrome amongst liveborn infants is 1 in 2,000 females according to D.W.Smith and 1 in 10,000 females according to J.L.Simpson & M.S.Golbus . There are not many studies available for the incidence amongst spontaneous abortions , but one by DR. J.L.Simpson gives 8.6 % due to Turner ( 45 , OX ) in spontaneous abortion cases .
Monosomy X ( i.e. Turner ) is the signal most common chromosomal abnormality in spontaneous abortions , accounting for 20 - 25 % of abnormal specimens . There are no definite figures available for hydrops fetalis cases .
Etiology :- Faulty chromosomal distribution leading to XO individual with 45 chromosomes . The paternal chromosome is the one more likely to be missing . There has been no significant older age factor for this neuploidy . On the contatry it is more common in the young mothers ( Warburton et. al. 1980 ) .This has been our observation also, especially amongst the hydropic fatuses and in the first trimester abortion cases . It is generally a sporadic event in a family , although there are as yet no adequate data on risk of recurrence . Mosaicism doesnot ensure survival till term . However the incidence of sex chromosome mosaiciam is higher in liveborns than in aborted 45 XO Fetuses .
Patients who had one abortion with 45 XO karyotype doesnot mean that we will have only the similar type of recurrence . Wharton et. al. 1987 , has showed that the mothers who had 45 XO fetuses also had normal Fetuses , Monosomies , Triploidies in future .
The above discussion definitely emphasises one point that we must advise prenatal diagnosis during the next pregnancy .
The clinical features of Turner syndrome are summarised below . The interested readers are referred to the classical text book - Smith?recognizable patterns of human malformation , 5 th Edn.
Clinical Features of Turner?Syndrome :-
Common Features :-
1 . Short stature
2 . Edema of fingers and toes
3 . Mild pectus excavatum
4 . Anomalous auricles , mostly prominent .
5 . Narrow maxilla and palate .
6 . Relatively small mandible .
7 . Inner canthal folds .
8 . Short neck and low posterior hair line .
9 . Webbed posterior neck .
10. Cubitus valgus.
11. Medial Tibial exostosis .
12. Broad chest and widely spaced nipples .
13. Short 4 th metacarpals/ metatarsals
14. Bone dysplasia with coarse tubular pattern .
15. Narrow hyperconvex or deep set nails .
16. Excessive pigmented naevi .
17. Distal A.T.D. angle .
18. Loose skin about neck in infancy
Other anomalies :-
1 . Horse shoe kidney .
2 . Double or cleft renal pelvis .
3 . Cardiac defects - V.S.D. , Coarctation of aorta etc.
4 . Perceptive hearing deficits.
5 . Abnormal angulation of radius to carpal bones .
6 . Short mid phalanx of the 5 the finger ( cleinodactyly ).
7 . Scoliosis , kyphosis .
8 . Spina bifida .
9 . Vertebral fusion .
10. Cervical rib.
11. Anomalous sell turcica .
12. Ptosis .
13. Strabismus .
14. Blue sclerae .
15. Catarct .
16. Mental Retardation .
17. Haemangiomata of intestine .
18. Idiopathic hypertension .
Fetal Changes :-
1 . Hydrops fetalis .
2 . Cystic Hygroma .
3 . Single Umbilical artery .
4 . I.U.G.R.
5 . Congenital Heart Defects .
Adult Turner?Syndrome with additional features :-
1 . Hypertension .
2 . Diabetes Mellitus .
3 . Delayed Puberty , Amenorrhea ,
Menstrual disturbances and
Hydrops in other Cytogenetic abnormalities :
DR. L. P. Shulman from Memphis
( U.S.A. ) published his data of 18 cases of hydrops in 1998 where hydrops was detected as space suit hydrops in the first trimester of the pregnancy and C.V.Bx or Amniotic Fluid karyotyping was done on all the patients . His results are given below :
Shulman et. al. :-
Total No. of cases 18
Chromosome abnormalities 15
( 83.3 % )
Sex chromosome abnormal 7
Normal Chromosomes 3 ( 16.7 % )
Turner Syndrome ; 45 , XO - classical 6 / 15 ( 40.0 % )
Turner Syndrome Mosaic ; 45 , XO / 46 , XY 1 / 15 ( 6.67 % )
Trisomy - 21 ; 47 , XX or XY + 21 5 / 15 ( 33.33 % )
Trisomy 18 ; 47 , XX or XY + 18 3 / 15 ( 20.00 % )
The ratio of 7 : 8 of sex chromosome to autosome abnormalities is greater than that observed ( approximately 1 : 4 ) among fetuses with isolated prominent nuchal translucency .
Hydrops in Syphilis :- Hydrops is quite variable in its frequency . Tan et. al. Found it in 40 % of his series , while any number of others failed to mention it at all ! The edema may be so severe that infant is thought be the product of a severely Rh sensitized multiparous mother . It is mandatory that congenital syphilis be considered as the cause in every instance of perinatal non immune hydrops .
Parvovirus Infection :- This is one of the most important viruses responsible for fetal hydrops . Human Parvovirus was first discovered in 1975 and it was first associated with adverse pregnancy outcome in 1984 . This virus is a small single stranded DNA virus , singularly dependent on host cell function . Autonomous parvoviruses including the human parvovirus B . 19 are able to replicate without the help from another virus , but only in the proliferating cells . In general , mammalian parvoviruses are species specific . To date the only human parvovirus identified is B - 19 .
The diseases caused by Parvoviruses are :-
1 . Aplastic crisis in children with sickle cell disease .
2 . Erythema Infectiosum . ( E.I. )
3 . Febrile illness with arthargia and arthritis .
4 . Chronic anemia in immune compromised host .
5 . Haemo-phagocytic syndrome .
Infection with B - 19 is relatively common , seroprevalence studies indicate that 30 % to 60 % of adults have been infected . Modes of transmission of the virus have not been completely defined but appear to include respiratory secretions . Viremia occurs approximately one week after inoculation and is accompanied by rash and joint symptoms , approximately 10 days later . There is transient reticulocytopenia . There may be slapped cheek appearance of EI .
Laboratory Investigations :-
1 . Serologic diagnosis - Ig G & Ig M - B - 19 specific antibodies .
2 . Detection of DNA by P.C.R. appears to be the most sensitive test for detection of this virus .
Effects on pregnancy and fetus . :-
Fetal infection at all stages of pregnancy has been documented with a spectrum of consequences -
1 . Spontaneous abortions .
2 . Still birth .
3 . Severe non immune hydrops .
Fetal damage is not inevitable following maternal infection , and infact , a healthy infant is the most common product of a pregnancy complicated by parvovirus infection .
The risk of unfavourable outcome varies from less than 10 % to 38 % in different serieses published .
The evidence for treatogenicity is weak and till to date there is only one report of a congenital anomaly in a B - 19 infected fetus .
In the infected fetuses , the principal organ affected is the bone marrow . The red cell survival in fetuses is reduced from normal 120 days to between 45 and 70 days and profound anemia results from B - 19 induced erythroid bone marrow aplasia . Fetal blood sampling in one affected fetus revealed a Hb of 1.8 Gm / dL and reticulo-cytopenia . Usually the bone marrow recovers in 7 - 10 days .In immuno-immature infants prolonged infection may occur . Transfusion of infected fetuses with packed red blood cells has been successfully used to treat the intrauterine hydrops but experience is limited .
Limited data suggests that elevation of M.S.A.F.P. values may be a marker for the development of hydrops fetalis .
A possible immunologic origin of idiopathic nonimmune hydrops fetalis has been suggested . Of 324 cases of prenatally diagnosed NIHF , 49 (15.1 % ) could be classified as idiopathic . The proportion of parents sharing 4 or 5 H.L.A. antigens was increased significantly in the 38 patients of the idiopathic group as compared to 38 age and parity paired controls . Besides in 8 patients , an increased paternal histo-compatibility and a decreased incidence and percentage of lympho-cytotoxic antibodies was observed .
Maternal complications of nonimmune hydrops fetalis :-
1 . Poly-hydramnios :- commonest
2 . Anemia
3 . Preterm labour
4 . Pregnancy induced hypertension
5 . Post partum haeorrhage .
Protocol for management of nonimmune hydrops :-
Maternal causes :-
1. Obstetric history
2. Past medical history
3. Family H/O genetic disorders
4. Recent infections
5. Fetal activity
a. Blood group and antibodies
b. Viral screen / TORCH titre
d. G.T.T / Glycosylated Hb
e. Auto-antibody screen
f. Kleihauer - Betke count
g. Full blood count
h. Hb Electrophoresis
Fetal causes :-
U.S.G. Evaluation :
Doppler Blood Flow Studies :
a. Umbilical artery
b. Middle cerebral artery
d. Umbilical artery pressure
Fetal Blood Sample :
1. Full blood count
2. Bl.Gr. & Coombs test
3. Fetal blood abnormal Hb studies
5. Blood gases
6. Serum protein
7. Viral screen / TORCH titre
8. Metabolic disorders study
Aborted Fetus Or Dead Fetus :
1 . Complete autopsy of fetus
( if parents are willing ) .
2 . Clinical photographs of the fetus .
3 . X ray - complete babaygram.
4 . Collect blood as follows -
( Use Vacutainer tubes only ) .
5 ml in E.D.T.A. tubes
5 ml in heparinised tube
10 ml in plain tube .
5 . Two pieces of placenta of 1?1?
each in normal saline & formalin
( two separate sterile containers ).
To keep all the material at 2 - 8 centigrade temp. in fridge .
To inform geneticist within 24 hrs. or send the samples as eraly as possible to lab along with X-ray & clinical photographs of the fetus .
1 . Avron Y. Sweet & Edwin G. Brown , Fetal & Neonatal Effects of Maternal Diseases , 1991 , Page no. 162 - 163 .
2 . Duru Sushil Shah , An Introduction To Genetics and Fetal Medicine. Editor : Dr. Kamini Rao , Page no. 130 - 136 .
3 . J.L. Simpson & Golbus , Genetics in Obstetrics and Gynecology , 2nd Edition.Page no. 61 & 187 .
4 . L.P. Shulman & O.P. Phillips , Prenatal Diagnosis and Therapy , 1998 ,Proceedings of 8th international Conference on prenatal Diagnosis of genetic disorders ., Page no. 22 - 24 .
5 . Mary L. Kumar M.D., Fetal & Neonatal Effects of Maternal Disease by Avron Y. Sweet & Edwin G. Brown ( 1991 ) , Page no. 39 to 44.
6 . Smith's Recognisable Patterns of Human Malformation , 5 th edition , 1997 Page 843 - 844 .