PRENATAL DIAGNOSIS

Prenat Diagn 2011; 31: 186195.

Published online 4 January 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pd.2677

Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents?

Susana Santo1 , Sahar Mansour2 , Basky Thilaganathan1 , Tessa Homfray2 , Aris Papageorghiou1 , Sandra Calvert3 and Amar Bhide1 *
1

Fetal Medicine Unit, Academic Department of Obstetrics and Gynaecology, St Georges Hospital Medical School, London, UK 2 SW Thames Regional Genetic Service, St. Georges Hospital, London, UK 3 Neonatal Unit, St. Georges Hospital, London, UK Objective The aim of this study is to outline the aetiology and outcome of a series of fetuses with nonimmune hydrops (NIH), detected prenatally. The ndings are compared with a comprehensive review of recent reports. Methods This is a retrospective study reviewing all pregnancies complicated by NIH in the fetus and continued after 20 weeks of pregnancy over a period of 10 years. Outcome was obtained from postmortem reports, discharge summaries, communication with the clinicians or information from the parents. A literature search was also performed to identify all reports on NIH in the last 10 years. Results Seventy-one fetuses affected by NIH were included in this study. The aetiology of the NIH was identied prenatally in 40 cases. The most common causes of NIH were thoracic disorders, infections and cardiovascular disorders. Forty-four of the 71 (62%) fetuses were live-born. There were 10 neonatal deaths. Of the remaining 34 babies, 17 infants survived without morbidity. Conclusion The survival rate of NIH is at least 48% in this study. Prenatal identication of the cause is possible in 56% of cases. The risk of neurodevelopmental delay in those that survive is 3 of 28 (11%). Copyright 2011 John Wiley & Sons, Ltd.
KEY WORDS:

hydrops; non-immune; outcome; mortality; morbidity

INTRODUCTION Non-immune hydrops (NIH) accounts for 7687% of all cases of hydrops (Graves and Baskett,1984; Santolaya et al., 1992). NIH affects 1 : 1500 (Graves and Baskett, 1984) to 1 : 3750 deliveries (Hutchison et al., 1982), and the reported perinatal mortality rate ranges from 55 to 98% with this condition (Sohan et al., 2001). Although there are several reports on the aetiology, natural history and outcome of NIH, they have signicant limitations. First trimester screening for aneuploidies is likely to have reduced the relative contribution of chromosomal abnormalities to NIH in contemporary clinical practice as compared to older studies. Advances in ultrasound and genetic techniques may have led to an improvement in prenatal diagnosis of the underlying cause. Very few studies report on the outcome of survivors beyond discharge from the hospital. Many series report on the aetiology but do not make a distinction between prenatal or postnatal diagnosis, which is vital for appropriate counselling. Studies exclusively reporting infants born with NIH are inherently biased due to the exclusion of intrauterine deaths and pregnancy terminations.
*Correspondence to: Amar Bhide, Fetal Medicine Unit, 4th Floor, Lanesborough Wing, St. Georges Hospital NHS Trust, London SW17 0QT, UK. E-mail: abhide@sgul.ac.uk

The aim of this study is to outline the aetiology and outcome of a large, single-centre series where the inception cohort was assembled at the time of prenatal detection of NIH, and the cohort was followed up beyond discharge from the hospital. Also presented is an overview of data published in the last 10 years regarding the natural history of NIH in order to provide useful information for clinical practice. METHODS This is a retrospective study of all cases of NIH presenting to a tertiary referral Fetal Medicine Unit between 1999 and 2009. NIH was dened as the presence of fetal subcutaneous tissue oedema associated with serious effusion in one or more cavities including pericardial, pleural and abdominal effusions, in the absence of atypical red cell antibodies. All fetuses underwent detailed structural and cardiac ultrasound examinations. Trans-abdominal scans were performed using ultrasound equipment consisting of 35 MHz convex sector probe and GE Voluson E8, Toshiba Aplio, Aloka 4000 and Phillips iU22 ultrasound machines. Fetal karyotype, maternal viral screening (toxoplasmosis, cytomegalovirus and parvovirus B19) and KleihauerBetke testing were offered to every case. Maternal haemoglobin electrophoresis, treponemal screening and rubella immunity are part of booking
Received: 6 October Revised: 16 November Accepted: 16 November Published online: 4 January 2010 2010 2010 2011

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investigations and were checked from maternal records. Parents made the decision of pregnancy termination after an appropriate counselling. Postmortem examination was strongly recommended in cases undergoing pregnancy termination. The current analysis was limited to fetuses with NIH where the pregnancy continued beyond 20 weeks of gestation. Cases of hydrops in monochorionic twins due to twin-to-twin transfusion syndrome were excluded. The prenatal diagnosis was conrmed either on postnatal investigations or on postmortem examination. Outcome was obtained from postmortem reports, discharge summaries, clinic letters, communication with the general practitioners and referring physicians or information from the parents. A literature search of PubMed (National Library of Medicine) was performed to identify all reports in English language on NIH, published after January 1999 to October 2009. Abstracts from relevant scientic meetings but not subsequently published as full articles were excluded. The literature search was performed using the terms nonimmune, non immune, hydrops and fetalis to identify the reports. The terms nonimmune and hydrops yielded 133 articles, the search with non and immnune and hydrops yielded another 483 articles and with hydrops and fetalis yielded 907. The combined set included 1329 articles (Figure 1). The titles and abstracts of these were reviewed and a total of 32 articles were considered relevant. A further 12 articles were excluded because either they included only cases before 20 weeks of gestation or because the aetiology of hydrops could not be identied. The aetiology of NIH was classied into the following 11 categories: haematologic, cardiovascular, thoracic, infections, aneuploidy, syndromic/genetic, lymphatic dysplasia, extrathoracic tumours, inborn errors of metabolism, others and idiopathic (a further breakdown of disorders in each category is given in Appendix 1). The studies included in the review were classied into those dealing with prenatal and postnatal periods and postmortem series (Table 1). Outcome of NIH was reported as pregnancy termination, intrauterine death,

1329 articles

1297 EXCLUDED Case Reports Reviews

32 articles

12 EXCLUDED Hydrops 1st trimester Articlesthat do not give breakdown of causes / outcome

20 articles

Figure 1Details of literature research

live birth and survival beyond 28 days in prenatal studies. The outcome of postnatal studies of NIH was reported as survival rate. Analysis of morbidity was not possible due to lack of information in most articles.

RESULTS Over the 10-year period, 71 fetuses (70 singleton and 1 twin of a dichorionic twin pregnancy) affected by NIH were included in the study. The median maternal age was 32 years [interquartile range (IQR) 2636 years]

Table 1Studies included in the analysis of aetiology and outcome First author (year) Swain S (1999) Heinonen S (2000) Ismail KMK (2001) Sohan K (2001) Suwanrath-Kengpol C (2005) Hofstaetter C (2006) Liao C (2007) Ratanasiri T (2009) Nakayama H (1999) Wy CAW (1999) Haverkamp F (2000) Liu CA (2002) Mascaretti RS (2003) Simpson JH (2006) Trainor B (2006) Abrams ME (2007) Huang HR (2007)
Copyright 2011 John Wiley & Sons, Ltd.

Journal Aust NZ Obstet Gynecol Acta Obstet Gynecol Scand J Matern Fet Med Acta Obstet Gynecol Scand Gynecol Obstet Inv J Matern Fet Neonatal Med Fetal Diagn Ther J Med Assoc Thai Acta Paediatr Am J Perinatol BJOG Chang Gung Med J Rev Hosp Clin Fac Med S.Paulo Fetal Diagn Ther Ulster Med J Pediatrics Am J Perinatol

Number of cases 37 58 50 79 66 91 138 79 47 35 107 16 20 24 28 512 25

Selection of cases Prenatal Prenatal Prenatal Prenatal Prenatal Prenatal Prenatal Prenatal Postnatal Postnatal Postnatal Postnatal Postnatal Postnatal Postnatal Postnatal Postnatal
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71 fetuses with Non-immune Hydrops

S. SANTO et al.

Extrathoracic tumoursb

15 Terminations of pregnancy (21%)

12 Intrauterine deaths (17%)

44 Live births (62.0%)

Syndromes/ genetic

17 Intact

11 Morbidity

6 Lost follow-up

Table 2Includes prenatal studies that looked at all causes of non-immune hydrops and gave breakdown of causes (since 1999)

Lymphatica

Haematologic

Review of prenatal studies

The aetiology and outcome analysis of NIH in the nine prenatal studies included a total of 669 pregnancies. The relative contribution for aetiology and outcome is shown in Table 2. Three publications described the study population with a large proportion of haemoglobinopathies seen in population specic to east Asia (Ratanasiri et al., 2009; Suwanrath-Kengpol et al., 2005; Liao et al., 2007). These causes are unusual in most other populations. If these were excluded, the most frequent causes of NIH in prenatally diagnosed cases were aneuploidy
Copyright 2011 John Wiley & Sons, Ltd.

Number

1 1 132 (19.7)
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a Including b Including

32 77 1 20

and the median gestational age at the diagnosis of NIH was 27 weeks (IQR 2332 weeks). There was no signicant difference in fetal gender (51% male and 49% female). The cause of NIH was identied prenatally in 40 of 71 (56%) cases and postnatally in 18 of 71(25%) cases. In remaining 13 of 71 (18%) cases the cause of NIH could not be ascertained. The most common causes of NIH were thoracic, infections and cardiovascular disorders, accounting for 31 of 40 cases where the diagnosis was made prenatally. The details of diagnoses in individual cases are shown in Appendix 2. There were 12 (17%) intrauterine deaths (Figure 2). Forty-four of the 71 (62%) fetuses survived till birth with a median gestational age at delivery of 35 weeks (IQR 3238 weeks) and a mean birth weight of 2692 820 g. There were 10 (10/71, 14%) neonatal deaths. Seventeen infants (17/28, 61%) survived without morbidity. Twelve of the intact survivors, with no signicant morbidity, had NIH due to parvovirus (n = 7) or hydrothorax/idiopathic (n = 5). Eleven cases (11/28, 39%) had some co-morbidity that varied from some mild conditions to severe neurodevelopmental delay (3/28, 11%). Six were lost to follow-up. The mean duration of follow-up was 29 months (range 184 months). See Appendix 2 for more details.

Thoracic

1 8 7 3 20 2 10 28 9 3 21 14 9 2 6 11 7

Figure 2Patient pathway in the current study

Cardiovascular

Aneuploidy

14 23 22 3 2 90 (13.5)
cystic hygroma. placental tumours.

Ratanasiri T Liao C Hofstaetter C SuwanrathKengpol C Ismail KMK Sohan K Heinonen S Swain S Current study Total (%)

Author

50 79 58 37 71 669

79 138 91 66

8 10 4 7 12 88 (13.2)

Infection

5 11 2 6 6 77 (11.5)

2 11 2 13 53 (7.9)

10 1 2 29 (4.3)

2 3 12 2 2 25 (3.7)

34 survivors > 28 days (48%)

2 1 1

4 2

10 Neonatal deaths (14%)

1 3 2 3 3 18 (2.7)

Others

1 1 5 (0.7)

1 2

8 16 13 14 31 152 (22.7)

Idiopathic

39 11 11 9

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Table 3Outcome of pregnancy in prenatal studies Authora Ismail Sohan Kb Heinonen S Swain Sc Current study Total (%) Number 50 78 58 40 71 297 Live birth 22 33 7 12 44 118 (39.7) Termination pregnancy 19 30 42 4 15 110 (37.1) Intrauterine death 9 15 9 24 12 69 (23.2) Survival >28 days (%) 15 22 5 5 34 81 (30.0) (28.2) (8.6) (12.5) (47.9) (27.3)

a Ratanasiri T, Liao C and Suwanrath-Kengpol C articles were excluded because they report to populations with a high prevalence of haemoglobinopathies; Hofstaetter C article was excluded because only perinatal mortality rate was available. b One case was excluded because the outcome was note specied. c Three cases of twin-to-twin transfusion syndrome were included because outcome was not specied according to the cause of NIH.

Table 4Includes postnatal studies that looked at all causes of NIH and gave breakdown of causes (since 1999) Author Abrams ME Huang HR Simpson JH Trainor B Mascaretti RS Liu CA Haverkamp F Nakayama H Wy CAW Total (%) Number excluding frequent causesa 223 12 13 17 10 2 48 22 24 371 Lymphatic 29 6 2 20 6 2 65 (17.5) Syndromes/genetic 30 1 1 12 1 45 (12.1) Metabolic 7 1 8 (2.2) Idiopathic 157 6 10 17 8 2 16 16 21 253 (68.2)

NIH, non-immune hydrops. a Frequent causes of NIH that should be identied on the prenatal investigations were excluded (aneuploidy, cardiovascular, infections, thoracic, extrathoracic tumours, haematologic and others).

(19%), cardiovascular abnormalities (15%), infections (14%) and thoracic disorders (12%). The rate of pregnancy termination was 37%. The rates of intrauterine death, live birth and survival beyond 28 days were 23, 40 and 27%, respectively (Table 3).

Table 5Outcome of pregnancy in postnatal studies Author Abrams ME Huang HR Simpson JH Trainor B Mascaretti RS Liu CA Haverkamp F Nakayama H Wy CAW Total
a

Number 409 25 24 28 20 16 107 47 35 711

Survivors 223 12 9 14 9 3 61 18 17 366

Survivors (%) 54.5 48.0 37.5 50.0 45.0 18.8 57.0 38.3 48.6 51.5

Review of postnatal studies

A total of 814 infants were included. The aetiology and outcome of NIH in the nine postnatal studies are shown in Tables 4 and 5. To evaluate the rate of rare causes detected in the postnatal period, the frequent groups of NIH that are usually identied in prenatal investigations (aneuploidy, infections, cardiovascular disorders, thoracic, extrathoracic tumours and haematologic disorders) were excluded. The rate of rare causes was lymphatic 18%, syndromic/genetic 12%, metabolic 2% and idiopathic 68% (Table 4). The mortality rate was 48% (Table 5).

a Newborns (103) were excluded because they were transferred to another neonatal care unit.

DISCUSSION The data from the current study show that in a prescreened population the survival rate of NIH is at least 48%. The perinatal mortality rate is 39% (12 intrauterine deaths and 10 neonatal death out of 56). The commonest underlying causes are thoracic, infectious
Copyright 2011 John Wiley & Sons, Ltd.

and cardiovascular in origin. Prenatal identication of the cause is possible in 56% of cases, but the cause remains unexplained in 18% of cases even after postnatal investigations. The survival rate of those fetuses born alive is at least 64%, and 61% of those that survive have no morbidity. The risk of neurodevelopmental delay in those that survive is 3 of 28 (11%); however a further eight cases (28%) had other morbidity. So, 39% of survivors (11/28) had some co-morbidity. Parvovirus infection is associated with a very positive prognosis (Appendix 2). NIH is an end-stage process for a heterogeneous group of disorders and by itself constitutes a poor
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S. SANTO et al.

prognostic factor for any particular disorder. Hydrops may represent a primary disturbance in the mechanisms that regulate uid movements between vascular and interstitial spaces, or more frequently it can be a consequence of compensatory mechanisms invoked by the fetus to preserve adequate supply of oxygen and substrates in the face of cardiovascular dysfunction (Apkon, 1995). Ultrasound examination establishing the diagnosis of hydrops fetalis is the starting point. The main problem is not how to recognize hydrops but to recognize the underlying cause. The identication of the cause of hydrops is crucial because the prognosis of the fetus with hydrops is directly dependent on the underlying condition (Jones, 1995). As the list of conditions that can be associated with NIH is long, the evaluation of the fetus requires an integrated approach that should begin with a detailed ultrasound examination of fetal anatomy and blood ow. Further investigations should be based on the ultrasound ndings and may include invasive tests and maternal blood testing (Jones, 1995).

What is the probability of nding a cause on prenatal evaluation?

Literature review of prenatal studies shows that a cause of hydrops was identied in 77% of the cases but it is unclear if this was achieved only by prenatal investigations. When studies with high prevalence of haemoglobinopathies are excluded, the most frequent causes of NIH are aneuploidies, infections and cardiovascular and thoracic disorders. Our results are largely in keeping with these studies (table 2). A low rate of chromosomal abnormalities (2/71, 3%) in this study is most likely due to prior rst trimester screening and a high rate of pregnancy termination of chromosomally abnormal pregnancies in the rst or second trimester. If aneuploidies are largely eliminated early in the pregnancy in a pre-screened population such as this study, the relative proportion of other conditions, including idiopathic causes, would increase. This would lead to a reduction in the proportion of cases where prenatal ascertainment of the aetiology is possible. The difference may also reect different prevalence of disorders between populations. Some studies reporting on prenatal series included pregnancies at different gestational ages and this may be responsible for the differences found between studies. Different protocols of NIH investigation may also account for the variation of idiopathic rates (range 849%). Therefore, NIH should be managed in tertiary referral centres with facilities to perform a complete fetal and maternal investigation in order to nd the cause of hydrops and if possible to establish a specic plan for the pregnancy.

cases but remained unexplained in 13 (18%) despite postnatal work-up. This information was difcult to extract from published literature. In the prenatal studies included in this review only two articles (Heinonen et al., 2000; Sohan et al.,2001) reported the rate of postnatal diagnoses of NIH (9 and 17%). The higher proportion of diagnosis in the postnatal period in this study is most likely to be due to elimination of chromosomal abnormalities. This would result in a higher proportion of rare causes such as lymphatic, syndromic/genetic and metabolic disorders diagnosed only with the help of postnatal investigations. In postnatal studies, the likelihood of identication of rare causes of NIH was higher than in prenatal studies, as expected. Although investigation after birth can be helpful to establish the aetiology of NIH, it is important to remember that most of rare disorders (particularly the ones considered in the syndromic/genetic group) are associated with signicant morbidity and this should be taken into account when counselling parents during pregnancy especially when no cause of hydrops can be found prenatally. When prenatally diagnosable causes of NIH are excluded, the rate of idiopathic causes in postnatal studies is still very high (68%; see Table 4). This shows that the aetiology of NIH may remain unclear in a signicant proportion of infants.

What is the chance of survival in NIH?

The data of this study show that 34 of 71 (48%) infants with hydrops fetalis survive. This rate is higher than that reported by many prenatal series (Table 3). In the literature review, the survival rate of NIH was 27 and 52% in prenatal and postnatal studies, respectively. These gures should be interpreted carefully in the face of some bias. A signicant proportion of fetuses with chromosomal abnormalities is likely to reduce the survival rate. Conversely, rarity of aneuploidies is likely to increase the survival rate. The data of this study demonstrate exactly this. In a pre-screened population, the likelihood of being born alive is higher than previously reported. Other reasons for the difference include differences in the rate of pregnancy termination, differences in neonatal care, inclusion of cases diagnosed 1020 years ago (particularly postnatal series), availability of prenatal intervention such as a shunt placement and a differential rate of intrauterine deaths again related to aneuploidies. In the series of postnatal studies the survival rate varied over a wide range (1957%). This may reect different rates of preterm delivery and variable neonatal care unit protocols. Postnatal studies also have the bias of selecting only newborns that survive to birth and reach the neonatal unit excluding intrauterine fetal deaths and deaths immediately after birth.

If no cause is found prenatally, what is the chance of nding a cause of NIH after birth?
The data from this study show that cause of NIH could be ascertained in the postnatal period in further 18 (25%)
Copyright 2011 John Wiley & Sons, Ltd.

In the live birth what is the probability of morbidity?

Our data showed that 17 of 28 (61%) of the survivors had normal development. Six infants were lost to
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follow-up. Specic diagnoses including parvovirus and tachya-arrhythmia were associated with a much better prognosis. This information was difcult to extract from published studies, as most of prenatal reports of this review did not report short or long follow-up of survivors. In the group of postnatal studies, both Haverkamp et al. (2000) and Nakayama et al. (1999) reported only on neurological morbidity.

Treatment modalities are very limited. Mortality rates are high. Early diagnosis of NIH gives parents an opportunity of informed choice about the future of the pregnancy. Counselling about NIH requires a careful understanding of the limitations of the available data and a decision of what information should be given based on prenatal or on postnatal studies. Findings of this study and review of the literature are useful for counselling prospective parents of a fetus affected with NIH. APPENDIX

What morbidity is seen in cases that are not normal?

This study demonstrated that 39% (11/28) had comorbidity. The morbidity ranged from mild conditions such as feeding difculty and episodes of tachyarrhythmias, to signicant neurodevelopmental delay (3/28, 11%). Long-term follow-up was assessed in only two studies included in the review. Haverkamp et al. (2000) studied the psychomotor development of 28 of 61 surviving children from a series of 107 live-born cases. Neurological morbidity was seen in 4 of 28 (14%) children. Two presented with minor neurological dysfunction and a further two suffered from spastic cerebral paresis. Nakayama et al. (1999) evaluated 19 survivals beyond 1 year of age from a series of 51 newborns with NIH and 3 of them (16%) had severe psychomotor development delay and 3 had mild retardation (16%).

Table 1Disorders included in each group of non-immune hydrops (NIH) causes in the literature review Aneuploidy Trisomy 13 Trisomy 21 Trisomy 18 Turner syndrome Mosaicism 46XY/45X Triploidy 22q deletion Partial mole Others Parvovirus Cytomegalovirus Toxoplasmosis Rubella Syphilis Herpes Chlamydia Congenital viral infection Bacterial Hypoplastic left ventricle Hypoplastic right ventricle Small heart syndrome Single ventricle Ventricular septal defect Atrioventricular malformations Common atrium with ventricular septal defect Double outlet RV Endocardial cushion defect Complex abnormalities Anomaly Ebstein Aortic stenosis Aortic valve atresia Pulmonary stenosis Pulmonary valve atresia Tricuspid regurgitation Complex valvular pathology Tetralogy Fallot Transposition great arteries Coarctation of the aorta Hypoplastic aortic arch Patent ductus arteriosus Truncus arteriosus Absent ductus venosus Cardiac tumour Cardiomyopathy

Infection

Limitations of the present study

These study ndings are applicable only to populations pre-screened for chromosomal abnormalities. In the absence of screening, one should expect a higher proportion of fetuses with chromosomal abnormalities. However, most western countries offer screening for chromosomal abnormalities in some form or the other, and the ndings of this study are likely to be applicable to contemporary practice. Despite meticulous attempts to obtain follow-up, no information was available in six infants. Even if one assumes that they did not survive, the survival rate is 39%, which is higher than reported in many reports. No formal assessment of neurodevelopmental outcome was performed, and no tests were applied. Instead, information from parents and caregivers describing the development as normal was relied upon. When formal tests are applied, a proportion of even normal population scores below a set threshold (Squires et al., 1997) and a matched control group would have been required. In any case, it is unlikely that severe developmental delay would be classied as normal; so at worst, mild developmental delay may have been missed. The follow-up period was as short as 1 month in some cases, and developmental delay may be detected at a later date. The diagnosis and management of NIH continue to be a challenge for obstetricians and neonatologists.
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Cardiovascular

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Table 1(Continued )

S. SANTO et al.

Table 1(Continued ) Rhabdomyoma Congenital cardiomegaly Myocardial hypertrophy Fibroelastosis Arrhythmia Tachyarrhythmia Supraventricular tachycardia WolffParkinsonWhite syndrome Complete heart block AV block type Wenckbach Infantile arterial calcication Inferior vena cava thrombosis Hemangioma of iliac artery Cerebral venous stula Anomalous pulmonary venous return Abnormal venous system Vascular ring Hydrothorax Diaphragmatic hernia Cystic adenomatoid malformation Lung sequestration Mediastinal teratoma Mediastinal tumour Myobroma Pulmonary hypoplasia Pulmonary airway malformation Achondrogenesis tumours Akinesia/Hypokinesia sequence Arthrogryposis multiplex congenita Beckwith Wioedemann syndrome Caudal regression syndrome Conrads syndrome Costello syndrome Dwarsm Dysmorphism Gonadoblastoid testicular Haemophagocytic lymphohistiocytosis Lethal contracture Meckels syndrome Multiple pterygium syndrome Myotonic dystrophy Noonan syndrome Osteodysplasia Osteogenesis imperfecta type III Thanatophoric dysplasia Tuberosis sclerosis Multiple anomalies Cystic hygroma Chylothorax Chylous ascites Lymphatic dysplasia Metabolic Congenital hypoproteinaemia Gangliosidosis type 1 Metabolic storage disorder (mucopolysaccharidosis) Mucopolysaccharidosis (Morquios Type A) Nieman Pick C Storage disorder Abdominal tumours Cervical teratoma Chorangioma Lymph hemangioma Sacro-coccygeal teratoma Anaemia unknown cause Deciency of glucose 6 phosphate desidrogenase Dyserythropoietic anaemia Hb Barts Hb H Leukemia Myeloproliferative disorder Neonatal alloimmune thrombocytopenia Pancytopenia Acardiac twin Anencephaly Brain abnormality Cloacal malformation Feto-maternal haemorrhage Gastroschisis Hydrocephalus Intracranial bleeding Laryngeal atresia Meconium ileus Megacolon Meningomyelocele Mineralization of trophoblastic basement membrane Mirror syndrome Nephrotic syndrome Prune-Belly Renal dysplasia Urethral atresia Urinary tract malformation Utero-placental insufciency VACTERL association

Extrathoracic tumours

Haematologic

Thoracic

Others

Syndromes/genetic

Lymphatic

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Table 2Breakdown of gestational age of non-immune hydrops (NIH) diagnosis, causes and outcomes of this study

Categories of NIH Number 2 1 1 27 1 1 1 1 1 1 1 1 8 29 (2) 25 1 2

Diagnosis

Gestational age at diagnosis in weeks (number of cases) Prenatal diagnosis Termination of pregnancy Intrauterine death Live birth Neonatal death

Morbidity Normal development (2) Feeding problems; cardiac problem not otherwise specied Normal development

Haematologic

Aneuploidy 1 1 1 1 1 1 1 1 9 9 28 34 1 1 30 1 18 21 1 1 19 22 1 1 1 30 1 1

1 1

28 35

1 1

1 1

Cardiovascular

Dyserythropoietic anaemia Neonatal alloimmune thrombocytopenia Deciency of glucose-6-phosphate dehydrogenase Anaemia of unknown cause Mosaic Turner syndrome 45,X(16)/46,XY(13) 46,XX,inv(12)(p11.2q24.1) (6)/46,XX(29) Coarctation of the aorta Stenosis of the pulmonary valve and pulmonary trunk Structural heart defect Absent ductus venosus

PERINATAL OUTCOME OF NON-IMMUNE HYDROPS

Complete heart block

AV block Wenckbach type Supra ventricular tachycardia

Infection

Parvovirus

Partial dystrophy of unknown cause; normal development Required pacing but normal development Sporadic episodes of tachycardia; no medication Normal development (7); no follow-up (1) No follow-up

Thoracic

Cytomegalovirus Syphilis Toxoplasma Hydrothorax

2 1 1 10

21, 22 (3), 23 (2), 24 (2), 25 (1) 20, 22 30 27 19, 21, 27, 29, 30 (2), 31 (3), 34 22, 26, 28

2 1 10

2 1

1 8

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Echogenic lung lesion

Mild respiratory distress on medication and normal development (1); normal development (2); no follow-up (3)

194

Lymphatic

Lymphatic dysplasia

26 (2)

Syndromes/Genetic

Chylothorax Costello syndrome

1 1

32 33

1 1

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Dysmorphism 1 1 1 1 2 1 1 2 32 21 22, 31 1 1 23 (2) 1 1 1 1 1 28 1 1 1 1 28 1 1 21 24 1 1 1 1

32

Generalized lymphatic dysplasia; (generalized ooedema, ascites, narrowed trachea, hypothyroidism, normal neurodevelopment No follow-up Severe neurodevelopment delay. Feeding by gastrostomy. Tracheomalacia, CPAP during night Neurodevelopment impairment, seizures, poor vision and hearing

Metabolic

Akinesia/Hypokinesia sequence Arthrogryposis congenita multiplex; acetylcholine receptor Ab negative Gonadoblastoid testicular dysplasia Haemophagocytic lymphohistiocytosis, osteogenesis imperfecta type III Mucopolysaccharidosis

S. SANTO et al.

Extrathoracic tumours (including placental) Others 1 1 1 13 33 20, 21, 23 (2), 25, 27, 32 (2), 33 (3), 35, uncertain (1) 1 24 1 32 1 5

Niemann Pick C Storage disorder Chorangioma

Kyphosis, hyperextensibility of joints and normal neurodevelopment (1) Normal development (1)

Cloacal common outow tract

1 1 1 6

1 2

Feto-hemorrhage

Intracranial bleeding

Idiopathic

De-functioning colostomy with surgical follow-up Red blood cell transfusion after birth, normal development Normal development (3); neurodevelopment delay (1)

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REFERENCES
Abrams ME, Meredith KS, Kinnard P, Clark RH. 2007. Hydrops fetalis: a retrospective review of cases reported to a large national database and identication of risk factors associated with death. Pediatrics 120: 8489. Apkon M. 1995. Pathophysiology of hydrops fetalis. Semin Perinatol 19: 437446. Graves GR, Baskett TF. 1984. Nonimmune hydrops fetalis: antenatal diagnosis and management. Am J Obstet Gynecol 148: 563565. Haverkamp F, Noeker M, Gerresheim G, Fahnenstich H. 2000. Good prognosis for psychomotor development in survivors with nonimmune hydrops fetalis. BJOG 107: 282284. Heinonen S, Ryyn anen M, Kirkinen P. 2000. Aetiology and outcome of second trimester non-immunologic fetal hydrops. Acta Obstet Gynecol Scand 79: 1518. Hofstaetter C, Hansmann M, Eik-Nes SH, Huhta JC, Luther SL. 2006. A cardiovascular prole score in the surveillance of fetal hydrops. J Matern Fetal Neonatal Med 19: 407413. Huang HR, Tsay PK, Chiang MC, et al. 2007. Prognostic factors and clinical features in liveborn neonates with hydrops fetalis. Am J Perinatol 24: 3338. Hutchison AA, Drew JH, Yu VY, et al. 1982. Non-immunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol 59: 34752. Ismail KMK, Martin WL, Ghosh S, et al. 2001. Aetiology and outcome of hydrops fetalis. J Matern Fetal Med 10: 175181. Jones DC. 1995. Nonimmune fetal hydrops: diagnosis and obstetrical management. Semin Perinatol 19: 447461. Liao C, Wei J, Li Q, et al. 2007. Nonimmune hydrops fetalis diagnosed during the second half of pregnancy in Southern China. Fetal Diagn Ther 22: 302305. Liu CA, Huang HC, Chou YY. 2002. Retrospective analysis of 17 liveborn neonates with hydrops fetalis. Chang Gung Med J 25: 826831.

Mascaretti RS, Falc ao MC, Silva AM, et al. 2003. Characterization of newborns with nonimmune hydrops fetalis admitted to a neonatal intensive care unit. Rev Hosp Clin Fac Med Sao Paulo 58: 125132. Nakayama H, Kukita J, Hikino S, et al. 1999. Long-term outcome of 51 liveborn neonates with non-immune hydrops fetalis. Acta Paediatr 88: 2428. Ratanasiri T, Komwilaisak R, Sittivech A, et al. 2009. Incidence, causes and pregnancy outcomes of hydrops fetalis at Srinagarind Hospital, 19962005: a 10-year review. J Med Assoc Thai 92: 594599. Santolaya J, Alley D, Jaffe R, Warsof SL. 1992. Antenatal classication of hydrops fetalis. Obstet Gynecol 79: 256259. Simpson JH, McDevitt H, Young D, Cameron AD. 2006. Severity of nonimmune hydrops fetalis at birth continues to predict survival despite advances in perinatal care. Fetal Diagn Ther 21: 380382. Sohan K, Carroll SG, De La Fuente S, et al. 2001. Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand 80: 726730. Squires J, Bricker D, Potter L. 1997. Revision of a parent-completed development screening tool: ages and stages questionnaires. J Pediatr Psychol 22: 313328. Suwanrath-Kengpol C, Kor-anantakul O, Suntharasaj T, Leetanaporn R. 2005. Aetiology and outcome of non-immune hydrops fetalis in Southern Thailand. Gynecol Obstet Invest 59: 134137. Swain S, Cameron AD, McNay MB, Howatson AG. 1999. Prenatal diagnosis and management of nonimmune hydrops fetalis. Aust N Z J Obstet Gynaecol 39: 285290. Trainor B, Tubman R. 2006. The emerging pattern of hydrops fetalis incidence, aetiology and management. Ulster Med J 75: 185186. Wy CA, Sajous CH, Loberiza F, Weiss MG. 1999. Outcome of infants with a diagnosis of hydrops fetalis in the 1990s. Am J Perinatol 16: 561567.

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Prenat Diagn 2011; 31: 186195. DOI: 10.1002/pd