Placenta previa increta/percreta in Japan: a retrospective study of ultrasound findings, management and clinical course

AIM: Placenta accreta is an abnormally firm attachment of placental villi to the uterine wall, which may cause postpartum hemorrhage resulting in maternal morbidity and mortality. The purpose of the present study was to clarify the incidence, clinical background and prognosis of placenta previa increta/percreta treated with different modalities in Japan. METHODS: Medical records of cases with placenta previa increta/percreta in eight tertiary centers between January 1994 and December 2004 were reviewed. Placenta accreta without actual invasion into the myometrium confirmed by pathology was not included in placenta increta/percreta. Details of obstetric history, maternal background, ultrasonographical findings, the course of delivery, subsequent complications and management were noted. RESULTS: Among the total of 59,008 deliveries, 45,261 were by the vaginal route (76.7%) and 13 747 by cesarean section (23.3%). In this study, 408 cases were diagnosed as placenta previa (0.69%), 18 of these being placenta increta and 5 placenta percreta. Only 1.1% of cases of placenta previa without prior cesarean section were increta/percreta, in contrast to 37% of placenta previa after prior cesarean sections. Mean intraoperation blood loss was 3630 +/- 2216 g (increta) and 12,140 +/- 8343 g (percreta). One patient with placenta previa percreta died of hemorrhage. Stepwise treatment (cesarean section without separation of the placenta, arterial embolization and hysterectomy) was applied for 4 cases, which had the least blood loss. CONCLUSIONS: Placenta previa increta/percreta is a life-threatening disease. Patients who undergo hysterectomy after uterine arterial embolization demonstrate reduced intraoperation blood loss, and this treatment should be incorporated to reduce maternal morbidity.     

Placenta accreta: epidemiology, molecular mechanism (hypothesis) and some clinical remarks

OBJECTIVE: To develop the hypothesis on biochemical mechanism of the placenta accreta and to review the epidemiological information on that complication. STUDY DESIGN: Data collected in 1995-2002 in the Medline System were the main source of analyzed literature. RESULTS: Placenta accreta occurs in approximately 1 of 2500 deliveries, however among women with placenta praevia, the incidence is nearly 10%. Independent risk factors for placenta accreta are previous cesarean delivery and maternal age > or =35 years. Postpartum hemorrhage is the main cause of maternal mortality. Hysterectomy is often performed to save the life of the mother. Ligation of internal pelvic arteries is considered to be ineffective procedure in about 50%. An another option in management of hemorrhage is embolisation of pelvic arteries. Recombinant factor VIIa is recommended is a new agent in pharmacological therapy. Our hypothesis is as follows: The complex of uPA/uPAR (urokinase plasminogen activator/receptor of urokinase plasminogen activator complex) plays crucial role in the generation of plasmin-dependent proteolysis, which takes place in the surface of trophoblast. Penetration of the villi into the tissues is controlled by plasminogen activator inhibitors--plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2), mainly by PAI-2. PAI-2 inactivates uPA/uPAR complexes forming triplicate complexes. If the PAI-2 concentration in placenta and myometrium is low, the invasion of placenta villi is excessive. CONCLUSION: Disturbance of balance between plasminogen activator and their inhibitors (PAI-1 and PAI-2) in placenta and myometrium can lead to the formation of placenta accreta.     

Relationship between placenta previa and maternal age, parity and prior caesarean deliveries

OBJECTIVE: The purpose of this study was to determine the incidence of placenta previa and to asses the relationship between the incidence of placenta previa and maternal age, parity, prior abortion and cesarean deliveries. MATERIALS AND METHODS: The records of all patients with the diagnosis of placenta previa during the period between 1992 and 2002 at Hospital in Chojnice were reviewed. To determine the relationship between the incidence of placenta previa and maternal age, parity, prior abortion and cesarean deliveries the statistical analyses were carried out. The level of significance was set at 0.05. RESULTS: From a total 11,091 deliveries 24 (0.2%) women had placenta previa. The occurrence of placenta previa increased with maternal age and was the highest in women aged 35 or older--0.8% of all deliveries and the lowest in women aged <25 years--0.07%. The incidence of placenta previa in women with previous deliveries was significantly higher compared to the group of primiparas and increased as the number of prior deliveries increased. The association between previous abortion and cesarean section and placenta previa was not confirmed. CONCLUSION: Advancing maternal age and multiparity appears to increase the occurrence of placenta previa. In this study the relationship between previous abortion and cesarean section was not confirmed.     

Transplacental, amniotic, urinary, and fetal fluid dynamics during very-large-volume fetal intravenous infusions

With rapid intravenous infusion of very large volumes of isotonic saline solutions into the fetus, the fluid could stay within the fetal body, thereby creating hydrops fetalis, be transferred into the amniotic fluid through the fetal kidneys, thereby creating polyhydramnios, or be transferred across the placenta into the maternal circulation. This study was designed to explore these possibilities. After a 1-hour control period, 10 near-term chronically catheterized ovine fetuses were infused intravenously with 4 L (greater than 100% of fetal weight) of either isotonic saline solution or lactated Ringer's solution over 4 hours. Fetal arterial pressure was significantly elevated by 7 mm Hg throughout the infusion (p less than 0.00001). Venous pressure underwent a transient rise (4.8 mm Hg) at 20 minutes of infusion and remained elevated (2.7 mm Hg) during the rest of the infusion (p less than 0.00001). Fetal urine flow increased by an average of 5.7 +/- 0.4 ml/min throughout the infusion (p less than 0.00001) and accounted for 34.1% +/- 2.6% of the infused volume. Estimated fetal extracellular fluid volume increased by 17.7% +/- 1.8% of the infused volume. Because fetal fluid retention, urine flow, and amniotic fluid volume changes accounted for only half of the infused fluid, the remainder of the infused volume must have crossed the placenta and entered the maternal circulation. Given the above changes in vascular pressures, this requires a filtration coefficient of the placenta 50 to 100 times the previously reported values. Thus we conclude that relatively small changes in fetal vascular pressures dramatically alter the filtration capacity of the ovine placenta and transplacental volume flow.     

Review: Placenta,evolution and lifelong health

The intrauterine environment has an important influence on lifelong health, and babies who grew poorly in the womb are more likely to develop chronic diseases in later life. Placental function is a major determinant of fetal growth and is therefore also a key influence on lifelong health. The capacity of the placenta to transport nutrients to the fetus and regulate fetal growth is determined by both maternal and fetal signals. The way in which the placenta responds to these signals will have been subject to evolutionary selective pressures. The responses selected are those which increase Darwinian fitness, i.e. reproductive success. This review asks whether in addition to responding to short-term signals, such as a rise in maternal nutrient levels, the placenta also responds to longer-term signals representing the mother’s phenotype as a measure of environmental influences across her life course. Understanding how the placenta responds to maternal signals is therefore not only important for promoting optimal fetal growth but can also give insights into how human evolution affected developmental history with long-term effects on health and disease.     

Severely reduced presence of tissue macrophages in the basal plate of pre-eclamptic placentae

Pre-eclampsia is a disorder of unknown aetiology peculiar to human pregnancy. A well-described pathological feature being shallow trophoblast invasion into the spiral arteries during placenta development. Epidemiological studies have revealed an increased risk in pregnancies of primipaternity, and an association with the maternal-fetal HLA-DR relationship, both suggesting the involvement of an immunological component. We were therefore interested in the distribution of HLA-DR expressing myeloid cells in the decidua of healthy and pre-eclamptic placentae. We have studied the monocytes in maternal and fetal peripheral blood as well as in the placenta and identified the cluster of differentiation (CD) 14(+)myeloid cells in the basal plate as mannose receptor (ManR) positive tissue macrophages. In a comparison between peripheral blood monocytes from healthy pregnant and pre-eclamptic women we found no significant difference in the subpopulation size of CD14(+)/CD16(+)monocytes. The number and location of macrophages in the placental villi was similar. However, while the basal plate of the normal decidua contained numerous CD14(+), HLA-DR(bright), ManR(+)tissue macrophages, this compartment was virtually void of these phagocytic cells in the pre-eclamptic placenta. This novel finding suggests that in pre-eclampsia not only the migration of endovascular cytotrophoblasts is disturbed, but that also maternal macrophage migration is affected.     

Induced abortion: A risk factor for placenta previa

A threefold increase in the incidence of placenta previa, from one in 318 deliveries (0.3%) in 1972–1974 to one in 109 deliveries (0.9%) in the twelve-month period ending June 30, 1980, was noted at Vanderbilt University Hospital. Two large groups of patients not present in 1972–1974 were found to be responsible for this increased incidence of placenta previa: one-way maternal transports and women who had had induced first trimester abortions. The frequency of maternal transports having placenta previa was 3.3% (p < 0.0001), and the frequency of placenta previa in women after an induced first trimester abortion was 3.8% (p < 0.0001). When correction for maternal transports was made, the endogenous induced first trimester abortion population had a frequency of placenta previa of 2.1% (p < 0.004), whereas the remainder of the endogenous population had an incidence of placenta previa similar to that found in the years 1972–1974. Induced first trimester abortion is seen as a significant factor predisposing to placenta previa.     

Pathology of the placenta

The placenta has a considerable functional reserve capacity, easily repairs ischaemic damage, is able to compensate for toxic injury and does not appear to age. Most of the macroscopically visible abnormalities of the placenta are of no functional significance, the major exception to this general banality being the uncommon large haemangioma which can cause complications in the mother, fetus and neonate. Most of the histological abnormalities seen in the placental villi represent a reaction to alterations in either maternal or fetal blood flow through the placenta, but a failure of adequate maturation of the villous tree may impair the functional efficiency of the placenta, as may defective trophoblastic differentiation. Infections of the placenta are important but do not influence placental function, whilst there is currently no firm evidence that the placenta ever suffers immune-mediated damage. Intrinsic placental 'insufficiency' is extremely rare and it is becoming increasingly clear that this clinical syndrome is usually due to a restricted supply of maternal oxygen and nutrients as a result of inadequate transformation of the spiral arteries into uteroplacental vessels. This failure of placentation represents an abnormality of the relationship between fetal and maternal tissues at a relatively early stage of pregnancy, and it is only by gaining a better understanding of this relationship that the problems posed by such conditions as pre-eclampsia and idiopathic intrauterine growth retardation will be answered.     

Placenta praevia: incidence,risk factors and outcome

Objective: Aim of this study was to evaluate the incidence, potential risk factors and the respective outcomes of pregnancies with placenta praevia.

Methods: Data were prospectively collected from women diagnosed with placenta praevia in 10 Austrian hospitals in in the province of Styria between 1993 and 2012. We analyzed the incidence, potential risk factors and the respective outcomes of pregnancies with placenta praevia. Differences between women with major placenta praevia (complete or partial placenta praevia) and minor placenta praevia (marginal placenta praevia or low-lying placenta) were evaluated.

Results: 328 patients with placenta praevia were identified. The province wide incidence of placenta praevia was 0.15%. Maternal morbidity was high (ante-partum bleeding [42.3%], post-partum hemorrhage [7.1%], maternal anemia [30%], comorbid adherent placentation [4%], and hysterectomy [5.2%]) and neonatal complications were frequent (preterm birth [54.9%], low birth weight <2500?g [35.6%], Apgar-score after five minutes <7 [5.8%], and fetal mortality [1.5%]. Women with major placenta praevia had a significant higher incidence of preterm delivery, birthweight <2500?g and Apgar-score after five minutes <7.

Conclusions: Placenta praevia was associated with adverse maternal (34.15%) and neonatal (60.06%) outcome. The extent of placenta praevia was not related with differences regarding risk factors and maternal outcome.     

Comparison of leucine, serine and glycine transport across the ovine placenta

To estimate the transport rate of maternal glycine across the placenta [1-¹³C]glycine and L-[1-¹³]serine were infused intravenously in pregnant sheep using both continuous and bolus infusions. Each tracer was infused together with L-[1-¹³C]leucine, to enable a comparison with the placental transport of an essential amino acid. At steady state, fetal plasma leucine enrichment was 40 per cent of maternal enrichment, indicating that approximately 60 per cent of the entry rate of leucine into fetal plasma is derived from protein breakdown in the placenta and fetus. Fetal plasma glycine enrichment was 11 per cent of maternal and there was no detectable fetal serine enrichment. The direct flux of maternal leucine into the fetal circulation was approximately 3.0 (bolus experiments) to 3.6 (continuous infusion experiments) pmol/min (kg fetus) and greater than the estimated 1.4 μmol/min (kg fetus) direct flux of maternal glycine, despite the fact that the net umbilical uptake of glycine exceeds that of leucine. This supports the conclusion that placental glycine production is a quantitatively important contribution to fetal glycine uptake via the umbilical circulation. The fetal glycine supply from the placenta is provided by a relatively small direct maternal glycine transplacental flux and a larger contribution derived from serine utilization within the placenta for glycine production.     

The effect of cesarean delivery rates on the future incidence of placenta previa,placenta accreta,and maternal mortality

Objective.?The overall annual incidence rate of caesarean delivery in the United Sates has been steadily rising since 1996, reaching 32.9% in 2009. Primary cesareans often lead to repeat cesareans, which may lead to placenta previa and placenta accreta. This study's goal was to forecast the effect of rising primary and secondary cesarean rates on annual incidence of placenta previa, placenta accreta, and maternal mortality.

Methods.?A decision-analytic model was built using TreeAge Pro software to estimate the future annual incidence of placenta previa, placenta accreta, and maternal mortality using data on national birthing order trends and cesarean and vaginal birth after cesarean rates. Baseline assumptions were derived from the literature, including the likelihood of previa and accreta among women with multiple previous cesarean deliveries.

Results. If primary and secondary cesarean rates continue to rise as they have in recent years, by 2020 the cesarean delivery rate will be 56.2%, and there will be an additional 6236 placenta previas, 4504 placenta accretas, and 130 maternal deaths annually. The rise in these complications will lag behind the rise in cesareans by approximately 6 years.

Conclusions.?If cesarean rates continue to increase, the annual incidence of placenta previa, placenta accreta, and maternal death will also rise substantially.     

Evaluation of elevations in maternal serum alpha-fetoprotein: a review.

Maternal serum AFP screening has had significant clinical impact on reducing unrecognized anencephaly and open neural tube defects at delivery. In addition, a growing number of other associations with maternal serum AFP elevations have become apparent since antepartum screening has become commonplace. We present in this review a clinically oriented approach to understanding the physiologic basis of maternal serum AFP elevations, both true- and false-positives. Compartmentalization of etiology, fetal and maternal, and routes of communication, amniotic fluid and placenta, allows a more logical approach to developing a differential diagnosis in this group of patients. In evaluating an elevation in maternal serum AFP, it is first necessary to consider the amount of fetal production by confirming the gestational age of the fetus and the number of fetuses present. Adjustments for maternal factors (weight, race, diabetes) must also be made. Fetal developmental defects which may lead primarily to leakage of the fetal proteins into the surrounding amniotic fluid with secondary elevations of maternal serum AFP enter into the differential diagnosis. The placenta itself is probably not a production source of AFP, but when the placenta is abnormal, a greater amount of AFP may be transported to the maternal circulation. Although our thoughts frequently do turn first to an increased maternal serum AFP reflecting an increased AFP concentration in the amniotic cavity with greater transference "across the membranes," in fact a far more common etiology is an increased transfer from the fetal circulation to the maternal via the fetal-maternal interface within the placenta. This is supported by the simple fact that the vast majority of maternal serum AFP elevations are not associated with amniotic fluid AFP elevations; the amniotic fluid AFP concentrations are usually normal. Thus, in circumstances where the fetal anatomy is grossly normal and there is not another explanation for elevations in maternal serum AFP, the placenta, either secondary to providing increased areas of transport or in providing an abnormal endothelial barrier, allows for greater transfer of fetal serum, and thus AFP, into the maternal compartment. An abnormal placenta is also a likely explanation for the increased risk of adverse pregnancy outcome that is associated with increased maternal serum AFP elevations for which no obvious etiology is found. The case herein reported suggests that an abnormal placenta which provides an altered interface for AFP flow between the fetal and maternal circulations may in fact be the etiology of the significant elevations of maternal serum AFP seen in cases of triploidy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vascular organization of the hystricomorph placenta: a comparative study in the agouti, capybara, guinea pig, paca and rock cavy

The placental vasculature of five hystricomorph rodents was examined by latex injection of the blood vessels, immunohistochemistry and scanning electron microscopy of vessel casts. The pattern of branching of the vessels is described at the level of fine structure. The placenta is divided into lobes separated by interlobular trophoblast. Fetal arteries course through the interlobular areas and give rise to capillaries from which blood drains into veins at the centre of the lobes. Maternal blood reaches the placenta through spiral arteries that pass around the perimeter of the subplacenta. They supply large maternal blood sinuses, lined by trophoblast, which run through the interlobular areas and into the centre of the lobes. Here they supply fine channels that run parallel to the fetal capillaries, so that maternal blood flows from the centre of the lobe to the periphery. This arrangement provides the morphological basis for countercurrent exchange. The maternal channels of the labyrinth drain into spaces formed by the latticework of the interlobular trophoblast and thence through venous lacunae to a basal venous lacunar ring. The subplacenta is supplied by a single fetal artery. The vessels within the subplacenta pursue a tortuous course with dilatations and constrictions as in an endocrine gland.     

Maternal floor infarction: relationship to X cells, major basic protein, and adverse perinatal outcome.

OBJECTIVE: Maternal floor infarction of the placenta is characterized by gross placental abnormalities and histologic evidence of X-cell proliferation. Previously, pregnancy-associated major basic protein has been localized to the placental X cell and identified at elevated levels in serum and amniotic fluid in all normal pregnancies. Here we test the hypothesis that pregnancy-associated major basic protein is localized to the X cells in maternal floor infarction and that it contributes to the pathophysiologic features of pregnancies complicated by maternal floor infarction. STUDY DESIGN: Seven patients with eight pregnancies complicated by maternal floor infarction were evaluated. We analyzed placental tissue, serum, amniotic fluid, and placental cyst fluid for pregnancy-associated major basic protein. RESULTS: Placental tissue from pregnancies complicated by maternal floor infarction had increased numbers of X cells and fibrinoid material that occupied or surrounded degenerating villi and that stained intensely for pregnancy-associated major basic protein. Serum pregnancy-associated major basic protein levels were variable and likely cannot be used to predict the occurrence of maternal floor infarction. CONCLUSION: Pregnancy-associated major basic protein, a potent cytotoxin, is localized to X cells and is deposited in close proximity to chorionic villi in maternal floor infarction and may contribute to the pathophysiology of this disorder.     

Water intoxication-a dangerous condition in labor and delivery rooms

Water intoxication, a form of acute hyponatremia, has been described in various clinical situations. Although hyponatremia is a common metabolic disorder in hospitalized patients, it is generally not well known as a hazard in the labor and delivery room. However, several factors predispose laboring women to develop hyponatremia. Moreover, because the fetus acquires water from the maternal circulation via the placenta, and there is a close correlation between maternal and cord blood serum sodium levels, the newborn infant of a hyponatremic mother is also at considerable risk of developing water intoxication. We review the epidemiology, pathophysiology, clinical features, and treatment of this hazardous disorder. We emphasize the need for awareness of this condition, and call attention to the risk of fluid overload during labor.     

Placental compressibility: implications for indirect diagnosis of posterior placenta previa.

A number of problems beset the indirect diagnosis of posterior placenta previa using transabdominal ultrasound. We add a new potential complicating factor. In 128 pregnancies at or beyond 30 weeks' gestation, measurements were taken from the fetal skull to the maternal sacrum before and after compression. Up to 69% compressibility of the placenta was found in vivo and in vitro. Modified fetal skull to maternal sacrum measurement criteria were devised from the results. Placenta previa is highly unlikely if the measurement from the fetal skull to maternal sacrum is less than 10 mm before compression or less than 7 mm after compression. Placenta previa is probable if the measurement is greater than 20 mm before compression or greater than 15 mm after compression. In 40% of the cases, posterior placenta previa could not be excluded. We conclude that placental compressibility is an additional confounding problem for indirect ultrasound assessment of posterior placenta previa and that indirect assessment should be attempted only if maneuvers to image the lower uterine segment directly are unsuccessful.     

Effect of diagnostic and therapeutic cordocentesis on maternal serum alpha-fetoprotein concentration

We investigated the affect of cordocentesis (n = 36) and intravascular transfusion (n = 14) performed with a fixed needle guide on maternal serum alpha-fetoprotein levels. In 50% of the procedures, the placenta was anterior and punctured. For all patients, maternal serum alpha-fetoprotein levels rose 70.8% +/- 28%. The magnitude of the rise was unrelated to the number of attempts necessary, gestational age, or the initial maternal serum alpha-fetoprotein levels concentration. The location of the placenta was the sole identified variable related to the rise. A total of 44% of the patients had a significant increase in maternal serum alpha-fetoprotein level when the placenta was anterior. In contrast, only 4% of the patients had a significant rise in maternal serum alpha-fetoprotein level when the placenta was other than anterior. There was no difference in the frequency of a significant rise in maternal serum alpha-fetoprotein level concentration between the patients who underwent cordocentesis and those who underwent intravascular transfusion. On the basis of these findings, we recommend that when maternal isoimmunization is a potential concern and the placenta is anterior, the umbilical cord should be approached either through a window or laterally from the placenta.     

Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus

In addition to effects on appetite and metabolism, the hormone leptin is required for reproduction in mammals. Maternal plasma leptin is increased above non-pregnant levels in all mammals thus far examined, including humans. The increase in plasma leptin appears to result in part from upregulation of adipose leptin secretion (e.g., in mice), or from production and secretion of leptin from the placenta (e.g., in humans and some bats). The placenta may also modulate maternal leptin levels via production of a plasma leptin-binding protein (mice, humans). Thus, the placenta plays a coordinating role in regulation of maternal leptin during pregnancy. In this study, the hypothesis that the placenta is also a target organ for leptin in diverse taxa was tested by examining the expression of leptin receptors (Ob-R) in placentae from species of distantly related mammalian taxa, Mus musculus (the laboratory mouse) and Myotis lucifugus (the little brown myotis, also called the little brown bat). A partial sequence of M. lucifugus Ob-R cDNA was first obtained and found to share approximately 78-88% homology at the nucleotide level with known mammalian Ob-R cDNAs. Using probes and primers designed from this sequence, receptor expression was detected in numerous tissues of M. lucifugus, including placenta, which expressed two major receptor isoforms as judged by molecular size. In both species, Ob-R mRNA expression in placenta significantly increased from early to late gestation. Expression of Ob-R mRNA was not affected by cAMP treatment in vitro. The increase in Ob-R mRNA expression in placenta was specific, since Ob-R mRNA expression did not change during gestation in either species in hypothalamus, the major site of the central actions of leptin. Thus, Ob-R is expressed in placenta throughout gestation in mice and bats, and its expression increases over the course of gestation, which raises the possibility that leptin may exert temporally distinct effects on placental growth or function throughout gestation. Because similar placenta-specific changes in leptin receptor expression occurred in species from distantly related mammalian taxa which collectively comprise approximately 70% of all known mammalian species, it is possible that placental actions of leptin are conserved across mammals, even in those species (such as the Swiss-Webster strain of mouse) in which the placenta does not itself produce leptin.     

Fetal arrhythmias: diagnosis, prognosis, treatment; apropos of 33 cases

From October 1993 to February 1998, 33 cases of fetal cardiac arrhythmia were investigated by doppler-echocardiography at the Lille infantile and congenital cardiology department. Extrasystolic arrhythmias were the most frequently encountered disorder (25 fetuses, i.e., 76% of cases: 24 instances of extrasystolic auricular arrhythmia and one case of extrasystolic ventricular arrhythmia). They were invariably benign, and apart from one case only required standard monitoring. Tachycardia was observed in 15% of cases (three cases of supraventricular tachycardia [SVT] and two cases of auricular flutter [AF]). In no instance was a cardiopathic syndrome noted. A number of efficient treatments have been described, but the prognosis is often poor in the presence of hydrops fetalis. Direct fetal treatments (cordocentesis) are currently under evaluation, and at present can only be used as a last resort. In our series, one fetus died 15 minutes after transplacental Flecaine (flecainide) administration. Two of the three SVT and the two AF cases were successfully treated. Bradycardia, which was unassociated with extrasystolic arrhythmia, was found in 9% of cases. It is concluded that Flecaine is probably the treatment of choice for supraventricular and ventricular fetal tachycardia, as it has no teratogenic effect and crosses the placenta at a fetal concentration that is 80% of the maternal level. However, the administration of this drug is not without risk. It is known to possess certain negative side effects, and its pharmacological profile and maternal and fetal health risks have not yet been fully investigated. At present, no entirely safe and efficient treatment for fetal cardiac arrhythmia has been found.