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involve visceromegaly and obstruction of the hydrops can be determined at the reaction studies for parvovirus, toxo-
of venous return, decreased erythropoi- time of diagnosis, since several etiologies plasmosis, and cytomegalovirus infec-
esis and anemia, and/or hypopro- are confirmed or excluded based upon tion. Such testing should be performed
teinemia. Although such disorders are a ultrasound findings (eg, twin-to-twin in a structurally normal fetus in which
relatively uncommon cause of NIHF, transfusion, cardiac arrhythmias, and no other cause has been identified.
they are important because of the high structural anomalies associated with An important step in the evalua-
recurrence risk of these mainly auto- NIHF). tion of NIHF is to exclude a genetic
somal recessive disorders. Careful his- Management is guided by the pres- abnormality. Genetically transmitted
tology of the placenta, liver, spleen, ence or absence of additional anomalies. disorders account for about one
and bone marrow will often provide a Sonographic evaluation should include third of cases of NIHF, and include
clue that a metabolic storage disorder a detailed survey for anomalies of the chromosomal abnormalities, hemo-
was present. For many such disorders, fetus, umbilical cord, and placenta, and globinopathies, skeletal dysplasias,
testing is available to determine a diag- estimation of amniotic fluid volume. A metabolic storage disorders, and eryth-
nosis and for prenatal diagnosis in a fetal echocardiogram should be in- rocyte enzymopathies. A complete fam-
subsequent pregnancy. Panels of causa- cluded, as fetal cardiac anomalies are ily history is thus imperative to rule out a
tive storage disorders can be tested for among the most common causes of known inherited disorder in the family
in some laboratories, and this should NIHF. and to assess for consanguinity, which
be considered for cases of NIHF in In a structurally normal fetus, the first will increase the likelihood of a recessive
a structurally normal fetus in which step is to rule out alloimmunization as a disorder. Although idiopathic NIHF
another cause has not been identified, cause. The maternal blood type and has a low recurrence risk, the risk for
or with cases of recurrence within a Rh(D) antigen status are assessed as part some cases of NIHF may be as high
family.76,77 of routine prenatal care, along with an as 25%, making genetic counseling an
A number of other syndromes have indirect Coombs test (an antibody integral part of the management of any
been associated with NIHF. Many of screen) to evaluate for circulating red patient with NIHF.
these are disorders associated with blood cell antibodies. These results
lymphatic dysfunction, such as Noonan should be reviewed, and if the indirect What maternal risks are associated
and multiple pterygium syndrome, both Coombs test was previously normal, it with NIHF?
of which frequently present with cystic should be repeated. Maternal blood Women with NIHF may develop mirror
hygroma; idiopathic chylothorax, in studies should also include a complete syndrome, an uncommon complication
which a local pleuromediastinal lymph blood cell count with differential in which the mother develops edema
vessel disturbance occurs as the possible and indices, Kleihauer-Betke stain for that “mirrors” that of her hydropic fetus.
pathogenic mechanism; yellow nail syn- fetal hemoglobin, and parvovirus B19 Mirror syndrome may represent a form
drome, a dominantly inherited congen- serology. Serologic test results for syph- of preeclampsia, and is characterized by
ital lymphedema syndrome; and ilis should be reviewed or repeated, and edema in approximately 90%, hyper-
congenital pulmonary lymphangiectasia. consideration should be given to acute tension in 60%, and proteinuria in 40%
Familial recurrence in some of these phase titers for cytomegalovirus and of cases.81 As it is uncommon and likely
cases suggests a hereditary maldevelop- toxoplasmosis. underdiagnosed, the incidence is un-
ment of lymphatic vessels.6,14,19,78 It is particularly important to perform clear. Additional associated findings with
middle cerebral artery Doppler studies the syndrome include headache, visual
What is the appropriate evaluation to assess for the presence of fetal anemia, disturbances, oliguria, elevated uric acid,
when fetal hydrops is detected? which may be treatable with intravas- liver function tests, or creatinine levels,
Sonographic identification of the cular transfusion. The fetus with NIHF low platelets, anemia, and hemodilu-
hydropic fetus is not difficult. The diag- due to severe anemia will have increased tion.82 A review of the literature (1956
nostic challenge is to establish the etiol- velocity through the middle cerebral through 2009) by Braun et al81 noted
ogy and determine the appropriate artery.79 that among 56 cases of mirror syndrome,
therapy (if available) and timing of de- A fetal karyotype, fluorescence in situ the major maternal morbidity was pul-
livery. It has been reported that the cause hybridization studies, and/or chromo- monary edema, which occurred in 21%.
of hydrops can be determined in about somal microarray analysis should be Resolution occurs with either the treat-
60-85% of cases, although this includes offered with or without identified so- ment of the hydrops or with delivery.81,82
postnatal evaluation.13 nographic anomalies.80 This can be There have been case reports in
Figure 2 outlines the various steps in performed by amniocentesis or fetal which pregnancies with mirror syn-
the evaluation of the hydropic fetus. It is blood sampling; the latter allows direct drome and various treatable causes of
especially important to rule out poten- analysis of fetal hematocrit and hemo- hydropsesecondary to fetal arrhythmia,
tially treatable conditions, as well as ge- globin if anemia is suspected. Invasive hydrothorax, parvovirus, and bladder
netic disorders with a risk of recurrence testing also allows testing for lysosomal obstructionehave experienced resolu-
in future pregnancies. Often, the etiology storage disorders, and polymerase chain tion of both hydrops and mirror
TABLE 2
Therapy for selected etiologies of nonimmune hydrops21,54,58,59,61,63,64
Etiology Therapy Recommendation
Cardiac tachyarrhythmia, Maternal transplacental administration Treatment with antiarrhythmic medication unless
supraventricular tachycardia, of antiarrhythmic medication(s) gestational age is close to term or there is maternal
atrial flutter, or atrial fibrillation or obstetrical contraindication to therapy
Fetal anemia secondary to Fetal blood sampling followed by Fetal intrauterine transfusion if anemia is confirmed,
parvovirus infection or intrauterine transfusion unless pregnancy is at an advanced gestational age
fetomaternal hemorrhage and risks associated with delivery are considered to
be less than those associated with procedure
Fetal hydrothorax, chylothorax, Fetal needle drainage of effusion Consider drainage of large unilateral pleural effusion(s)
or large pleural effusion associated or placement of thoracoamniotic resulting in NIHF, or, if gestational age is advanced,
with bronchopulmonary sequestration shunt; if gestational age is advanced, consideration of needle drainage prior to delivery
needle drainage prior to delivery in
selected cases
Fetal CPAM Macrocystic type: fetal needle drainage Consider drainage of large macrocystic CPAM that has
of effusion or placement of thoracoamniotic resulted in NIHF; if large microcystic CPAM has
shunt; microcystic type: maternal resulted in NIHF, we suggest that management options
administration of corticosteroids, include maternal corticosteroid administration
betamethasone 12.5 mg IM q24
h 2 doses or dexamethasone
6.25 mg IM q12 h 4 doses
TTTS or TAPS Laser ablation of placental anastomoses Consideration of fetoscopic laser photocoagulation of
or selective termination placental anastomoses for TTTS or TAPS that has
resulted in NIHF <26 wk
Twin-reversed arterial Percutaneous radiofrequency ablation Referral for consideration of percutaneous
perfusion sequence radiofrequency ablation that has resulted in NIHF
For each of these etiologies, it is recommended that treatment be performed at tertiary care center or center with expertise in relevant therapy.
CPAM, congenital pulmonary airway malformation; IM, intramuscular; NIHF, nonimmune hydrops fetalis; TAPS, twin-anemia polycythemia sequence; TTTS, twin-twin transfusion sequence.
SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.
reported to be as high as 60%.91 With prenatally and referred to tertiary cen- urgent treatment or referral to a
chylothorax as the underlying etiology, ters, which are more likely to contribute specialized center; those with a lethal
the mortality may be as low as 6%; to large series in the literature. prognosis, for whom pregnancy termi-
however, when the infant has associated The long-term prognosis for survivors nation or comfort care are the only op-
anomalies, almost two-thirds do not of NIHF also depends upon the under- tions realistic to offer; and cases in which
survive.14 Treatable causes of hydrops, lying etiology. After intrauterine trans- the etiology is idiopathic and the prog-
such as fetal arrhythmia or infection fusion for hydrops secondary to nosis is likely poor but uncertain. Given
with parvovirus B19,92 have a better infection with parvovirus B19, there is the poor overall prognosis, pregnancy
prognosis. In a large series of newborns potential for delayed psychomotor termination should be offered if NIHF is
admitted to the neonatal intensive care development and abnormal neurological identified prior to viability. It is impor-
unit, the independent risk factors for outcomes.93 It is unclear if this is tant in counseling that the potential for
death in logistic regression analyses were because of the hydrops, a direct conse- maternal complications with expectant
younger gestational age, low 5-minute quence of the parvovirus infection, management be anticipated, including
Apgar score, and need for high levels of from severe anemia, or associated mirror syndrome. Serial evaluation of
support during the first day after birth with the transfusion. Finally, fetuses maternal blood pressure is therefore
(higher levels of inspired oxygen support with supraventricular tachycardia may recommended.
and greater need for high-frequency develop Wolff-Parkinson-White syn-
ventilation).14 drome later in life.94 What are the fetal therapy options
Temporal trends suggest that among available for NIHF?
cases of liveborn infants with NIHF, the Management of NIHF Selected etiologies of NIHF for which
associated mortality has not improved The cornerstone of counseling and fetal therapy should be considered are
over 2 decades. Comparing the mortality management for this condition is a listed in Table 2. Therapy options may
among hydropic newborns delivered in thorough evaluation for the underlying include intrauterine transfusion(s)
1993 through 2003 vs 2003 through etiology of the hydrops (Figure 2). for fetal anemia, medications such as
2009, there was no significant difference Pregnancy management decisions will antiarrhythmic agents, drainage of large
in mortality in the 2 time periods, 47% depend on the etiology, in particular pleural effusions, corticosteroids for
vs 67%, respectively.91 In addition to the whether there is a treatable cause and CPAMs, or specialized procedures such
small sample size, an explanation for the the gestational age that NIHF develops as laser coagulation of placental anasto-
lack of improvement in survival over or is first identified. Cases generally fall moses for twin-twin transfusion syn-
time may be that the more severe cases into 1 of 3 categories: those amenable to drome. The list is not intended to
are now more frequently diagnosed fetal therapyewhich often require be comprehensive but rather to serve as a
TABLE 3
Society for Maternal-Fetal Medicine recommendations for nonimmune hydrops
Recommendations Grading of recommendations (Table 4)
We recommend that initial evaluation of hydrops include an antibody screen (indirect 1C
Coombs test) to verify that it is nonimmune, targeted sonography with echocardi- Strong recommendation, low-quality evidence
ography to evaluate for fetal and placental abnormalities, MCA Doppler evaluation for
anemia, and fetal karyotype or chromosomal microarray analysis, regardless of
whether structural fetal anomalies are identified (Figure 2)
We recommend that fetal therapy decisions be based on underlying etiology, in 1C
particular whether there is a treatable cause (Table 2) and the gestational age at Strong recommendation, low-quality evidence
which NIHF develops or is first identified
As prematurity is likely to worsen prognosis, we recommend that preterm delivery 1C
be undertaken only for obstetric indications Strong recommendation, low-quality evidence
We recommend that pregnancies with NIHF due to nonlethal or potentially treatable 1C
etiologies be considered candidates for corticosteroid therapy and antepartum Strong recommendation, low-quality evidence
surveillance, and that they be delivered at a center that has capability to stabilize
and treat critically ill neonates
We recommend that in most cases, development of mirror syndrome is an indication 1C
for delivery Strong recommendation, low-quality evidence
MCA, middle cerebral artery; NIHF, nonimmune hydrops fetalis.
SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.
Weak recommendation, risks and burdens, some uncertainly important limitations (inconsistent results, likely to be better for some patients under some
guideline. With the exception of open Most fetuses with NIHF secondary hydrops represents an advanced stage
fetal surgery, therapy is sometimes to an etiology listed in Table 2 are can- of multiple underlying pathophysiol-
offered to pregnancies identified as didates for antepartum surveillance. If ogies. Fetuses with NIHF are at risk
being at risk for NIHF, with the under- fetal therapy is attempted but does not for preterm delivery and thus for
standing that the prognosis worsens if ameliorate the hydrops, the prognosis is prematurity-related morbidities that
hydrops develops. significantly worse.20,61 If the NIHF may compound their hemodynamic
Counseling for pregnancies with is idiopathic, counseling about the compromise. Pregnancies with NIHF
NIHF amenable to fetal therapy should guarded prognosis should include limi- would reasonably be candidates for
include a discussion of potential risks, tations in available treatment options, antepartum corticosteroid therapy if
benefits, and alternatives that takes into but in the absence of a contraindication, the gestational age is between 24-34
consideration the severity of the under- antepartum testing may be considered. If weeks, if the underlying etiology
lying condition and the anticipated there are questions about the postnatal of the hydrops is not considered lethal,
response to the intervention. If the pa- prognosis, consultation with a neonatol- and if intervention is planned on behalf
tient declines therapy or is unable to ogist or other pediatric subspecialist may of the fetus should deterioration of the
receive therapy, the prognosis is poor. be helpful. fetal condition occur. If any type of fetal
Given the specialized nature of fetal therapy is planned (Table 2) and the
therapy, patients should receive care When is the optimal timing of delivery? gestational age is between 24-34 weeks,
from physicians with expertise providing There are no management trials of corticosteroid administration should be
the treatment offered, which in some delivery timing in the setting of NIHF considered.
cases may require evaluation at a upon which to base recommendations.
specialized center. Many hydropic fetuses succumb prior What is the optimal mode of delivery?
to viability. There is no evidence that If the fetus is potentially treatable or
When is antepartum fetal surveillance elective preterm delivery will improve considered viable, and if the decision
appropriate in NIHF? the outcome. In one retrospective series, to proceed with delivery is based on
Antepartum surveillance is generally preterm birth <34 weeks was a poor findings of antepartum surveillance or
used in the setting of maternal or prognostic factor.90 Based on expert concern about deterioration of the
pregnancy complications associated opinion, development or worsening of fetal condition (eg, based on sono-
with an increased risk for fetal demise, NIHF in a pregnancy that has reached graphic findings), cesarean delivery may
and when findings from surveillance about 34 weeks would seem a reason- be indicated. Prior to delivery of the
will assist with delivery decisions. For able indication for delivery, although hydropic fetus, consideration should be
NIHF, antepartum testing has not been given the wide spectrum of etiologies given to whether drainage of a large
definitively shown to improve perinatal and severity of NIHF, care should be effusion may improve the efficacy of
outcomes, and all indications for individualized. In the absence of clinical neonatal resuscitative efforts. Rarely, ef-
testing are considered relative.95 There deterioration or other indication for fusions may be so large as to pose a risk
are no management trials or observa- earlier intervention, delivery by 37-38 for trauma to the infant during delivery.
tional series of the utility of ante- weeks should be considered. As dis- Depending on the degree of associated
partum surveillance in the setting of cussed previously, we recommend de- effusions and anasarca, consideration
NIHF upon which to base recommen- livery in most cases if mirror syndrome should be given to the potential for
dations. Whether an individual preg- develops. dystocia at delivery. If a decision has
nancy with NIHF may benefit from been made not to intervene for fetal
surveillance depends on the etiology of Should corticosteroids be given? indicationseto provide comfort care
the hydrops, the underlying patho- There are no studies that specifically only, vaginal delivery is preferred unless
physiology, and the potential for pre- address the utility of antepartum corti- otherwise contraindicated.
natal or postnatal treatment. costeroid therapy to ameliorate the
Fetuses with NIH may be candidates sequelae of prematurity in the setting Where should delivery occur?
for antepartum surveillance if: (1) of NIHF, and there are similarly no data If the NIHF is considered to have an
the underlying etiology of the hydrops to suggest that corticosteroid adminis- etiology that is potentially amenable to
is not considered lethal, (2) the preg- tration is detrimental in pregnancies postnatal treatment, or if the etiology of
nancy has reached a viable gestational complicated by hydrops. In 2 retrospec- the hydrops is idiopathic, the pregnancy
age, and (3) the findings from surveil- tive series, neonatal survival was not should be delivered at a center with a
lance would be used to assist with timing improved in those who received corti- level-III neonatal intensive-care unit that
of delivery. In such cases, deterioration costeroids.9,96 This was likely due to has the capability to stabilize and treat
of testing results or worsening of the the overall extremely high morbidity critically ill neonates. This may require
sonographic findings of hydrops might and mortality among infants with transfer of the pregnant patient prior to
prompt delivery. NIHF in these cohorts, and that delivery.
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