Obstetrics and Gynecology

Fetal Hydrops

Fetal Hydrops

1. What every clinician should know

Clinical features and incidence

Fetal hydrops (FH) is defined as excessive fluid accumulation within at least two fetal extravascular compartments. This can include pleural effusion, ascites, pericardial effusion and skin edema. It is not in itself a final pathological diagnosis but the end-stage of a disease process. It is a serious condition which can be broadly classified as immune or non-immune fetal hydrops. These can be distinguished by the presence or absence of circulating antibodies against red cell antigens in the maternal serum. Absence of such antibodies confirms non-immune hydrops.

Immune hydrops (IH) can be differentiated from non-immune fetal hydrops (NIFH) by performing a maternal indirect Coombs test to screen for antibodies associated with blood group incompatibility. Isoimmunization usually occurs due to prior blood transfusions, in which setting atypical antibodies can occur in 1-2% of recipients. Rhesus isoimmunization is the most common cause of IH. The Rhesus (Rh) system is made up of 5 antigens D, C, c, E and e. The D antigen confers Rh positivity. A number of other antibodies than can precipitate isoimmunization such as Kell (Anti K1 and K2), MNS, Duffy (Fya, Fyb) and Kidd (Jka, Jkb).

The incidence of IH or hemolytic disease of the fetus and newborn (HDFN) has decreased with the routine use of Rhesus Immunoglobulin (RhIG) for the prevention of Rh isoimmunization. RhIG is administered prophylactically in the third trimester of pregnancy to all Rh negative women in the U.S. and many European countries. It is also recommended for any sensitizing event during pregnancy and after delivery of an Rh positive infant. The risk of IH in a first Rh-sensitized pregnancy is approximately 8-10%. A review of the national birth certificate registry in the U.S. in 2003 reported an incidence of 6.8 cases per 1,000 births.

The diagnosis of IH should prompt the clinician to refer the patient for urgent review to a referral unit with appropriate maternal-fetal medicine expertise. There should be access to apporpriate hematology support, as well as the resources to perform percutaneous umbilical blood sampling (PUBS) with fetal transfusion if necessary. Additionally, appropriate neonatal expertise to manage the expedited delivery of the fetus with subsequent neonatal care is required.

In cases where there are no maternal antibodies detected a diagnosis of non-immune fetal hydrops (NIFH) can be confirmed. It is a heterogeneous disorder caused by a large number of underlying pathologies. Once IH is excluded by an indirect Coombs test a detailed fetal ultrasound should be performed to identify anatomical defects known to be associated with NIFH. A recent meta-analysis by Bellini et al identified 6,361 individuals from 225 relevant articles on NIFH. They established 14 different diagnostic categories and a patho-physiologic basis for each category. They found the most common etiologies were: cardiovascular (21.7%), idiopathic (17.8%), hematologic (10.4%), chromosomal (13.4%), infectious (6.7%) and thoracic (6%).

Other rarer causes include; anatomical disorders of the gastrointestinal tract, genitourinary tract, neurological abnormalities, vascular causes, neoplastic or metabolic disorders, and placental or cord abnormalities. Once NIFH is detected on initial ultrasound, a complete sonographic and laboratory evaluation is required, as detailed below.

The optimal mode of delivery for both IH and NIFH is uncertain although casesarean delivery is advisable in almost all cases to avoid potential soft tissue injury. The long-term outcomes will depend on the underlying pathology and gestational age at delivery.

At risk pregnancies

  • If there is a history of a prior pregnancy affected with isoimmunization which resulted in a intrauterine death, intrauterine transfusion or neonatal exchange transfusion, then such patients are at high risk of developing hemolytic disease of the fetus and newborn. Antenatal care for such patients should therefore occur in association with an institution where advanced fetal ultrasound and fetal therapy are available.

  • A maternal history of blood transfusion places patients at risk of having circulating autoantibodies with a risk to the fetus in a subsequent pregnancy.

  • Pregnancies in which the fetus is prenatally diagnosed with certain congenital malformations known to be associated with NIFH should have regular sonographic surveillance for the development of features of NIFH.

  • Special consideration should be made for those couples who may be carriers of certain hereditary conditions that could result in an affected fetus with the potential to develop fetal hydrops.

2. Diagnosis and differential diagnosis

The majority of cases of fetal hydrops are diagnosed on routine prenatal ultrasound. Some cases may present with rapidly increasing abdominal girth, abdominal discomfort, increased symphysio-fundal height for gestation or in preterm labor precipitated by polyhydramnios. A small number may present with a rare condition known as "mirror syndrome" (Ballantyne syndrome), in which the mother develops atypical pre-eclampsia like features (peripheral edema, pulmonary edema, hypertension and proteinuria).

This condition may be misdiagnosed as pre-eclampsia. However it is a separate clinical entity with case reports of the maternal condition improving with resolution of the hydrops in-utero. In most cases however, such "mirror syndrome" cases warrant prompt delivery in the maternal interest.

Fetal hydrops can be diagnosed on fetal ultrasound examination when there is an abnormal fluid collection within two fetal compartments. This includes fetal ascites (Figure 1), pleural or pericardial effusion (Figure 2, Figure 3) and skin edema greater than 5mm (Figure 4). Other sonographic findings can include polyhydramnios, an enlarged placenta and a cystic hygroma.

Figure 1.

Ascites

Figure 2.

Pleural effusion

Figure 3.

Pericardial effusion

Figure 4.

Skin edema

Skin edema or subcutaneous edema is defined by skin thickness greater than 5mm. The placenta can be considered thickened if it measures greater than 6cm from myometrial to placental edges. Ascites is diagnosed when an echolucent rim is seen within the entire fetal abdomen in a transverse plane. A pericardial effusion can be diagnosed when an echolucent rim of at least 3mm is seen around both cardiac ventricles.

When fluid is seen within the thorax but outside the pericardium, a pleural effusion can be diagnosed and this may be unilateral or bilateral. Other ultrasound features may include tricuspid regurgitation, which is demonstrated on color Doppler interrogation of the right side of the fetal heart, and polyhydramnios, which is confirmed by amniotic fluid index greater than 25cm or maximum vertical pocket of fluid greater than 10cm.

Key features on ultrasound :

  • Skin edema

  • Pleural effusions

  • Pericardial effusion

  • Ascites

  • Polyhydramnios

  • Tricuspid regurgitation

The key test to be carried out once fetal hydrops is detected on fetal ultrasound is a maternal indirect Coombs test for antibodies that can categorize the fetal hydrops into either immune or non-immune hydrops.

Maternal antibodies detected

An array of different circulating maternal antibodies are known to be associated with hemolytic disease of the fetus and can ultimately cause hydrops. Rhesus isoimmunization is the most common cause of IH. The Rhesus system is made up of 5 antigens: D, C, c, E and e. The D antigen confers Rhesus positivity. There are a number of other antibodies than can precipitate isoimmunization, the most common being Kell (Anti K1 and K2), MNS, Duffy (Fya, Fyb) and Kidd (Jka, Jkb).

Once such antibodies are detected titers should be checked every 4 weeks until 28 weeks and every 2 weeks thereafter. The indirect Coombs test determines the degree of alloimmunization by measuring the maternal IgG response. This can be reported as reciprocals of the last tube dilution used (e.g. 1:8 or 1:32) or as international units (IU) per milliliter. For the non-Rhesus antibodies, frequency of testing should be individualized.

Table I. Critical Values for Anti-D Levels

Table I.

Critical Values for Anti-D Levels
International Units Titer Levels Association with HDFN
<4IU <1:8 Rare
4-15IU 1:8-1:32 Intermediate
>15IU >1:32 High

In the setting where IH has been diagnosed, paternal zygosity is not essential as it will not alter the management of the patient. IH should be treated as an emergency and the patient should be transferred to a tertiary referral unit with the ability to perform percutaneous umbilical blood sampling and urgent intrauterine transfusion (IUT). A formal detailed fetal ultrasound should be performed to assess the severity of the hydrops and eliminate any other possible cause of fetal hydrops.

Middle cerebral artery Doppler

As an anemic fetus attempts to improve oxygenation to the brain, cardiac output increases. The blood has a reduced viscosity due to the anemia. Both of these factors lead to increased velocity of blood flow. The peak systolic velocity (PSV) of blood flow through the middle cerebral artery correlates with moderate to severe fetal anemia. (Figure 5) Mari et al first described the use of the MCA Doppler PSV in monitoring pregnancies at risk of anemia. (MCA Doppler, Figure 5).

Figure 5.

Middle cerebral artery (MCA) Doppler study

The results of their study concluded that a threshold of 1.5 multiples of the median (MoM) could be used to predict moderate to severe anemia. The MCA is a particularly suitable vessel for such surveillance as it is relatively straightforward to achieve good quality Doppler waveforms, with excellent inter-observer and intra-observer variability. It is essential that a standardized technique is used if the published data from Mari et al are used for clinical management. This involves adequate magnification of an axial image through the fetal head, with orientation of the image such that there is a zero degree angle of insonation of the ultrasound beam with the MCA vessel.

The use of the MCA Doppler PSV to diagnose fetal anemia has radically changed the managment of IH and NIFH. In the setting of IH or NIFH, if the MCA Doppler is abnormal, it is almost certain that fetal anemia is the underlying cause, and arrangements should be made to proceed with urgent percutaneous umbilical blood sampling and possible intrauterine transfusion as soon as possible.

Maternal antibodies not detected

In this situation the underlying cause of the fetal hydrops is more difficult to determine as there is a broad range of associated etiologies. A detailed fetal ultrasound examination should be performed, which may require referral to a tertiary level maternal-fetal medicine center.

All of the fetal conditions listed in Table II should be considered in the differential diagnosis of non-immune fetal hydrops:

Table II.

Conditions associated with Fetal Hydrops, grouped by cause
Cardiovascular (22%)MalformationsArrythmiasOthers Hypoplastic left heartAtrioventricular canal defectAtrial septal defectVentricular septal defectTetralogy of FallotHypoplastic right ventricle Ebstein’s anomalyTruncus arteriosusTransposition of the great vesselsAortic stenosis or atresiaPulmonary stenosis of atresiaCardiomyopathyEndocardial fibroelastosisPremature closure of ductus arteriosusAtrial flutterSupraventricular tachycardiaBradyarrhythmiaHeart blockWolff-Parkinson-White syndromeHigh-output failureCardiac rhabdomyoma or other neoplasia
Idiopathic (18%) Unknown
Chromosomal (13%) 45XTrisomy 21Trisomy 18Trisomy 13TriploidyTetraploidyOther
Haematological (10%) Alpha thalassemiaParvovirus B19 InfectionFeto-maternal transfusion/In-utero hemorrhageGlucose-6-Phosphate Dehydrogenase deficiencyRed cell enzyme deficiencies
Infectious (7%) Parvovirus B19CytomegalovirusToxoplasmosisSyphilisHerpesRubella
Thoracic (6%) Congenital cystic adenomatoid malformation of lungDiaphragmatic herniaIntrathoracic massPulmonary sequestrationChylothoraxAirway obstructionPulmonary lymphangiectasisPulmonary neoplasiaBronchogenic cyst
Twinning Twin to twin transfusion syndromeAcardiac twin
Genetic syndrome Noonan syndromeArthrogryposisMultiple pterygiumPena-Shokeir syndromeNeu-Laxova syndromeTuberous sclerosisMyotonic dystrophyPrune-belly syndromeCornelia de Lange syndrome
Genitourinary Congenital nephrosis (Finnish)Polycystic kidneyUrethral stenosis or atresiaRenal vein thrombosis
Skeletal dysplasia AchondroplasiaAchondrogenesisOsteogenesis ImperfectaShort rib polydactylyThantophoric dwarfismOthers
Inborn errors of metabolism Gaucher diseaseGM1 gangliosidosisMucolipidosesMucopolysaccharidosesSialidosis
Gastrointestinal Esophageal or intestinal atresiaMidgut volvulusMeconium peritonitisIntestinal duplicationMalrotationHepatic fibrosisCholestasisBiliary atresiaHepatic vascular malformations

A multi-disciplinary team approach involving maternal-fetal specialists, neonatologists, geneticists and relevant pediatric sub-specialists is appropriate when a diagnosis of non-immune hydrops is confirmed. A detailed genetic history from both parents to determine any underlying hereditary conditions is required, as well as evaluation for recent exposure to infections and drug use.

Maternal blood should be analyzed for antibody screen. Further laboratory work-up should include a Kleihauer-Betke screen, complete blood count and erythocyte indices, hemoglobin electrophoresis and glucose-6-phosphate dehydrogenase deficiency. A TORCH (TOxoplasmosis, Rubella, Cytomegalovirus (CMV) and Herpes simplex) screen, rapid plasma reagent test (RPRT) and parvovirus B19 IgG and IgM titers should be tested to help exclude recent infection as a possible cause.

Once a detailed fetal ultrasound has been carried out to detect any structural defects or makers of fetal aneuploidy, an amniocentesis should be offered to determine the fetal karyotype. A sample of amniotic fluid can also be sent for alpha-feto-protein levels (raised in Finnish nephrosis and sacrococcygeal teratoma) and polymerase chain reaction (PCR) testing for infectious agents outlined above. Relevant metabolic testing can be performed as deemed necessary from the genetic history.

A fetal echocardiography should be performed to identify cardiac structural abnormalities and rhythm disturbances. A middle cerebral artery (MCA) Doppler study (Figure 5) should be performed to identify fetal anemia. Mari et al proved the sensitivity of the MCA peak systolic velocity Doppler in non-invasively identifying the fetus with moderate to severe anemia. This has essentially replaced the need for invasive percutaneous umbilical blood sampling purely as a diagnostic test for fetal anemia. Such a comprehensive assessment of the fetus will help clarify whether the hydrops is idiopathic or secondary to an underlying condition. The more detailed the evaluation, the less likely a final diagnosis of idiopathic NIFH will be obtained.

Table III. Checklist for the diagnosis of fetal hydrops

Table III.

Checklist for the diagnosis of fetal hydrops
Indirect Coombs
Detailed fetal ultrasound examination
Fetal echocardiography
MCA Doppler study
Maternal serum for:
CBC
TORCH
Parvovirus IgG/IgM
Kleihauer Betke
Hemoglobin electrophoresis
Glucose-6-phosphate dehydrogenase def.
Amniocentesis for:
Fetal Karyotype (PCR/FISH)
Alpha-feto-protein
PCR (infectious agents, metabolic screen)

3. Management

Immune hydrops

Antepartum

Arrangements should be made to transfer the patient to a tertiary referral maternal-fetal medicine unit with the ability to perform percutaneous umbilical blood sampling (PUBS) and intrauterine fetal blood transfusion. This will require the back-up support of hematology and blood transfusion laboratory staff. If the gestational age is between 24 and 34 weeks gestation a course of betamethasone or dexamethasone should be administered to reduce complications of prematurity.

Maternal blood should immediately be sent to assist in processing blood for fetal transfusion, which needs to be ready at the time of PUBS. This is generally group O red cells packed to a hematocrit of approximately 80%, less than 4 days old, irradiated, anti-CMV, Kell negative and negative for the antigen to which the mother is sensitized.

Performance of the fetal intrauterine blood transfusion is under sterile conditions. A decision should be made with neonatologists in advance of the procedure as to whether the fetus is considered viable at the time of the procedure. If the fetus is considered viable, it is optimal to perform the procedure in an operating room environment with immediate availability of anesthesiology support, in case urgent delivery is required.

The target for fetal blood sampling and possible transfusion is usually the umbilical vein at the placental cord insertion site. This target can vary however, depending on the gestational age, placental and fetal positions. Other potential targets include the umbilical vein at the fetal cord insertion site or the intrahepatic umbilical vein. The umbilical vein is cannulated under direct ultrasound guidance with a 20-gauge spinal needle. A sample is withdrawn into a heparinized tuberculin syringe and laboratory staff should be on standby to perform an immediate determination of fetal hematocrit, hemoglobin, platelet count, total bilirubin blood type and antibody screen.

An elevated mean corpuscular volume confirms the blood is fetal in origin. If the fetus is active and there is concern that this movement may dislodge the needle pancuronium or vecuronium may be used to temporarily reduce fetal movements. Once the hematocrit has been established a formula can be used to estimate the volume of blood to be transfused to correct the fetal anemia. Care should be taken not to fluid overload the fetus with the transfusion. It is advised that the goal of the first transfusion should be to bring the hematocrit to 20-25% and not greater than four times the starting hemtocrit.

Over-loading the already hydropic fetus can cause sudden intrauterine death. In cases where only an initial partial transfusion has been completed, a repeat transfusion should be performed within 48-72 hours to complete the treatment. If the underlying cause is confirmed to be hemolysis from Rhesus isoimmunization, then a schedule of repeat transfusions should be carried out at 2-3 weekly intervals until 35 weeks gestation. Such intervals can be optimized depending on subsequent MCA Doppler evaluation.

After fetal intervention in the potentially viable fetus close observation is necessary. This can be in the form of daily fetal heart rate testing and biophysical profile evaluation, with the level of surveillance decreasing if there are signs of hydrops resolving. Sonographic growth estimations should be carried out every 2 weeks.

Delivery

Timing and mode of delivery can be variable, depending on the severity of the hydrops, gestational age and response to transfusion. In the scenario where the fetus responses well to the initial transfusion and repeated transfusions and monitoring show resolution of the hydrops, it is reasonable to offer a trial of labor. These pregnancies should not continue beyond 38 weeks' gestation.

If there is no improvement in the hydrops despite correction of the fetal anemia or if there is non-reassuring fetal testing then emergency delivery by cesarean may be necessary. Cesarean delivery is considered safer to avoid soft tissue dystocia and injury to the mother and fetus, although there is limited evidence to support this claim.

Non-immune hydrops

In cases of non-immune hydrops the management plan depends on the etiology and the gestational age at presentation. A diagnosis of an underlying condition must first be rigorously excluded by following the checklists outlined above. If a treatable cause of the hydrops is identified then the management plan can be amended accordingly. However, the prognosis is likely to be poor in many cases, especially if there is an underlying cardiac malformation or aneuploidy. If the fetus is pre-viable then termination of pregnancy may be offered after counseling with a relevant multidisciplinary team.

Expectant management

If the fetus is considered viable careful sonographic surveillance should be implemented. It may be reasonable to admit the mother for daily non-stress testing in the form of fetal heart rate tracing and biophysical profile evaluation. Assessment of fetal growth should be carried out every 2 weeks and the fetal anatomy re-assessed at each ultrasound. If the fetus is between 24 and 34 weeks gestation then bethamethasone or dexamethasone should be administered to reduce complications of prematurity. The timing of delivery depends on fetal testing and gestation. With non-reassuring fetal testing delivery should be expedited. Otherwise expectant management may be followed up to a maximal gestational age of 37 weeks.

Fetal therapy

  • In cases where anemia is identified by MCA Doppler studies, intrauterine fetal transfusion can treat the anemia and hydrops may improve. The steps for fetal transfusion are outlined in the section for immune hydrops.

  • Medical therapy may be administered to correct fetal arrhythmias.

  • Fetal surgical treatments in the form of thoracentesis or thoracoamniotic shunts can be used to treat pleural effusions. These treatments are likely only be useful for conditions where the hydrops is secondary to intrinsic thoracic malformations, rather than as an effective therapy for generalized hydrops.

  • Other experimental procedures have also been described, such as intraperitoneal albumin infusions, peritoneal-amniotic shunts and open fetal surgical resection of teratoma. However, given the limited data to support the efficacy of these procedures, they should likely be considered experimental.

Delivery

As with immune hydrops the optimal mode of delivery for a fetus with hydrops is unclear but if the fetus is considered viable it will usually be by means of cesarean section to reduce maternal and fetal trauma.

Special considerations

Care of the neonate

Delivery of any fetus affected by hydrops should be at a tertiary referral unit with appropriately experienced neonatologists and relevant pediatric subspecialists. Intubation may be required and technically challenging due to the possibility of marked skin edema. For adequate ventilation thoracentesis and paracentesis may have to be carried out in the immediate neonatal period. The resuscitation of a hydropic neonate also may require umbilical cannulation and the use of blood products, albumin and diruetics to stabilize the infant.

4. Complications

Preterm labor

Polyhydramnios commonly coexists with fetal hydrops and may result in preterm premature rupture of membranes and/ or preterm labor. Decisions on whether or not to use tocolytic medications or indeed continue treatment once the diagnosis of preterm labor is established may be difficult. While there may be value in delaying delivery until corticosteroids and the fetal work-up are complete, tocolytics are likely to have very limited value in such cases. Additionally, there may be a role for amnioreduction to relieve symptomatic polyhydramnios in the mother, which might also reduce the chances of preterm labor or preterm rupture of membranes.

Maternal compromise

In pregnancies affected by fetal hydrops there is an associated risk to the mother with respect to developing "mirror syndrome" (Ballantyne syndrome), an atypical pre-eclampsia-like syndrome. There is also an increased risk of antenatal hemorrhage, likely related to uterine overdistension associated with polyhydramnios. Each patient should be educated about the signs and symptoms of both conditions and advised to present to hospital should relevant clinical features develop. In these situations the maternal condition takes precedence, as the prognosis for the fetus in most cases will be relatively poor.

Recurrence risks

In immune hydrops the recurrence risk is significant and is dependent on the paternal Rhesus (Rh) status. If the father is homozygous for Rh(D) allele, then all of the offspring will be Rh D positive and at risk of developing hydrops. If the father is heterozygous then there is a 50/50 chance that a future fetus may be RhD positive and at risk. If the fetus is Rh(D) negative then the patient can be reassured that there should be no chance of recurrent fetal hydrops. PCR amplification for fetal DNA from maternal serum is now possible as early as 14 weeks, which may allow for accurate determination of the fetal Rh status early in a subsequent pregnancy.

It is difficult to assign a recurrence risk in cases of non-immune hydrops as it will depend on the specific underlying etiology. Such recurrence risk counseling will be dependent on a detailed post mortem examination being carried out to determine the precise underlying pathology. While occasional cases of recurrent idiopathic non-immune hydrops have been reported, such recurrences are likely to be quite rare.

5. Prognosis and Long-term outcome

The prognosis for any fetus with hydrops is extremely guarded. With the advances in monitoring and treatment of Rh sensitized pregnancies immune hydrops is rarely seen. There is limited data regarding outcomes after treatment for hydrops specifically, although a small series showed a survival rate of 88% after intrauterine transfusion. The focus is now largely on the long-term neurological outcomes for fetuses at 2 and 3 years of age who underwent in-utero transfusion. Weisz et al in 2009 reported that there was no difference between children who were treated with intrauterine transfusion for severe anemia and those who had mild to moderate anemia in terms of cognitive and motor development.

Perinatal mortality rates in non-immune hydrops range between 40% and 90% depending on the underlying condition. Survival rates for a hydropic fetus delivered prematurely with cardiac malformations approach zero percent. For those that survive the risk of neurodevelopmental delay is in the region of 11%.

A retrospective study carried out in 2007 by Abrams et al reviewed a large national database of 253,651 discharges form 162 neonatal intensive care unit (NICU) and identified 598 patients discharged from the NICU with a report of fetal hydrops. The mortality rate in this cohort was 36%. The most common causes for hydrops identified were; congenital heart disease 13.7%, cardiac arrhythmias 10.4%, congenital anomalies 8.7%, chromosomal abnormalities 7.5%, congenital viral infection 6.7%, congenital anemia 5% and congenital chylothorax 3.2%. Prematurity, low 5-minute Apgar score and need for high levels of support during the first day after birth were all independent risk factors associated with death.

6. What is the evidence for specific management and treatment recommendations

Bellini, C. "Etiology of Nonimmune Hydrops Fetalis: A Systematic Review". Am J Med Genet. vol. Part A 149A. 2009. pp. 844-51.

(This is an excellent systematic review and meta-analysis of non-immune hydrops specifically aiming to identify the causes and frequency of all causes of non-immune hydrops. 51 papers were reviewed that included 5,437 cases of non-immune hydrops. 14 different etiologic categories were identified and they also provide a pathophysiologic basis for each cause listed.)

Weisz, B. "Outcomes of severely anaemic fetuses treated by intrauterine transfusions". Arch Dis Child Fetal Neonatal Ed. vol. 94. 2009. pp. F201-4.

(There is limited evidence available for long-term outcomes in pregnancies affected by hydrops. This study set out to examine the effect of severity of fetal anemia on neonatal outcome and long-term development. It included 54 pregnancies affected by alloimmunization. Of the 54 fetuses included; 21 were considered to have mild-moderate anemia and 33 severe cases including cases of hydrops. The overall survival rate after IUT was 87%. The two groups were followed up to age 5. The long term outcomes were measured in terms of abnormal motor development, abnormal cognitive function, paramedical therapy and attendance at "normal" formal education. There was no difference found between the two groups. This is important information to have available when counseling patients.)

Opekes, D. "Doppler Ultrasonography versus Amniocentesis to Predict Fetal Anemia". N Engl J Med. vol. 355. 2006. pp. 156-64.

(A multi-center prospective trial that set out to assess whether Doppler measurements of the peak systolic velocity of blood flow in the middle cerebral artery were at least as sensitive and accurate as measurement of amniotic-fluid (delta) OD 450 for diagnosing severe fetal anemia in the alloimmunized pregnancy. A total of 165 fetuses were included with 74 diagnosed with severe anemia after fetal blood sampling. The sensitivity of the MCA Doppler PSV study was 88% and specificity ws 82%. This proved that Doppler ultrasonography was more sensitive and accurate than the measurement of amniotic-fluid (delta) OD 450.)

Mesogitis, S. "Fetal intravascular transfusion for hydropic disease due to Rhesus isoimmunization". Fetal Diagnosis and Therapy. vol. 20. 2005. pp. 431-6.

(A retrospective study that looked at the outcomes of 18 hydropic fetuses treated with intrauterine blood trasnfusions. Their overall survival rate was 88.9%. Intrauterine reversal of hydrops occurred in 90% of "mildly" hydropic fetuses and 57% of "severely" affected fetuses. They concluded that the survival after intra-uterine transfusion was dependent on the severity of the hydrops.)

Mari, G. "Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses". N Engl J Med. vol. 342. 2000. pp. 9-14.

(The purpose of this study was to determine the value of noninvasive methods of diagnosing fetal anemia. A total of 111 fetuses were examined during the course of this study. Hemoglobin concentrations in blood obtained by cordocentesis were measured and the PSV in the MCA Doppler were also measured. This study found that the sensitivity of an increased PSV in the MCA Doppler for the prediction of moderate or severe anemia was 100%. They had a false positive rate of 12 percent. This was the first study to demonstrate how the MCA Doppler PSV could be used to monitor alloimmunized pregnancies.)

Hernandez-andrade, E. "Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops". Ultrasound Obstet Gynaecol. vol. 23. 2004. pp. 442-5.

(This study investigated the potential value of the fetal MCA-PSV in the assessment and management of non-immune hydrops. It was a cross-sectional study of 16 pregnancies referred to tertiary unit for futher investigation of fetal hydrops. There was a significant association between the delta (the difference in SD from the normal mean for gestation) MCA-PSV and delta hemoglobin concentration. This determined that measurement of the fetal MCA-PSV can identify a sub-group of fetuses affected with non-immune hydrops as a result of fetal anemia.)

Abrams, ME. "Hydrops Fetalis: A retrospective review of cases reported to a large national database and identification of risk factors associated with death". Paediatrics. vol. 120. 2007. pp. 84-9.

(This is a large retrospective review that provides information on the neonatal outcomes of infants with a diagnosis of fetal hydrops. It is a large cohort of 598 affected fetuses. The incidence of hydrops in this population who were admitted to NICU is 0.28%. It also analyses the risk factors associated with a poorer outcome such as prematurity and etiology.)

Bianchi, DW, Crombleholme, TM, D'Alton, ME. "Fetology: Diagnosis and Management of the Fetal Patient (Chapters 27 & 28)". McGraw Hill. 2000.

(These chapters outline the management of the fetal patient affected by hydrops fetalis from pre-natal diagnosis to delivery and the immediate neonatal period. It draws on the most recent medical evidence and expert opinion to provide a comprehensive multi-disciplinary approach to managing these complex pregnancies.)
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