Pediatric & Perinatal Pathology Associates, PSC

Abruptio placentae, Retroplacental hematoma, Premature placental separation
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Literature Review


A.     Introduction.

The normal separation of the placenta during the third stage of labor occurs within the decidua, the soft endometrial layer. In effect, the placenta does not separate from its firm attachment to the endometrium, but the decidualized endometrium is shed and the placenta travels with it. If the placenta separates before delivery of the infant, and blood cannot egress, then a hematoma may form in the decidual layer beneath the placenta forming a retroplacental hematoma (RPH). If this premature separation causes clinical symptoms of uterine tenderness, occult hemorrhage, fetal distress or maternal coagulopathy, then the clinical consequences of the premature separation are designated placental abruption, or in older terminologies, abruptio placentae or accidental hemorrhage. This review will first examine the mechanism of normal placental separation, then look at proposed mechanisms of premature separation, and then look at some of the clinical consequences of placental abruption. The review is not exhaustive.

B.     Incidence of placental abruption and related mortality

A study  from the 1960’s found a rate of fetal death of approximately 1.2 per 1000 births  for " Fetal death associated with antepartum bleeding or retro-placental blood clot, excluding placental previa" [1]. In the same institution in the 1980's, the rate fell to .7/1000 attributed to better care. A study in 1970, using clinical criteria as well as pathological criteria of hematoma with depression or disruption found an incidence of 130 abruptions /26,743 deliveries (0.5%). There was 30% fetal mortality which yields 1.4 deaths/ 1000 deliveries [2]. There is disparity in the rates in these studies, but a range of large or lethal retroplacental hematomas is most likely between 0.5 to 4 / 1000 deliveries. Smaller, incidental hematomas are likely to be at least as frequent.

A major problem in all epidemiologic papers on abruption is the variable definitions from different studies. A study of 189 abruptions over 5 years from a population of 8,000-9000 deliveries per year (approximately 0.4%) had 189 stillbirths and 21 neonatal deaths (55% perinatal death rate for abruptions)[3]. All cases had to have a retroplacental clot or crater and the vaginal hemorrhage had to mixed or concealed. They did not accept any cases diagnosed as “revealed accidental hemorrhage”. These cases occurred before electronic monitoring (1965-1969), but clearly the diagnostic criteria were adequate to identify a clinically significant condition. Twenty nine patients had plasma fibrinogen levels below 200mg/100ml, and there was one maternal death.

A later study (1967-1989) in Norway had a 0.6% incidence of abruption with a 32% perinatal mortality[4]. This study was based on physician reporting of 523,977 pregnancies. Compared to the British population study, both reasonably large, the increased incidence of abruption was associated with a lower incidence of perinatal mortality. One possible explanation is that more vaginal bleeding without premature placental separation was included in the physician reported abruption cases. The Norwegian study also found an increased incidence of reported abruption in a subsequent pregnancy following a pregnancy with abruption (odd ration 6.4).

There is no study of the incidence of retroplacental hemnorrhages/hematomas of the placenta independent of clinical abruption.

C.     Myometrial contraction/ decidual shearing mechanism of placental separation

The contents of the uterus prevent shortening of the myometrial muscle during contractions, at least while the cervix is closed. With expulsion of the contents, the myometrium contracts and shortens markedly (from an average uterine diameter of 21 cm to 5 cm)[5]. The placenta cannot contract. The resulting stress tears the decidua, and the placenta is expelled.  The key role of the decidua had been suspected since the early 18th century. Monro described his dissection of the pregnant uterus “I observed the smooth tense chorion from which the fungous substance separated most easily, and it did likewise from the placenta. (Edin Med 1734)”.[6] This “fungous substance” would later be termed decidua. This fundamental mechanism of placental separation occurs because contraction of the myometrium shears the decidua beneath the rigid placenta. The spiral arteries and endometrial veins traverse the decidua and must be torn apart with placental separation. These vessels can hemorrhage and a hematoma could form with normal separation if the process was focally delayed.

A study of frozen sagittal sections of rhesus monkeys in labor demonstrated two observations relevant to placental separation[7]. First, the thinning of the uterus is not uniform. Second, the separation of the placenta begins in the second stage of labor. Interval radiographs of placental separation in breech and anencephalic deliveries, demonstrated that 17 started at the lower (cervical side) edge of the placenta, and only three commenced centrally [8]. In 20 cases radio-opaque dye was injected into the umbilical artery or vein after cord clamping in breech deliveries prior to delivery of the head. In two cases, the dye was injected in the prolapsed umbilical cord of anencepahlic fetuses. This dye delineated at least the main placental vessels if the injection was venous, with more distal detail by arterial injection. In 18 timed cases, placental separation was complete within 5 minutes of delivery of the infant, and in 6 of those is was complete at the end of the second stage of labor. Some of the authors detailed observations follow: “Study of the soft tissue outlines of the uterus emphasizes that retraction is a process which occurs in all planes, affecting the circumference, width and depth of the uterus as well as its length. At any one time, however, one part of the organ may be more affected than another,  ... retraction in mainly one plane may persist until complete expulsion of the fetus …ultimately uniform retraction takes place.” “There were 3 cases in which placental separation occurred before there was evidence of significant uterine retraction. In the remainder, retraction appeared to precede separation.” A plausible hypothesis is that local contraction of the lower uterine segment in the process of cervical dilatation and fetal descent shortens sufficiently to shear the overlying decidua.

Modern ultrasound technology can demonstrate the contraction of the uterus and consequent separation of the placenta in the third stage of labor. A color Doppler flow study in 55 women found that in the third stage of labor, blood flow stopped at a median of 2.5 (0-230) seconds after delivery with median latent phase of 91 (2-367) seconds and detachment phase of 39 (15-250) seconds[9]. The separation in the vast majority of cases starts at the caudal pole of the placenta and detachment may occur in phases which prolongs that phase. Another ultrasound study of 101 women confirmed that separation usually starts at one pole, most often the lower, and is usually multiphasic with separation and thickening of the adjacent myometrium occurring together[10]. In fundal placentas, the fundal portion usually separates last.

A different concept of placental separation was suggested by in vitro study of the placenta[11]. The author argued that the Bernoulli theorem implies that the intervillous blood flow should reduce blood pressure in the intervillous space compared to the amniotic fluid. A model of in vitro perfusion is used in which increasing the perfusion pressure is counteracted with increasing amniotic fluid pressure to maintain the position of the placenta. The plots were not linear at 45 degrees. The difference between a given rise in perfusion pressure compared to a given rise in amniotic pressure is considered due to flow via the Bernoulli effect. Decreased flow would then result in a higher pressure lifting the placenta upward. This is a very simplified model and there is little evidence that pressure differences can separate the placenta. The chorionic plate is tightly glued to the basal decidua, and the placental does not actually separate, but the decidua cleaves releasing the placenta with superficial decidua still attached.

After rupture of the membranes at term, the infant’s body and residual fluid must prevent significant myometrial shortening. Rupture of membranes with polyhydramnios could result in sufficient myometrial shortening to separate the placenta. A similar degree of myometrial shortening could occur after delivery of one twin, particularly with rupture of both sacs in early gestation [12, 13]. Sufficient myometrial shortening to separate the placenta might occur with rupture of membranes in the second trimester because the amniotic fluid volume is proportionately more than in later gestation. A correlation between preterm premature rupture of membranes (PROM) and abruption has been reported [14-16]. Complications of placental separation are more common at younger gestation including the need for manual removal and post partum hemorrhage[17]. The basis for this resistance to removal is not known, but could account for the higher incidence of apparent retroplacental hematoma if placental separation is partial and delayed. The hematomas could occur before or after delivery of the infant.

In one study, eight of 143 women, who delivered between 24 and 34 weeks of gestation, following at least 24 hours after PROM and without signs of abruption on admission, developed abruption compared two of 143 controls (P<.05)[14]. The clinical indicators of abruption had to be severe enough to warrant delivery and “verified by gross placental examination after delivery”. Only one of the cases had a 5 minute Apgar score of less than 5, and the estimated percentage of abruption was 50% or less in 6 cases. One case met clinical criteria for chorioamnionitis. Except for vaginal bleeding at or after PROM (6 cases), there were no other differences between features, including decreased amniotic fluid, between mothers with and without abruption,. Another study found 19 abruptions in 298 patients, 25 to 36 weeks of gestation with PROM managed expectantly (incidence of 6.3%) compared to an 2.2% incidence of abruption without PROM [15]. Abruption was defined as a retroplacental hematoma indenting the placental substance, and was found in 53 of 1946 deliveries (incidence 2.7%). “The diagnosis was confirmed by histologic examination in all cases.” No pathological criteria are given. Ten of 81 PROM patients with a maximal amniotic fluid < 1 cm had abruption compared to 6 of 169 with a fluid pocket > 2 cm (P<0.01).

The mechanism of the association of preterm PROM with retroplacental hematoma may be simply myometrial shortening and incomplete placental separation. Two other mechanisms have been proposed. One is that the retroplacental hemorrhage is primary and causes the ruptured membranes. A study of cultured decidual cells found that thrombin upregulates matrix metalloproteinase[18]. Progesterone blunts the effect. The study used decidua scraped from the membranes which is likely contaminated by chorionic epithelium. The authors postulate that abruption causes decidual thrombin which via metalloproteinase weakens the membranes and leads to membrane rupture. The hypothesis does not attempt to quantify or localize the in vitro regulation in the living organism, but merely presents a hypothesis. If indeed abruption causes PROM, a more logical explanation is that the extension of a retroplacental separation beneath the membranes would both stretch and devitalize that portion of the membrane causing rupture both by weakening and a focal increase in wall tension. There is no direct evidence of this hypothesis.

The second mechanism proposes that chorioamnionitis causes abruption and chorioamnionitis is associated with preterm PROM. A study using the data from the New Jersey-Placental Abruption Study found a statistically significant correlation of histological chorioamnionitis and abruption (P<.05) that was stronger with severe chorioamnionitis[19]. This study postulates that acute inflammation causes “destabilization of the utero-placental interface, culminating in placental abruption, premature rupture of membranes, and preterm labor.” They acknowledge that their data cannot prove this hypothesis. The criteria for abruption in this study include a retroplacental clot or hematoma on the placental surface. Retroplacental hematoma diagnosed by direct observation as Cesarean section should be reliable. However following a vaginal delivery the hematoma could have formed after delivery of the infant. There were no histological criteria for the hematoma. The study also did not utilize any measure of severity such as fetal measures of asphyxia, maternal coagulation status, or size of the hematoma. In a table comparing the mean gestational age with PROM and abruption, there were 17 abruptions in PROM patients with no chorioamnionitis compared to 11 with any grade of chorioamnionitis. This argues against a consistent causative role for chorioamnionitis. (The percentages of PROM in each chorioamnionitis category did not add up to 100%, so I may have misinterpreted the table.) This study cited a study of thrombin enhanced interleukin-8 expression in term decidua as providing a potential mechanism for chorioamnionitis induced abruption[20]. That study argued instead that the abruption led to fibrin that caused decidual secretion of interleukin-8 that caused neutrophil migration into the decidua. They did not argue that decidual neutrophils caused abruption.

Jersey-Placental Abruption Study also cited a study of nitric oxide synthesis in chorioamnionitis and abruption. The study sampled placental villi and maternal serum from 10 patients with clinical symptoms of chorioamnionitis, and 6 patients with clinical abruption and a retroplacental hematoma[21]. The chorioamnionitis patients had histological chorioamnionitis, but it is not clear whether the abruption cases also had histological chorioamnionitis. Gestational age is not mentioned as a factor in sampling, but the results suggest that most of the patients were very preterm. Quantification in placental histology is fraught with difficulty because the placetone flow of the intervillous blood results in visible local differences in villous maturation related to local differences in oxygen and blood flow. Thus, local blood flow changes would have to be accounted for by extensive random or intentional systematic sampling of the villi. Part of the study results depend on the interpretation of immunoperoxidase staining intensity, a measure that is subjective and not necessarily linear with concentration. The abruption samples were taken above the hematoma in areas that would have experienced complete anoxia. All of this makes interpreting the results of the study difficult. Even if the study results are true, they only demonstrate an up-regulation of nitric oxide production in Hofbrauer cells and syncytiotrophoblast from placentas with chorioamnionitis and from devitalized villi over abruption. Conceptually this result does not translate into a mechanism of abruption in the basal decidua.

A study of pathology in 90 placentas from second trimester fetal loss found more acute inflammation and possibly (P=.05) more histological evidence of abruption than in controls (second trimester induction for anomalies)[22]. The study excluded cases with fetal death or twins. While not surprising that spontaneous preterm labor has more acute inflammation than induced, the finding of increased abruption might contradict the mechanical hypothesis of second trimester abruption. There are two reasons to suspect the results. The first is that the timing of rupture of membranes and loss of fluid may have been different between induced and spontaneous labor, many of whom would have had premature rupture of membranes. Second, there are no validated histological criteria of abruption. Those suggested in the paper “evidence of retroplacental hemorrhage and any associated villous ischemic changes including increased syncytial knots, villous stromal hemorrhage, and villous infarction” tends to favor longer duration retroplacental hemorrhages. The criteria have not been independently validated as evidence of placental separation. Increased syncytial knots might be expected adjacent to an infarction over time, but are not usually a criteria of acute devitalization. This paper also lumps chronic inflammation such as plasma cells in the basal decidua, and chronic inflammation at the chorio-decidual junction with acute membrane inflammation, and there is no validated basis for doing this. They are likely the result of different pathogenesis.

A study of 30 severe, third trimester abruptions (defined as antepartum hemorrhage, firm tender uterus, maternal shock, and fetal distress or death) found no significant difference in the incidence (23% v 28%) nor in the severity of chorioamnionitis compared to 60 control placentas[23]. The opposite conclusion was reached in a study of 37 women, less than 36 weeks of gestation who had heavy vaginal bleeding, intact membranes, a live fetus, and histological evaluation of the placenta compared to 51 controls with similar criteria[24]. An adherent retroplacental clot with depression of the maternal surface was present in all cases, and 27 had histologic evidence of abruption including “decidual necrosis, villous crowding, and marginal and pervillous fibrin deposition”. There was no attempt to explain or validate these histologic criteria. 14 abruption infants had a five minute Apgar score less than 7. Fifteen cases (41%) compared to 4 controls of 51 controls had histological evidence of chorioamnionitis. The paper states that 4 of 51 is 4% (which it is not)  and is statistically significant at P <.001. One difference in the study is the very low incidence of chorioamnionitis in controls. One difference between these two studies is that the mean gestational age was 34 weeks in the first study and 30 weeks in the second which would increase the expected number of chorioamnionitis cases. This could explain the difference in the case incidences of chorioamnionitis 23% v 41%, but not the low control incidence of 4 (really 8%). The most likely explanation is the skewed control population in the second study which included 36 hypertensive disorders, and the rest with other serious medical complications Chorioamnionitis is associated with preterm labor. If these pregnancies were delivered because of these complications at the same mean gestation as those delivered with preterm labor, even if with suspected abruption, the controls would be expected to have a lower incidence of chorioamnionitis.

Chorioamnionitis does not involve the basal decidua (that is decidua beneath the placenta). There is an association of chorioamnionitis with abruption in preterm infants but this is because preterm labor is associated with chorioamnionitis. Chorioamnionitis does not cause basal plate inflammation, and is unlikely to be a direct cause of placental separation.

A perhaps unique hypothesis about abruption related to uterine shortening was the proposal that orgasm could initiate abruption. The Collaborative Perinatal Project found a highly significant correlation of coitus since the last antenatal examination before delivery and the incidence of antenatal hemorrhage “severe enough to raise the clinical possibility of premature placental separation[25]. Hemorrhages with a retroplacental hematoma were designated abruption, those without were “hemorrhage of unknown origin”. Both types of hemorrhage correlated with coitus, and with significantly increased perinatal mortality. The only exception was the group with abruption at 24-27 weeks of gestation, which is precisely the group that may have separation based on loss of uterine volume with membrane rupture. The mechanism of the association is not known, but orgasm may cause uterine contraction which conceivably could cause abruption by decidual shearing. The study has not been reproduced.

D.    Uterine venous occlusion as a mechanism of placental separation

Vena cava occlusion can lead to abruption, a mechanism observed by direct compression in humans [26].  The study was based on experimental production of abruption in the dog by occlusion of the inferior vena cava and the left ovarian vein. The first patient had direct compression of the vena cava, but not the ovarian veins, for 5.5 minutes and then delivery of the infant by Cesarean section. The uterus was seen to become congested externally. Immediately after delivery of the infant, the placenta was palpated and found to be almost completely separated. A second patient had 5 minutes of direct vena caval occlusion and developed a central keyhole separation of the placenta involving to of the placenta. Both patients had immediate systemic hypotension with caval compression. The second patient had vena caval pressure measurements that started below 30 cm of water and with direct pressure rose to above 40 cm of water. This mechanism of abruption was proposed as one of the complications of the “supine hypotensive syndrome’, although as pointed out by Harris, in most cases of hypotension there is no abruption[27, 28].Only a minority of women experience hypotension in the supine position, and it is possible that the two cases studied were susceptible. A study of inferior vena caval pressure with a transducer inserted in the femoral vein at the time of Cesarean section in 8 gravid women demonstrated that the abdominal vena caval pressures were as high as those seen with manual compression of the vena cava in non-gravid [29]. Thoracic caval pressures were normal and the abdominal caval pressure dropped to normal after removal of the infant. Most interestingly after the section, manual compression of the vena cava elevated pressure as it would in a nongravid patient, but unlike the nongravid patient there was not a sharp fall in systolic blood pressure. This was interpreted logically as evidence that the mothers had developed sufficient collaterals to be able to bypass the inferior vena cava. They did not compress the vena cava prior to delivery, but the hemodynamics in the women studied make it unlikely that this maneuver would have elevated uterine venous pressure. A ninth woman with polyhydramios was studied who had even higher vena caval pressures (35 mm Hg compared to 18-24 Hg in the others). Normal pressures in the vena cava in the study appeared to be < 5 mm Hg. A report of two pregnant woman requiring vena caval ligation just below the renal veins to prevent pulmonary embolism had no complications from the occlusion[30]. Kerr suggests that in the human experimental cases, lifting the uterus to get to the vena cava may have directly obstructed uterine veins as the mechanism of abruption[31]. In a follow up paper to the two experimental cases, the authors report that in five subsequent women, compression did not lead to abruption[32].The authors then discuss their observations of the distention of uterine veins over the placental insertion with different manipulations of the uterus. The discussion states “In all these investigations no mother or infant was injured. Nevertheless, we plan in the near future to continue the investigation in pregnant rhesus monkeys.” I could not find such studies published. In experimental vena caval occlusion, there was prompt development of a Couvelaire uterus, that is extensive hemorrhage into the myometrium[33]. This implies that the elevated venous pressure in the capillary-venule bed of the uterus ruptures vessels in more than the basal decidua. Elevated uterine venous pressure should also distend the intervillous space and parietal decidual veins. There is no published evidence that these features can be used to diagnose this mechanism of abruption. The pathology of two cases of Couvelaire uterus demonstrated extensive hemorrhage between myometrial fibers, and “in the walls of many (veins) free haemorrhage had occurred, just beneath the endothelium and communicated freely with the hemorrhagic effuisoins between the muscle fibers[34].” Intimal plaques were described in the arteries, which from the illustration, I think are common in gravid uteri.

A review of the published reports on supine hypotensive syndrome from 1922 to 1993 found several case reports of abruption associated with the syndrome[35]. Two cases had serious confounding factors respectively pre-eclampsia and obesity. The other three reports were of cases that delivered prior to 1960. I found no new English language reports of the association. A report from 1956 occurred when a near-term pregnant woman fainted for 5 minutes following 25 minutes supine on the examining table[27]. Two hours later she became symptomatic with pain and and a tender uterus. An eventual Cesarean section revealed that the placenta was approximately one third separated from the uterine wall by a dark hematoma. A single case can show a plausible temporal sequence, but alone can not prove causation.

I autopsied an 18 week gestation mother with lethal cerebral hemorrhage following an abruption related to a day at the amusement park. The forces from the roller coasters may have pressed the uterus against the vena cava. I also autopsied an infant with massive placental separation from a mother with a positive toxicology screen for benzodiazepines, but not cocaine. There was no definite history of a decreased mental status, but had she been asleep at the onset of abruption. The history is at least compatible with vena caval pressure or displacement of the uterus causing abruption. Thus, a compression of the vena cava or local compression of uterine veins has not been disproved as a cause of premature placental separation.

Another potential cause of uterine venous occlusion is thrombus. Ovarian vein thrombus is usually a post partum complication of delivery, but with some forms of maternal thrombophilia, the high turbulent flow in these veins might lead to prepartum occlusive thrombus.  Thrombosis of smaller veins in the basal decidua seems unlikely to lead to abruption, since the back pressure into the intervillous space would be dissipated by drainage through all the remaining veins. Local decidual venous occlusion has been proposed as the mechanism of subchorionic thrombo-hematoma. Perhaps there are veins large enough and without anastomosis in the uterus that could lead to decidual hemorrhage. The evidence of an association of thrombophilia with abruption is more likely due to a venous than arterial occlusion. Arterial thrombi would likely simply lead to infarction of the placenta supplied by that artery.

There are cases of an association of thrombophilia with abruption, such as with Protein C or S deficiency, and hyperhomocysteinemia [36, 37] [38]. A study of 27 cases of clinical abruption found a Leiden Factor V mutation in 8 patients (5 heterozygotes, 3 homozygotes) compared to one heterozygote in controls[39]. Abruption was defined as profuse vaginal bleeding in the third trimester and “clinical observation of the placenta after its expulsion or its extraction during a cesarean delivery”. Leiden mutation of exon 10 of the Factor V gene in another study was not associated with abruption, but an allelic polymorphism, M385T, in exon 8 of the gene is negatively associated with abruption [40]. The criteria for abruption in this study required a clinical diagnosis and pathological confirmation of a hematoma or histological confirmation, and one of three clinical criteria: 1) vaginal bleeding in late pregnancy, 2) increased uterine tone 3) fetal distress of death. There was no detail on the features that histologically confirmed abruption. An early study of activated protein C ratio in 29 patients with abruption found a level ≤ 2.5 in 17 of 27 patients compared to 5 in 29 controls (P=.00125)[39]. 15 patients with low protein C ratios were tested for the Leiden mutation and 3 were homozygous, and 5 heterozygous. The criteria for abruption were third trimester bleeding, not from placenta previa, and examination of the placenta after expulsion or at Cesarean section. Eleven patients suffered fetal death.

The New Jersey Placental Abruption study compared placental pathology in woman with an abruption between those with and without thrombophila based on a panel that included Factor V Leiden mutation, prothrombin gene mutation, lupus anticoagulant, and anticardiolipin (IgG and IgM)[41]. Of 135 woman in the study, 85 had a thromobphilia. That seems very high given that all eligible women were recruited for the study. Not surprisingly the study found an association of old placental infarction with the thrombophilia group, as infarction would be a consequence of thrombosis in a spiral artery. They cite other studies confirming the association of thrombophilia with placental infarction. As in their previous study it is not clear if the diagnosis of acute deciduitis and of recent infarction includes findings directly related to a recent RPH.

A study of hereditary thrombophilias and obstetrical complications evaluated 20 woman with grade 2-3 abruptions and found 5 with the Leiden mutation (odds ratio 4.9 (1.4-17.4)), 3 with MTHF mutation (2.0 (0.5-8.1)) and 5 with a prothrombin mutation (9.9 (1.8-43.6))[42]. A study of 110 women with a history of either, preeclampsia, abruption, or stillbirth found no predictive value of thrombophilia testing on subsequent complications[43]. This study is too small to directly disprove an association of any given thrombophilia with abruption, as only 17 cases had abruption to begin with and only 5 reoccurred, and few of any one type of thrombophilia. All mothers also received aspirin therapy in the subsequent pregnancy. The authors do not present the information on individual cases. The definition of abruption was clinical “with histologic analysis of the placenta to confirm the disease”. A study based on genotyping newborn screening cards found no association of antepartum bleeding with any Factor V, MTHFR or prothrombin mutations[44]. The type of bleeding was for any cause after 20 weeks gestation. The study did not specifically look at abruption.

            Thrombophilic assays of 101 women with a history of abruption or placental infarction sampled a mean of 48 months after pregnancy demonstrated significant risk if more than one factor was in combination compared to 92 control women[45]. The homocysteine levels were distributed with a larger tail in the study group, and the combination of high homocysteine and decreased factor C or S increased the risk compared to controls 3-4 times. The patients had no vitamin supplementation for at least 3 months. Because this study combines infarctions which would be expected with maternal thrombophilia, with abruption in which the association with thrombophilia is at least moot, and does not separately analyze the data, it can not prove an association of abruption per se with thrombophilia.

The New Jersey Placental Abruption study interviewed 212 mothers with abruption and 206 controls after delivery about thrombotic disease (deep vein thrombosis, pulmonary embolism, stroke, heart attack and other) in first degree relatives. There was a significant increase in disease in maternal (32 (7%) versus 13 (3%)) but not paternal relatives (7% for both)[46]. There is no simple explanation for this discrepancy between male and female relatives which may reflect chance.

There is an older literature suggesting that folate deficiency might be a factor in abruption [47, 48]. These studies from the 1960’s used hematologic parameters and FIGLU assay of urine as an indirect measure of serum folate. The first study found 23 abruptions in 407 women with megablastic anemia and increased FIGLU excretion. The author then studied in Singapore 11 women with abruption compared to women with other causes of antepartum hemorrhage and found similar results. The association was not found in a later study of random administration of folic acid in 2949 singleton pregnancies, but folate supplementation may have reduced the incidence of abruption [49]. This study reviewed other less conclusive studies that also failed to show an association.  One objection to the studies is their use of a complex bioassay for folate, but this objection does not apply to a study that failed to find macrocytic red cell changes in abruption cases [50]. An association of abruption was found with hyperhomocysteinemia [38]. A biologically plausible role for folic acid is in the prevention of the hypercoagulation in hyperhomocysteinemia. Previous studies of folate supplementation may not have had the power to uncover this effect on a subpopulation. A study using the Norwegian birth registry did find a reduced risk in for clinical abruption including retroplacental hematoma, in woman who had folate and or vitamin supplementation[51].

A symposium lecture by Eskes relates the complex relationship of folate, a cofactor for the 5,10 methylenetetrahydrofolate reductase (MTHFR) in its role in remethylation of homocysteine to methionine and control of blood levels of homocysteine[52]. The C677T mutation of MTHFR can result in elevated serum homocysteine, but is still sensitive to folate levels. Another study of 18 women with a history of abruption found no correlation with the C677T MTHFR mutation alone, but did find an association with the A1298C mutation, both heterozygous and homozygous combined with the C677T mutation[53]. The A1298C mutation does not elevate homocysteine levels. The definition of abruption was “diagnosed clinically and subsequently confirmed when more than 15% of the placental surface was covered with blood clots”.

A study of serum homocysteine levels in 84 women with a history of abruption or placental infarction found increased homocysteinemia in that group compared to controls[38]. The inclusion criteria are very mixed: “The diagnosis of placental abruption was based on either the combined presence of tender, hypertonic uterus and disseminated intravascular coagulation, and/or the histologic observation of a retroplacental hematoma with or without signs of infarction. Placental infarction was diagnosed if the placental was characterized by circumscribed areas of villous necrosis combined with a stillborn fetus or a severe growth retarded child,” This may not be a homogenous group. The published scatter plot of fasting plasma homocysteine levels shows in the study group compared to controls 8 patients who have values higher than the highest level in the control group (N=46). Since only a percentage of abruption or placental infarctions are likely related to hyperhomocyteinemia, this would be good evidence of the existence of such a subgroup, with many more cases than would be suspected.

Investigations of an association of abruption with polymorphisms in the methylenetetrahydrofolate reductase (MTHR) gene have been inconsistent. This enzyme is needed to convert homocysteine to methionine. A study by the New Jersey –Placenta Abruption Study found no association of abruption with  MTHR polymorphisms 677C to T or 1298A to C mutations[54]. The study uses broad criteria to define abruption and does not stratify by gestation or fetal outcome. There were no cases or controls with double homozygous mutations, nor any homozygous for the 1298 mutation with a heterozygous mutation at 677. There were no significant differences between cases and controls for plasma folate or homocysteine. This same group did find an association with a homozygous mutation (742G T) in the Betaine-homocysteine S-methyltransferase gene with abruption (25 cases of 196 abruptions compared to 17 of 191 controls, adjusted odd ratio 2.82 (1.84-4.97)[55]. Decreased function of this enzyme could lead to elevated homocysteine. The abruptions were not related to the homocysteine levels, but the assays were obtained without relation to dietary intake or folate supplementation. As in all the studies by the New Jersey Abruption Study, the inclusion criteria did not require evidence of a fetal distress or proof of significant predelivery placental separation, and did include very preterm infants.

Studies of the role of methionine/homocysteine metabolism on abruption are complicated by the effects of nutrition particularly folate and B6, by smoking and alcohol use, and by a possible interaction of multiple polymorphisms of the MTHFR gene on homocysteine levels and possibly on other aspects of disease. In all of the studies there are confounding factors of the intrinsic severity of thrombophilia, the role of therapy, and the inclusion of other common associations of abruption such as prematurity and preeclampsia that likely have non-thrombophilic mechanisms of abruption. That some studies have found the association, and since there is a plausible biologic mechanism in thromobsis of uterine veins, thrombophilia can not be dismissed as a risk factor for abruption.

E.     Arterial hemorrhage as a mechanism of placental separation

An arterial hemorrhage as a mechanism of placental separation implies that blood from a ruptured artery can dissect the basal decidua producing a hematoma. The blood in the trophoblast canalized arteries is at relatively low pressure and high flow, but a hematoma produced by these vessels would expand until it reached systemic blood pressure. A histological study of 462 preterm placentas found an association of basal hemosiderin (but not membrane hemosiderin) with several histological lesions that may be related to decidual arteriopathy in infants delivered between 22 and 32 weeks of gestation[56]. A history of clinical bleeding more than 72 hours prior to delivery was significantly associated with hemosiderin in both basal and membrane decidua (but looking at the data the basal hemosiderin had only negligible differences with the no hemosiderin rates). A table that showed significance levels but did not specify for which variables appeared to show an association of non-hypertensive abruption with a clinical history of bleeding in the first and second trimester. The authors conclude that their study suggests that abruption could be due to a long standing arteriopathy. I would interpret the results differently in that it appears that membrane hemosiderin is associated with vaginal bleeding which suggests that some abruptions are associated with hemorrhage beneath the membranes prior to clinical abruption. The evidence that basal decidual hemosiderin is a marker for potential abruption is weak.

Case reports of Doppler studies in patients with abruption suggest that there is elevated resistance in the uterine arteries. In one case, a mother with a history of five recurrent abruptions with 4 fetal losses was studied hours prior to an ultrasound documented abruption and stillbirth[57]. Her uterine arteries demonstrated a “very high” pulsatility index and a pronounced notch in the Doppler velocity waveform. The umbilical vessels and fetal carotids were normal. The placenta showed some small infarctions. A second case was studied during an abruption seen on ultrasound[58]. The uterine arteries had a systolic/diastolic ratio of 6 (normal <2.6). The umbilical artery had a dicrotic notch and a S/D ratio of 8 (normal <3.7). No placental examination was described. The evidence of elevated uteroplacental resistance in both cases could have been due to mild preeclampsia in both mothers with poor trophoblastic invasion and widening of spiral arteries although arterial spasm can not be excluded. The explanation of increased umbilical resistance is more difficult to understand as the typical pathological picture is one of villous congestion with acute RPH. I had assumed such congestion was due to fetal vascular ischemia and dilatation since the dilatation also occurs with infarction, but perhaps the mechanism involves a chorionic venous constriction. Both the histological and the Doppler studies support a possible arterial disease mechanism in premature placental separation.

1.      Epidemiologic risk factors and arterial disease

Most population surveys have found assoiciations of abruption with maternal diseases that could be causing an arterial disease including chronic hypertension, pregnancy induced hypertension and use of vasoactive drugs such as cocaine and cigarettes. A review of 415 cases of abruption from 36,875 unselected deliveries at one hospital found significant associations with intrauterine growth retardation, histological chorioamnionitis, rupture of membranes > 24 hours, preeclampsia, chronic hypertension, and cigarette smoking[59]. Removal of growth retardation from the regression model had little effect on the other associations. The definition of abruption were two or more criteria of four : “1) antepartum hemorrhage after 20weeks of gestation, 2) uterine pain or tenderness, 3) fetal distress of death, 4) blood clot behind the placenta”. The findings were not related to gestational age.

A study using ICD-9 codes from the National Hospital Discharge Survey (approximately 400 hospitals) from 1979 to 1987 found rates of reported abruption to be 0.8 to 1.2 % with higher numbers in the most recent data[60]. The total number of abruptions was approximately 286,000 and at a rate of 1%, the total deliveries must have been near 28 million. The incidence of coagulopathy was 2.5% and of stillbirth 7.1% with abruption compared to 0.05% and 1.2% in those without. The associated complications were twins, PROM, chorioamnionitis, chronic hypertension and preeclampsia. A study of abruption in Peru using the criteria of the New Jersey Abruption  study group found that previous stillbirth was a significant risk factor for abruption., but there was no study of the prior stillbirths to see their relationship to RPH or preeclampsia[61]

There are many differences in the definition used for abruption in epidemiologic studies. Abruption causing fetal distress or maternal defibrination may have different risks from those associated with antepartum hemorrhage and a small adherent hematoma on the placenta. Stratifying the analysis of preterm infants from term might aid separation of different mechanisms of abruption. Some of the epidemiologic abruption studies use, often with modification, the classification of Page, King and Merrill[62]:

“Grade 0. These are clinically unrecognized before delivery (diagnosis based upon examination of the placenta).

Grade 1. These show external bleeding only, or mild uterine tetany, but no evidence of maternal shock.

Grade 2. In this group there is uterine tetany, ordinarily with uterine tenderness, possibly external bleeding, fetal distress (or death), but no evidence of maternal shock.

Grade 3. Here there is evidence of maternal shock or coagulation defect, uterine tetany, and intrauterine death of fetus.”

The authors emphasize that Grade 1 did not progress to Grade 2 or 3, and fetal mortality was related to the tendency for this grade to occur in premature infants, and not directly to abruption. Grade 2 often progressed to Grade 3 with time, and complications were related directly to the abruption. The authors excluded Grade 0 from their analysis. They also did not include preeclampsia/ eclampsia in the classification system because this disease had a contribution separate from the abuption to the maternal and fetal complications.

2.      Possible mechanisms of decidual arterial hemorrhage

a)     Arterial spasm

The decidual spiral arteries supplying the placenta have lost their media, but there must be a junction with arteries with a media capable of contraction. A persistent vasospasm of this media could cause necrosis and subsequent rupture of the distal vessel or even rupture from constriction of the muscular artery at the junction with the transformed spiral artery, leading to a deep arterial hemorrhage dissecting into the decidua. Possibly patients with abruption, analogous to Berger syndrome, may be unusually susceptible to the vasoconstrictive effects of the drugs or possibly a sudden rise in blood pressure may physically disrupt the artery.

Such spasm could  underlie the association of abruption with cigarette smoking or cocaine usage [63, 64] [59] [65] [66, 67]. The abruption following cocaine use anecdotally has occurred minutes to hours following snorting the drug[68, 69]. A study of 29 maternal cocaine users that evaluated placental pathology did not find an increased incidence of retroplacental hemorrhage (1 case) compared to controls, although 4 had a clinical history of abruption[70]. Five had chorionic villous hemorrhage. The control patients, all randomly selected, also had a high incidence of chorionic villous hemorrhage (3 of 20) which seems improbable in my experience. Such intravillous hemorrhage is associated with premature placental separation.

Histological studies have not shown a consistent lesion associated with abruption and cigarette smoking. A study of women with abruption found a statistical increase of intervillous thrombus in the 20 smokers versus 169 non-smokers[67]. The study did not define criteria for gross sampling of lesions, and intervillous thrombi may not be consistently sampled as a lesion. More importantly there is no evidence that intervillous thrombus is an indicator of placental hypoxia. Based on immunostaining of fetal hemoglobin, the lesion is the result of fetal hemorrhage into the intervillous space with thrombosis of fetal and maternal blood. The same study found, at P = .04, a reduction in placental infarctions in smokers. This suggests increased decidual arterial thrombi in the non-smokers.

b)     Arterial hemorrhage into an infarction

An infarction in the brain, although initially bland, may secondarily develop an expanding hemorrhage. Neuropathologists designate such a lesion as a red infarction.  The infarcted brain, like the decidua, is a tissue with little firm structure to restrain a hemorrhage. Infarctions of the placenta occur from occlusion of spiral arteries in the base of the placenta. Diseases that cause such infarctions such as pre-eclampsia or maternal thrombophila are also associated with retroplacental hemorrhage.  Decidual vessels in an infarction are connected to deeper and to collateral arteries at systemic pressure that could produce an expanding retroplacental hemorrhage in the decidua equivalent to a red infarction of the brain.

Many studies have found an association of pre-eclampsia with abruption. A study of 170 women with abruption from 22,905 deliveries over a decade at one Finnish hospital found a significant correlation with pre-eclampsia[71]. The authors point out that pre-eclampsia was a poor guide to risk since only 2.8% of pre-eclamptic patients developed abruption and only 13% of abruptions were associated with pre-eclampsia. This study, as do most epidemiologic studies of abruption, has an arbitrary but typical definition of abruption: “At least two of the following criteria was required for diagnosis: 1) vaginal bleeding in late pregnancy 2) uterine tenderness with increased baseline uterine tone monitored externally 3) fetal distress or death, and 4) blood clot behind the placenta.” By having 2 criteria perhaps some cases of marginal or retromembrane bleeding are eliminated, but if 1 and 2 are the criteria used, not all may be selected. If 3 and 4 used, many preterm infants will be selected without evidence that the retroplacental clot was a cause of distress nor occurred prior to delivery of the infant, or at the least was not secondary to rupture of membranes in a very premature infant. This particular study accepted all cases over 20 weeks of gestation. They did not stratify for gestational age, but 59% of cases were preterm birth (which would have included many of the pre-eclampsia cases) compared to 6% of controls.  Of the cases 41% had one minute Apgar scores less than 7 and 26% had five minute scores less than 7. This data shows that some of the cases had fetal distress.  Severe fetal distress was rare with only 5 cases having a fetal venous pH  < 7.15. Pathological criteria and their limitations will be discussed below.

c)     Arteriopathy and arterial rupture

Hemorrhage may occur when a disease process weakens the wall of an artery under systemic pressure. This is a familiar mechanism in hypertensive hemorrhages in the brain. A common arteriopathy in pregnancy is acute atherosis which demonstrates microaneurysm formation, and fibrinoid necrosis of the media often with accumulation of lipid foam cells. This lesion is associated with pregnancy induced hypertension, but occurs only sporadically in that disease. The lesion is restricted to spiral arteries not canalized by trophoblast in both the basal and parietal decidua. In a study of 445 consecutive women with severe preeclampsia/ eclampsia, abruption was not associated with measures of clinical severity of the preeclampsia [72]. In my experience, acute atherosis also does not appear related to severity of preeclampsia.  An older study that included the pathologist who first described acute atherosis found the lesion only 7 times in 174 cases of premature placental separation associated with toxemia[73]. The study found in the same patient group an increased incidence of infarction but they did not compare to toxemic cases without infarction, and in the discussion it is clear that they also included infarction above the retroplacental hematoma. This study also proposed a classification of abruption that included the percentage of retroplacental hematoma , <1/6, 1/6 to 2/3, and almost to complete which were associated with progressive clinical severity. A reasonable hypothesis is that pre-eclampsia could cause retroplacental hemorrhage either through infarction or through necrosis of arterioles, that is acute atherosis.

Abruption is also associated with chronic hypertension [74] [65] [16, 75]. This may in part relate an increased risk of preeclampsia, but arteriolar lesions from hypertension alone may be significant. No correlation of retinal hypertensive arteriopathy and abruption is reported. If the common element of elevated blood pressure in weakened vessels contributes to the risk of retroplacental hematoma in chronic hypertension and in pregnancy related hypertension, then abruption should be related to the pressure at onset.

A retrospective chart review of 265 pregnancies more than 20 weeks gestation with the clinical diagnosis of abruption (275 infants with twins) found a 24% (13/55) incidence of abruption in eclampsia, 10% (29/290) in chronic hypertension, and 2% (54/2320) in preeclampsia from 24,258 deliveries[74]. Patients were counted more than once if they had overlapping diagnoses, e.g. chronic hypertension with superimposed preeclampsia. Abruption required “documentation of a retroplacental clot with depression or disruption of the underlying cotyledons”. The chronic hypertensives, even excluding those that developed eclampsia, still had twice the incidence of abruption. They also had a significantly higher incidence of previous abruption (24%) and of perinatal mortality with the current abruption (60%). The degree of hypertension did not correlate with fetal mortality in the chronic hypertensive patients, but did in the preeclamptic patients. These findings suggest that more than the pressure, rather the underlying vascular changes from chronic hypertension may be the significant etiologic factor. Note that distal spiral arteries are lost with each menstrual cycle and would not have chronic hypertensive change.  No detailed study of the retinal vessels, etiology or duration of the chronic hypertension was provided. As expected, maternal age was higher in the chronic hypertensive patients (28 years) than in those with just preeclampsia (20 years).

A review of birth certificate data that links mother and child found an inverse “dose response” curve of risk of abruption with percentile of birth weight that was parallel for chronic hypertension alone and for superimposed pregnancy hypertension and fetal growth retardation[75]. The risk of abruption was also highest with superimposed pregnancy induced hypertension. With chronic hypertension alone, the relative risk of abruption was increased after 32 weeks of gestation with a 1.8 times risk after 37 weeks of gestation. At the same gestation chronic hypertension with only PIH had a relative risk of 3.7 and of 4.8 with only growth retardation. Chronic hypertension with a large infant had no increased risk of abruption, unless there was also PIH with had a relative risk of 13.  The study had 30,189,949 births with 126,648 abruptions. The study admitted that the results could be skewed by various interventions, but I am equally concerned about the lack of a definition of abruption. Whatever the flaws, with such huge numbers, the correlation of at least clinically perceived abruption with maternal vascular disease and intrauterine ischemia appears well established.

The comparison of abruption in mothers with chronic hypertension or preeclampsia compared to not having those diseases found a significantly lower umbilical cord pH in the study group[76]. The grade of abruption was higher, but not significantly, and the mortality rate was similar. They used a simplified grading system: “1” is maternal bleeding, “2” is fetal distress, and “3” is fetal death.

Direct observation of a ruptured artery in abruption in has been attempted with placental bed biopsies. A ruptured decidual artery in continuity with a small basal decidual hemorrhage was identified using serial sections in a placenta with a larger 25 % placental separation from a woman with eclampsia [77]. Placental bed biopsy beneath abruption has demonstrated abnormal vessels [78]. This study did not have controls and failed to find vessels in 6 of 18 cases. The biopsies demonstrated intramyometrial hemorrhage. Four cases demonstrated a vessel with subintimal thickening, no elastica, and fibrin thrombus. The authors interpreted these vessels as possible arterio-venous malformation and as the possible site of hemorrhage. Subintimal thickening may be a biopsy artifact [79]. Placental bed biopsy studies have shown that acute atherosis can be found beneath the placenta in preeclampsia and in chronic hypertension with preeclmapsia[79]. This lends support to the concept that arteriolar lesions in preeclampsia could be the basis of retroplacental hematoma. These biopsy studies have not proven (nor disproven) that the complex remodeling of arteries by trophoblast could on occasion produce an abnormal vessel capable of initiating a hemorrhage and retroplacental hematoma.

F.           Hemorrhagic diathesis as a mechanism of placental separation

Hemorrhages associated with a bleeding diathesis may be occurring at the capillary level, but the effect is that of arterial bleeding since the concept of such bleeding is that a lower resistance pathway for arterial blood entering the decidua causes decreased and lower pressure in the intervillous space, and accumulation of blood until the intrauterine pressure equals arterial pressure and tamponade occurs.

There is a report of a mother with congenital hypofibrinoginemia who had only easy bruisability between pregnancies but had two fetal losses from abruption[80][rb1] . The obstetrical history was only that of severe pain and hemorrhage with no other details except that the second pregnancy was by Cesarean section and both infants were stillborn. No placental pathology was provided. A 32 week gestation woman with disseminated intravascular coagulation (DIC) and renal failure following a snake bite demonstrated a 75% placental separation seen at Cesarean section[81].  There was fetal death, and it was not possible clinically to be certain that abruption did not occur first, but DIC and renal failure were known complications of her Bothrops jararaca bite. No pathology was reported. A case of a needle induced laceration of the margin of the placenta during percutaneous umbilical blood sampling produced a marginal abruption[82] A study of thrombectomy in pregnant women had 5 perinatal deaths (with one set of twins) attributed to abruption that the authors attributed as likely due to anti-coagulation[83]. No details on the patients are given but some in the series had a family history of deep vein thrombosis or a known genetic thrombophilia. More than 90% of patients also had an arterio-venous fistula created in the groin. Could this procedure increase uterine venous pressure? 

G.     External forces causing placental separation

Abruption from the physical shearing of the placenta from the uterus occurs with motor vehicle accidents. External deceleration moves the placenta in relation to the uterine wall. Not surprisingly, the more severe the maternal trauma, the more likely abruption will occur [84] [85]. There have also been reports of delayed fetal death from abruption in less severe motor vehicle trauma [86] [87] [88]. A peculiar variant of trauma would be direct trauma from the fetus who may be able to jar or lift the margin of the placenta. Such fetal kicking was observed by ultrasound in two cases of mild antepartum hemorrhage[89]. Traumatic placental separation would be expected to involve the margin.

Obstetrical management of trauma patients includes looking for a Kleihauer-Bedtke or other test of fetal to maternal hemorrhage. Placental separation occurs in the decidua, and should not cause fetal hemorrhage. However, trauma could cause tearing of villi that are fixed in the chorionic plate and lead to fetal hemorrhage into the maternal intervillous blood, and may be another piece of evidence correlating with traumatic placental separation.

H.    The clinical consequences of premature placental separation

1.      Fetal asphyxia/ acidosis from devitalized placenta

Whether the abruption is clinically evident or silent, if a sufficient area of placenta is suddenly devitalized, the infant may die from asphyxia due to decreased gas exchange with the maternal circulation. If the fetus is rescued by delivery, the neonate may still suffer the consequences including hypoxic ischemic encephalopathy with a risk of persistent neurologic deficit.

            Particularly in automobile accidents, a delay of hours has often been noted between the trauma, the time of presumed onset of the abruption, and the fetal death. In partial placental separation, the mechanism of fetal injury may be more complicated than just the loss of a portion of placental exchange function. Examination of the placenta in these cases demonstrates that the devitalized placenta is much deeper red than the uninvolved segments. Microscopically, this is associated with marked vascular congestion, and sometimes intravillous hemorrhage [90]. ( A note on this cited study: Histological examination of placentas with either a >10% retroplacental hematoma or a description of separation at Cesarean section demonstrated intravillous hemorrhage usually adjacent to the RPH, and more frequently in younger gestation but present at any gestation. The authors conclude based on published papers of the association of RPH and positive Kleihauer Bedtke tests that fetal hemorrhage must proceed RPH since there is no maternal circulation to carry away fetal blood after the RPH. They also postulate intervillous hemorrhage as evidence of hyperfetal circulation and the source of fetal hemorrhage that must precede and therefore may be a cause of abruption. The logic is tenuous.)  To the extent that this congested devitalized placenta is being fetally perfused, the fetus will be shunting blood away from areas of gas exchange, and into dying tissue that would be expected to add a lactic acid load to the blood returning to the fetus. A small marginal abruption produced by needling the margin of the placenta during percutaneous umbilical blood sampling caused persistent fetal bradycardia that led to Cesarean section although the umbilical vein blood gas after delivery was not acidotic[82]. The child had a seizure in the nursery but was discharged without neurological deficit.

            A study following mothers with first trimester retroplacental or subchorionic (beneath the membranes) hematomas found significant correlations with multiple obstetrical complications later in gestation[91]. The largest relative risks of the hematoma (retroplacental and subchorionic combined) were for abruption or preclampsia. Retroplacental hematoma specifically was associated with perhaps related outcomes of preeclampsia, preterm delivery and fetal growth retardation. The study did not try to correlate the ultrasound finding with a pathological correlate in the delivered placenta. The hematoma was retroplacental in 68 of 159 pregnancies and large (greater than 50% of the size of the gestational sac) in 26 cases. The number of retroplacental hemorrhages that were large was not provided.

            A monkey fetus delivered with a presumption of stillbirth still had severe bradycardia at the time of autopsy[92]. The placenta showed two partial retroplacental hematomas, one older than the other. The brain showed severe cystic encephalomalacia including the spinal cord. The author did not estimate the percentage of the placenta devitalized by the separations, but they were relatively large judging from the illustration. The mother monkey had been asymptomatic although fetal movement had been absent for at least two weeks prior to delivery which were post dates.

            Logically, the larger the area of placenta separated from the uterus the more likely that stillbirth will result. A study based on obstetricians reported estimate of the abruption did show a correlation of percentage size of the separation and the logarithmic risk of stillbirth[93]. The curve begins to inflect upward after 40-50% separation. There was no validation of the obstetricians estimate to pathologic findings or to other clinical measures of severity of abruption such a fetal distress or maternal coagulopathy. The same study found an association of abruption with risk of intrauterine growth retardation that was adjusted for cofounding variables such as preeclampsia. The use of risk in this study does not imply causation, since an increased risk of small separations with prematurity could as easily be explained if small adherent hematomas with vaginal delivery were a consequence of preterm delivery. The definition of abruption in this study was the gross clinical examination of the placenta.

The perinatal collaborative study, from the 1960's, found abruption to account for 3.96 perinatal deaths / 1,000 births [94].  Abruption was defined as "an adherent retroplacental clot with depression or disruption of the underlying placental tissue or when there were otherwise classical clinical findings including external or occult bleeding, increased firmness of the uterus and death between 20 weks of gestation and the twenty eighth post natal day…” There were 138 stillbirths and 74 postnatal deaths in 53,518 pregnancies, and the rate of perinatal deaths for abruption was the second highest cause of death in the study. The study finds associations with many factors in a somewhat confusing mix, but does support the association with preeclampsia (intrapartum hypertension, fibrinoid necrosis of spiral arteries, and placental infarctions)  and with maternal cigarette smoking (P<0.06). There are many histological correlations but the relationship of the findings to the location or size of the retroplacental hematoma is not described, nor is the size of the hematoma. The study demonstrated two peak gestational incidences, the first from 20-29 weeks of gestation and the second after 38 weeks of gestation. If the first peak refers to the small marginal RPH seen in mid gestation, many of these were likely incidental to the infant’s death. The author’s also suggest their data supports a role for maternal undernutrition, but the data is unclear and weight gain over 37 weeks had only a P<0.1 which is not significant.

A review of abruption so severe as to the kill the fetus found a reduction from 1 in 420 (1956 to1969) to 1 in 830  (1974-1989, 207 cases in total deliveries 171,787) attributed in a change in racial distribution from a high risk black population (1 in 830) to a low risk Latin American population (1 in 1473)[50]. Sickle cell trait was not a risk factor for abruption. Preeclampsia was a risk factor for abruption, but could not account for the racial differences. Abruption recurred in 12% of subsequent pregnancies and was fatal in 7%. The recurrent cases were presented in individual detail and a striking observation is that almost all the cases first and second abruption were associated with low birth weight or less than term gestation.

2.      Coagulopathy in the mother

It is an axiom of the management of abruption that defibrination or disseminated coagulation is a potential complication of abruption. The mechanism is less clear. Early experimental studies had demonstrated that a cold saline rinse of placenta injected into pregnant animals caused consumption of fibrin and often pulmonary thromboemboli and less frequently cerebral thrombi [95]. Placental trauma in experimental animals produced the same results [95, 96] A reasonable hypothesis was that abruption would mimic these experimental results in that the margins of the retroplacental hematoma would wash placental or decidual thromboplastin into the maternal blood stream. More recent work suggests that the effects of placental separation on coagulation may be more complex, but that the underlying abnormality is initiated from the intravascular injection of thromboplastin[97]. This study correlated peripheral blood coagulation parameters, especially fibrinolytic, with the severity of the abruption by clinical criteria (which also correlated with their estimate of the observable extent of placental separation) in 19 patients presenting with abruption. In nine, they documented improvement after uterine evacuation, for example the mean FDP fell from 150.6 to 10.6 microg/ml following delivery.

One problem of normal separation is how the utero-placental blood flow is stemmed. A reasonable consensus is that myometrial contraction and elevated coagulation factors in pregnancy and local tissue injury lead to mural thrombi in the uterine vessels that had supplied the placental bed. The local elevation of clotting factors in the uterus has been measured directly in uterine vein blood following placental separation during Cesarean section in 12 patients[98]. Most striking was the elevation of whole blood clotting in the uterine vein compared to the pre-separation umbilical vein blood and to the peripheral blood drawn simultaneously. Factor VII activity was also increased in this 1970 study. Decreased flow in the uterus has been visualized directly with MR scan showing marked decrease of fundal perfusion at 5 hrs post partum. With retroplacental hematoma, blood flow is not stopped and local thrombotic factors in the decidua may be elevated. If there is still venous return beneath the retroplacental hematomas, perhaps these decidual factors are distributed systemically adding to risk of disseminated intravascular coagulation.

An ultrasound report of a mother whose history is suggestive of HELLP syndrome with a dropping hematocrit, but no mention of hemolysis, had both diffuse intravascular coagulation and a 4 x2 cm retroplacental hematoma documented at 18 weeks of gestation[99]. The last sentence of the placental description makes no anatomic sense “Breaks in the basal plate resulting in contact of necrotic decidua with maternal blood, were not demonstrated.” A retroplacental hematoma is always in the decidua, there is no need to rupture the basal chorionic plate for maternal blood to contact decidua.  The case found infarcted villi above the hematoma, and intervillous maternal blood would have been in contact with them. 

The review of clinical abruption cases in which Page et. al. presented their classification system reviews the literature up until that time on the evidence that abruption results in defibrination in the mother from the intravascular injection of thromboplastin[62]. Defibrination occurred only in the severe cases. They provided some evidence that renal cortical necrosis associated with abruption was not directly related to the shock and defibrination. The authors even recommended rupturing membranes to lower intrauterine pressure to decrease injection of the thromboplastin. I have not found studies that chemically identify the thromoboplastin nor determine whether it can be of decidual origin since decidual procoagulants appear to be necessary for normal postpartum coagulation of the placental bed (i.e. bleeding with placental accrete). Normal separation does not produce defibrination which could be due to rapid removal of the placenta from intervillous circulation.  The early experimental studies used a placental extract. I did not find studies confirming subclinical coagulation defects in small retroplacental hemorrhages.

I.        Miscellaneous topics

1.      CA-125

A preliminary study of 10 patients with abruption found a significantly elevated level of CA-125 in maternal serum[100]. Three had stillborn infants and the other 7 were classed as grade 2 on a system by Sher. Abruption criteria were those of Hurd, and “The diagnosis of abruption placentae was confirmed at delivery in each case with either gross examination of the placenta revealing a firmly adherent retroplacental clot wit disruption of the underlying tissue, pathologic diagnosis, or both”. Of the 10 cases, only 5 had values clearly above the controls, and only 2 were greatly higher. While no overall correlation with gestation or grade of abruption was found, the individual values for each patient with the clinical history might have given some insight. The postpartum controls were all elevated. The time course of CA-125 elevations in abruption and in normal separation would have been useful to evaluate the level as a test for abruption. The authors postulate that the CA-125 was being released from decidua. A rapid marker of placental infarction might better be able to separate retroplacetnal from retromembrane hemorrhage.

2.      Marginal and retromembrane hematomas

            Marginal hemorrhages may occur because of contraction of the lower uterine segment beneath the lower pole of the placenta. This may lead to vaginal bleeding, but demonstrate no pathological lesion, no fetal compromise, and no association with maternal disease. In other cases, the dissection of a retroplacental hematoma to the lower margin of the placenta may permit vaginal bleeding to decompress a dissecting retroplacental hematoma, and perhaps prevent a more complete separation of the placenta. In this later case, there should be a retroplacental hematoma as well as a marginal hemorrhage. A study of 24 patients with ultrasound prior to a Cesarean section divided into three equal presurgical clinical diagnoses, A) typical severe abruption B) suspected abruption confirmed by ultrasound, and C) threatened premature delivery with abruption diagnosed by ultrasound separated ultrasound findings into either a central thickening or an edge hematoma. Seven of the patients in group A and 3 in group B fell into the central thickened group.  Those with an edge hematoma had smaller areas of placental abruption, less coagulation abnormality and higher Apgar scores [101]. An alternative theory of marginal hemorrhage is the rupture of the large veins at the periphery of the placenta in the decidua and myometrium) [28]. A retrospective study of patients with a clinical diagnosis of abruption found that up to 25% had retromembranous (N=6) or retroplacental (N=6) hematomas on ultrasound[102]. Most of these patients had low grade abruptions based on a system that had grades 0 and 1 without significant complications, grade 2 with concealed hemorrhage, uterine tenderness, rare coagulopathy, and fetal distress. Grade 3 had in addition maternal hypotension, fetal death, and often coagulopathy. The data were not clear but most patients fall into the 0-1 group in which the only difference is that the group 0 is diagnosed after delivery by finding a retroplacental clot. This group especially in the preterm group could have a prolonged period before delivery without significant complications.

            The incidence of intrauterine hematomas seen in threatened abortion is relatively high. An ultrasound study with an incidence of 22% intrauterine hematomas in women with threatened abortion (hematoma volumes from <10 to >30ml, gestation ages from 2-24 weeks) found an increased risk of eventual fetal loss (16.3% versus 5.5%; P<.05)[103]. While one image shows the hematoma beneath the placenta, the study does not clearly differentiate the location of the hematoma, nor examine placental pathology at birth.

 A review of marginal separation considers that the association with premature labor and premature rupture of membranes is possibly causative[28]. Fragility of the marginal attachment and underlying large veins was postulated as the primary cause of the placental separation with consequent decidual injury producing prostaglandins and preterm labor. In part the review is based on the author’s pathological study of 90 preterm placentas with exclusions designed to have an uncomplicated sample of premature labor from 20 to 37 weeks of gestation compared to 45 term placentas[104]. He did find more pathological lesions in the premature placentas including more marginal hematomas, as well as marginal necrosis and fibrin. The study states “ At the placental margin, an adherent clot is present. This clot is readily differentiable from the clot often seen after normal postpartum separation in that the antepartum clot is adherent to the placenta and membranes and is removed only with difficulty. It is dark in color, frequently contains fibrin, and may be laminated. Polymorphonuclear infiltration is often noted.”  Except that I am not sure what is meant by “contains fibrin”, this is a fair description of a common observation. These observations do not prove that the hematoma precedes the onset of preterm labor. These finding might even occur in a prolonged third stage of labor in preterm gestation. The paper states that it is only speculation that the marginal separation causes preterm labor. The review also disposes of the concept of a marginal sinus of the placenta as being disproven by angiography of monkey placentas by Ramsey. In reviewing one of the papers on marginal sinus, the observations are based on gross examination of the delivered placenta[105]. The paper refers to abscission windows believed formed by the necessary disruption of transdecidual veins at the margin of the placenta.  The observation of the marginal sinus itself is likely an artifact of the separation of the decidua away from the junction of the membrane chorion and the basal plate chorion. The concept of venous bleeding from the lower margin of the placenta being likely venous blood and of different significance from abruption is reasonable. Likely venous return is obstructed by labor especially through collateral veins in the cervix or lower uterine segment, and this back pressure could rupture the large thin walled veins in the marginal decidua.

            An unusual complication of a retromembrane or marginal hematoma would be rupture into the amniotic cavity which has been reported by ultrasound observation[106]. The sometimes described “port wine” colored amniotic fluid with abruption is likely diffusion of hemoglobin through the overlying membranes, rather than direct hemorrhage. Hematomas confined to a retroplacental location can not color the amnion fluid, but those at the margin or under the membranes could. A role of retromembrane hematomas in devitalizing fetal membranes and causing rupture of membranes is not established

3.      The pathological identification of very acute abruption

When an abruption has a rapid and witnessed clinical onset, an emergency Cesarean section will usually deliver a living infant. Typically, the placenta will show a retroplacental hematoma in situ at Cesarean section. The pathologist often can not identify the retroplacental hematoma from the examination of the placenta. In a brief interval, there would also be no anatomic evidence of villous necrosis. The existence of clinical abruption without pathological retroplacental hematoma was noted by Gruenwald who also noted retroplacental hematomas without clinical abruption[107].  He reviewed the clinical chart and the pathology of 612 cases with either a clinical abruption or a pathological diagnosis of placental separation. And found that the two designations overlapped in less than half of either category alone. He did not define the pathological criteria for placental separation, but did classify them as marginal if they extended over the placenta less than 5 cm from the margin, and major if they extended over the central placenta for more than 5 cm from the margin. He did note that after 28 weeks of gestation having both diagnoses had a higher rate of perinatal mortality.

A recent paper by the New Jersey Placental Abruption Study also noted the poor correlation between the pathological and the clinical diagnosis of abruption with only 49 of 162 clinical abruptions confirmed pathologically[108]. This study also looked at a broader range of pathological correlations, but the results can not be interpreted since the cases included 55% with gestation under 35 weeks (7% below 25 weeks) compared to 12% in the controls. The cases had 14% preeclampsia compared to 1% of controls. Some of the lesions studied are already correlated with prematurity (lesions with acute inflammation) or preeclampsia (lesions such as infarction and villous changes of utero-placentla ischemia). Some of the lesions are of unproven significance and reliability such as villous dymaturation or decidual vasculopathy (which included muscular thickening, not just acute atherosis).

If a lack of findings can occur in the witnessed abruption, could it not also occur in very acute partial abruptions that occur just prior to vaginal delivery?  Adherence of the blood clot may not be a reliable criterion, since the conditions of post partum and immediately prepartum separation may be similar. In very acute separation, the overlying villi may show vascular dilatation compared to other areas. In some cases, this is associated with intravillous hemorrhage. The association with intravillous hemorrhage was postulated as a cause of abruption in a paper describing the lesion[90]. An equally plausible hypothesis is that a large retroplacental hematoma could cause both ischemia of the endothelium in the overlying villi, and sufficient hypoxia/acidosis to produce heart failure and elevated pressure in the right heart. An ischemic capillary or venule distended by increased pressure might hemorrhage.

J.      Experimental models

Abruption was produced in the rabbit by injection of a pregnancy urine extract called antuitrin-S (Parke, Davis and Co.)[109]. The uterus developed marked intramural hemorrhage in all layers associated with partial placental separation. Administration of daily subcutaneous doses of cocaine did produce abruption in rats that occurred near the time of fetal maturity. There was no histological study[110].

The experimental production of placental abruption in dogs was mentioned in reference to vena caval occlusion in humans. An industry study using this the vena caval occlusion in dogs, found that giving a “ganglionic blocker”, trimethaphan camphorsulphonate, reduced the number of abruptions produced[111]. The drug was being tested for its ability to protect the kidney following abruption, and the results were unexpected. The authors note that there is less increase in venous pressure in vena caval ligation when the drug is used. The same study was able to produce abruption but of lesser frequency by subjecting the pregnant dogs to hypoxia (10% oxygen environment). The authors speculate that the effect of vena caval ligation is to both elevate decidual venous pressure and produce tissue anoxia, both contributing to the abruption.


K.    References

1.         Fretts RC, Boyd ME, Usher RH, Usher HA: The changing pattern of fetal death; 1961-1988. Obstet Gynecol 1992, 79:35-39.

2.         Golditch IM, Boyce NE, Jr.: Management of abruptio placentae. Jama 1970, 212:288-293.

3.         Blair RG: Abruption of the placenta. A review of 189 cases occurring between 1965 and 1969. J Obstet Gynaecol Br Commonw 1973, 80:242-245.

4.         Rasmussen S, Irgens LM, Dalaker K: The effect on the likelihood of further pregnancy of placental abruption and the rate of its recurrence. Br J Obstet Gynaecol 1997, 104:1292-1295.

5.         Deyer TW, Ashton-Miller JA, Van Baren PM, Pearlman MD: Myometrial contractile strain at uteroplacental separation during parturition. Am J Obstet Gynecol 2000, 183:156-159.

6.         Boyd JD, Hamilton WJ: The Human Placenta. In. Cambridge: W. Heffer & Sons LTD; 1970: 209

7.         Danforth DN, Graham RJ, Ivy AC: The functional anatomy of labor as revealed by frozen sagittal sections in the macacus rhesus monkey. Surg Gyn Obstet 1942, 74:188-203.

8.         Macpherson J: A radiological study of the placental stage of labour. J Obstet Gynaecol Br Empire 1956, 63:321-330.

9.         Krapp M, Katalinic A, Smrcek J, Geipel A, Berg C, Germer U, Gembruch U: Study of the third stage of labor by color Doppler sonography. Arch Gynecol Obstet 2003, 267:202-204.

10.       Herman A, Zimerman A, Arieli S, Tovbin Y, Bezer M, Bukovsky I, Panski M: Down-up sequential separation of the placenta. Ultrasound Obstet Gynecol 2002, 19:278-281.

11.       Groeber WR: Antiabruption dynamics of the intervillous circulation in an artificial uterus. Am J Obstet Gynecol 1966, 95:640-647.

12.       Grisaru D, Jaffa AJ, Har-Toov J, Gull I, Peyser R: Prenatal sonographic diagnosis of intermembranous abruptio placentae in a twin pregnancy. J Ultrasound Med 1994, 13:807-808.

13.       Biskup I, Malinowski W: Ultrasound in abruptio placentae praecox of the second twin. 'Boomerang phenomenon'. Acta Obstet Gynecol Scand 1994, 73:515-516.

14.       Gonen R, Hannah M, Milligan J: Does prolonged preterm premature rupture of the membranes predispose to abruptio placentae. Obstet Gynecol 1989, 74:347-350.

15.       Vintzileos A, Campbell W, Nochimson D, Weinbaum P: Preterm premature rupture of the membraes: a risk factor for the development of abruptio placentae. Am J Obstet Gynecol 1987, 156:1235-1238.

16.       Ananth CV, Savitz DA, Williams MA: Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodologic review and meta-analysis. Obstet Gynecol 1996, 88:309-318.

17.       Dombrowski MP, Bottoms SF, Saleh AA, Hurd WW, Romero R: Third stage of labor: analysis of duration and clinical practice. Am J Obstet Gynecol 1995, 172:1279-1284.

18.       Mackenzie AP, Schatz F, Krikun G, Funai EF, Kadner S, Lockwood CJ: Mechanisms of abruption-induced premature rupture of the fetal membranes: Thrombin enhanced decidual matrix metalloproteinase-3 (stromelysin-1) expression. Am J Obstet Gynecol 2004, 191:1996-2001.

19.       Nath CA, Ananth CV, Smulian JC, Shen-Schwarz S, Kaminsky L: Histologic evidence of inflammation and risk of placental abruption. Am J Obstet Gynecol 2007, 197:319 e311-316.

20.       Lockwood CJ, Toti P, Arcuri F, Paidas M, Buchwalder L, Krikun G, Schatz F: Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin-enhanced interleukin-8 expression in term decidua. Am J Pathol 2005, 167:1443-1449.

21.       Nakatsuka M, Asagiri K, Kimura Y, Kamada Y, Tada K, Kudo T: Generation of peroxynitrite and apoptosis in placenta of patients with chorioamnionitis: possible implications in placental abruption. Hum Reprod 1999, 14:1101-1106.

22.       Srinivas SK, Ernst LM, Edlow AG, Elovitz MA: Can placental pathology explain second-trimester pregnancy loss and subsequent pregnancy outcomes? Am J Obstet Gynecol 2008, 199:402 e401-405.

23.       Woods DL, Edwards JN, Sinclair-Smith CC: Amniotic fluid infection syndrome and abruptio placentae. Pediatr Pathol 1986, 6:81-85.

24.       Darby MJ, Caritis SN, Shen-Schwarz S: Placental abruption in the preterm gestation: an association with chorioamnionitis. Obstet Gynecol 1989, 74:88-92.

25.       Naeye RL: Coitus and antepartum haemorrhage. Br J Obstet Gynaecol 1981, 88:765-770.

26.       Mengert WF, Goodson JH, Campbell RG, Haynes DM: Observations on the pathogenesis of premature separation of the normally implanted placenta. Am J Obstet Gynecol 1953, 66:1104-1112.

27.       Smith K, Fields H: The supine hypotensive syndrome: A factor in the etiology of abruptio placentae. Obstet Gynecol 1958, 12:369-372.

28.       Harris BA, Jr.: Peripheral placental separation: a review. Obstet Gynecol Surv 1988, 43:577-581.

29.       Scott DB, Kerr MG: Inferior Vena Caval Pressure in Late Pregnancy. J Obstet Gynaecol Br Commonw 1963, 70:1044-1049.

30.       Stone SR, Whalley PJ, Pritchard JA: Inferior vena cava and ovarian vein ligation during late pregnancy. Obstet Gynecol 1968, 32:267-273.

31.       Kerr MG: Clinical Implications of Inferior Vena Caval Occlusion in Pregnancy. Proc R Soc Med 1964, 57:705-706.

32.       Burchell RC, Mengert WF: Etiology of premature separation of the normally implanted placenta. Preliminary observations. Am J Obstet Gynecol 1969, 104:795-798.

33.       Couvelaire A: Classic pages in obstetrics and gynecology: Alexandre Couvelaire. Am J Obstet Gynecol 1973, 116:875.

34.       Williams JW: Premature separation of the normally implanted placenta. Surg Gynecol Obstet 1915, 21:541-554.

35.       Kinsella SM, Lohmann G: Supine hypotensive syndrome. Obstet Gynecol 1994, 83:774-788.

36.       de Vries JI, Dekker GA, Huijgens PC, Jakobs C, Blomberg BM, van Geijn HP: Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997, 104:1248-1254.

37.       Owen EP, Human L, Carolissen AA, Harley EH, Odendaal HJ: Hyperhomocysteinemia--a risk factor for abruptio placentae. J Inherit Metab Dis 1997, 20:359-362.

38.       Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, Boers GH, Eskes TK: Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996, 66:23-29.

39.       Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E: Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998, 179:1565-1567.

40.       Jaaskelainen E, Toivonen S, Romppanen EL, Helisalmi S, Keski-Nisula L, Punnonen K, Heinonen S: M385T polymorphism in the factor V gene, but not Leiden mutation, is associated with placental abruption in Finnish women. Placenta 2004, 25:730-734.

41.       Kinzler WL, Prasad V, Ananth CV: The effect of maternal thrombophilia on placental abruption: Histologic correlates. J Matern Fetal Neonatal Med 2009, 22:243-248.

42.       Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB: Increased frequency of genetic thrombophilia in women with complications of pregnancy [see comments]. N Engl J Med 1999, 340:9-13.

43.       Verspyck E, Borg JY, Roman H, Thobois B, Pia P, Marpeau L: Hereditary thrombophilia and recurrence of ischemic placental disease. Am J Obstet Gynecol 2009.

44.       Gibson CS, MacLennan AH, Janssen NG, Kist WJ, Hague WM, Haan EA, Goldwater PN, Priest K, Dekker GA: Associations between fetal inherited thrombophilia and adverse pregnancy outcomes. Am J Obstet Gynecol 2006, 194:947 e941-910.

45.       van der Molen EF, Arends GE, Nelen WL, van der Put NJ, Heil SG, Eskes TK, Blom HJ: A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000, 182:1258-1263.

46.       Peltier MR, Ananth CV, Oyelese Y, Vintzileos AM: Thromboembolic diseases in families of women with placental abruption. Epidemiology 2009, 20:733-737.

47.       Hibbard BM, Hibbard ED, Hwa TS, Tan P: Abruptio placentae and defective folate metabolism in Singapore women. J Obstet Gynaecol Brit Cwlth 1969, 76:1003-1007.

48.       Hibbard BM: The role of folic acid in pregnancy. J Obstet Gynaecol Brit Cwlth 1964, 71:529-542.

49.       Hall MH: Folic acid deficiency and abruptio placentae. J Obstet Gynaecol Br Commonw 1972, 79:222-225.

50.       Pritchard JA, Cunningham FG, Pritchard SA, Mason RA: On reducing the frequency of severe abruptio placentae. Am J Obstet Gynecol 1991, 165:1345-1351.

51.       Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK: Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study. Am J Epidemiol 2008, 167:867-874.

52.       Eskes TK: Clotting disorders and placental abruption: homocysteine--a new risk factor. Eur J Obstet Gynecol Reprod Biol 2001, 95:206-212.

53.       Gebhardt GS, Scholtz CL, Hillermann R, Odendaal HJ: Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 2001, 97:174-177.

54.       Ananth CV, Peltier MR, De Marco C, Elsasser DA, Getahun D, Rozen R, Smulian JC: Associations between 2 polymorphisms in the methylenetetrahydrofolate reductase gene and placental abruption. Am J Obstet Gynecol 2007, 197:385 e381-387.

55.       Ananth CV, Elsasser DA, Kinzler WL, Peltier MR, Getahun D, Leclerc D, Rozen RR: Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: risk of placental abruption. Mol Genet Metab 2007, 91:104-110.

56.       Salafia CM, Lopez-Zeno JA, Sherer DM, Whittington SS, Minior VK, Vintzileos AM: Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet Gynecol 1995, 173:1065-1070.

57.       Oosterhof H, Aarnoudse JG: Placental abruption preceded by abnormal flow velocity waveforms in the uterine arteries. Case report. Br J Obstet Gynaecol 1991, 98:225-226.

58.       Morrow RJ, Ritchie JW: Uteroplacental and umbilical artery blood velocity waveforms in placental abruption assessed by Doppler ultrasound. Case report. Br J Obstet Gynaecol 1988, 95:723-724.

59.       Kramer MS, Usher RH, Pollack R, Boyd M, Usher S: Etiologic determinants of abruptio placentae. Obstet Gynecol 1997, 89:221-226.

60.       Saftlas AF, Olson DR, Atrash HK, Rochat R, Rowley D: National trends in the incidence of abruptio placentae, 1979-1987. Obstet Gynecol 1991, 78:1081-1086.

61.       Sanchez SE, Pacora PN, Farfan JH, Fernandez A, Qiu C, Ananth CV, Williams MA: Risk factors of abruptio placentae among Peruvian women. Am J Obstet Gynecol 2006, 194:225-230.

62.       Page EW, King EB, Merrill JA: Abruptio placentae; dangers of delay in delivery. Obstet Gynecol 1954, 3:385-393.

63.       Hulse GK, Milne E, English DR, Holman CD: Assessing the relationship between maternal cocaine use and abruptio placentae. Addiction 1997, 92:1547-1551.

64.       Naeye RL: Disorders of the Placenta, Fetus and Neonate: Diagnosis and Clinical Significance. St Louis: Mosby Year Book; 1992.

65.       Spinillo A, Capuzzo E, Colonna L, Solerte L, Nicola S, Guaschino S: Factors associated with abruptio placentae in preterm deliveries. Acta Obstet Gynecol Scand 1994, 73:307-312.

66.       Ananth CV, Savitz DA, Luther ER: Maternal cigarette smoking as a risk factor for placental abruption, placenta previa, and uterine bleeding in pregnancy. Am J Epidemiol 1996, 144:881-889.

67.       Kaminsky LM, Ananth CV, Prasad V, Nath C, Vintzileos AM: The influence of maternal cigarette smoking on placental pathology in pregnancies complicated by abruption. Am J Obstet Gynecol 2007, 197:275 e271-275.

68.       Acker D, Sachs BP, Tracey KJ, Wise WE: Abruptio placentae associated with cocaine use. Am J Obstet Gynecol 1983, 146:220-221.

69.       Meeker JE, Reynolds PC: Fetal and newborn death associated with maternal cocaine use. J Anal Toxicol 1990, 14:379-382.

70.       Mooney EE, Boggess KA, Herbert WN, Layfield LJ: Placental pathology in patients using cocaine: an observational study. Obstet Gynecol 1998, 91:925-929.

71.       Toivonen S, Heinonen S, Anttila M, Kosma VM, Saarikoski S: Reproductive risk factors, Doppler findings, and outcome of affected births in placental abruption: a population-based analysis. Am J Perinatol 2002, 19:451-460.

72.       Witlin AG, Saade GR, Mattar F, Sibai BM: Risk factors for abruptio placentae and eclampsia: analysis of 445 consecutively managed women with severe preeclampsia and eclampsia. Am J Obstet Gynecol 1999, 180:1322-1329.

73.       Sexton LI, Hertig AT, et al.: Premature separation of the normally implanted placenta; a clinicopathological study of 476 cases. Am J Obstet Gynecol 1950, 59:13-24.

74.       Abdella TN, Sibai BM, Hays JM, Jr., Anderson GD: Relationship of hypertensive disease to abruptio placentae. Obstet Gynecol 1984, 63:365-370.

75.       Ananth CV, Peltier MR, Kinzler WL, Smulian JC, Vintzileos AM: Chronic hypertension and risk of placental abruption: is the association modified by ischemic placental disease? Am J Obstet Gynecol 2007, 197:273 e271-277.

76.       Morgan MA, Berkowitz KM, Thomas SJ, Reimbold P, Quilligan EJ: Abruptio placentae: perinatal outcome in normotensive and hypertensive patients. Am J Obstet Gynecol 1994, 170:1595-1599.

77.       Boe F: Vascular changes in premature separation of the normally implanted placenta: a preliminary report. Acta Obstet Gynecol Scand 1959, 38:441-443.

78.       Dommisse J, Tiltman AJ: Placental bed biopsies in placental abruption. Br J Obstet Gynaecol 1992, 99:651-654.

79.       Robertson WB, Khong TY, Brosens I, De Wolf F, Sheppard BL, Bonnar J: The placental bed biopsy: Review from three European Centers. Am J Obstet Gynecol 1986, 155:401-412.

80.       Ness PM, Budzynski AZ, Olexa SA, Rodvien R: Congenital hypofibrinogenemia and recurrent placental abruption. Obstet Gynecol 1983, 61:519-523.

81.       Zugaib M, de Barros AC, Bittar RE, Burdmann EA, Neme B: Abruptio placentae following snake bite. Am J Obstet Gynecol 1985, 151:754-755.

82.       Feinkind L, Nanda D, Delke I, Minkoff H: Abruptio placentae after percutaneous umbilical cord sampling: a case report. Am J Obstet Gynecol 1990, 162:1203-1204.

83.       Pillny M, Sandmann W, Luther B, Muller BT, Tutschek B, Gerhardt A, Zotz RB, Scharf RE: Deep venous thrombosis during pregnancy and after delivery: indications for and results of thrombectomy. J Vasc Surg 2003, 37:528-532.

84.       Aitokallio-Tallberg A, Halmesmaki E: Motor vehicle accident during the second or third trimester of pregnancy. Acta Obstet Gynecol Scand 1997, 76:313-317.

85.       Rogers FB, Rozycki GS, Osler TM, Shackford SR, Jalbert J, Kirton O, Scalea T, Morris J, Ross S, Cipolle M, et al: A multi-institutional study of factors associated with fetal death in injured pregnant patients. Arch Surg 1999, 134:1274-1277.

86.       Fries MH, Hankins GD: Motor vehicle accident associated with minimal maternal trauma but subsequent fetal demise. Ann Emerg Med 1989, 18:301-304.

87.       Kettel LM, Branch DW, Scott JR: Occult placental abruption after maternal trauma. Obstet Gynecol 1988, 71:449-453.

88.       Pearlman MD, Tintinallli JE, Lorenz RP: A prospective controlled study of outcome after trauma during pregnancy. Am J Obstet Gynecol 1990, 162:1502-1507; discussion 1507-1510.

89.       Eden J: Can the fetus cause placental separation? Aust N Z J Obstet Gynaecol 1988, 28:119-120.

90.       Mooney EE, al Shunnar A, O'Regan M, Gillan JE: Chorionic villous haemorrhage is associated with retroplacental haemorrhage. Br J Obstet Gynaecol 1994, 101:965-969.

91.       Nagy S, Bush M, Stone J, Lapinski RH, Gardo S: Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol 2003, 102:94-100.

92.       Myers RE: Cystic brain alteration after incomplete placental abruption in monkey. Arch Neurol 1969, 21:133-141.

93.       Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH: Placental abruption and adverse perinatal outcomes. Jama 1999, 282:1646-1651.

94.       Naeye RL, Harkness WL, Utts J: Abruptio placentae and perinatal death: a prospective study. Am J Obstet Gynecol 1977, 128:740-746.

95.       Schneider CL: Thromboplastin complications of late pregnancy. In Toxemia of Pregnancy Human and Veterinary. Edited by Hammond J, Browne FJ, Wolstenholme GEW. Philadelphia: The Blakiston Company; 1950: 163-181

96.       Brown LJ, Stalker AL: Experimental defibrination. 3. The maternal and foetal microcirculation following placental separation or trauma. Microvasc Res 1969, 1:403-409.

97.       Gilabert J, Estelles A, Aznar J, Galbis M: Abruptio placentae and disseminated intravascular coagulation. Acta Obstet Gynecol Scand 1985, 64:35-39.

98.       Bonnar J, Prentice CR, Monicol GP, Douglas AS: Haemostatic mechanism in the uterine circulation during placental separation. Br Med J 1970, 2:564-567.

99.       Spirt BA, Kagan EH, Aubry RH: Clinically silent retroplacental hematoma: sonographic and pathologic correlation. J Clin Ultrasound 1981, 9:203-205.

100.     Witt B, Miles R, Wolf G, Koulianos G, Thorneycroft I: CA-125 Levels in Abruptio Placentae. American Journal of Obstetrics and Gynecology  1991, 164:1225-1228.

101.     Kikutani M, Ishihara K, Araki T: Value of ultrasonography in the diagnosis of placental abruption. J Nippon Med Sch 2003, 70:227-233.

102.     Sholl JS: Abruptio Placetae: Clinical management in nonacute cases. Am J Obstet Gynecol 1987, 156:40-51.

103.     Borlum KG, Thomsen A, Clausen I, Eriksen G: Long-term prognosis of pregnancies in women with intrauterine hematomas. Obstet Gynecol 1989, 74:231-233.

104.     Harris BA, Jr., Gore H, Flowers CE, Jr.: Peripheral placental separation: a possible relationship to premature labor. Obstet Gynecol 1985, 66:774-778.

105.     Schneider CL: Rupture of the marginal sinus of the placenta; abscission windows. Obstet Gynecol 1958, 11:715-721.

106.     Hill LM, Breckle R, Gehrking W: Abruptio placentae: an unusual ultrasonic presentation. Am J Obstet Gynecol 1984, 148:1144-1145.

107.     Gruenwald P, Levin H, Yousem H: Abruption and premature separation of the placenta. The clinical and the pathologic entity. Am J Obstet Gynecol 1968, 102:604-610.

108.     Elsasser DA, Ananth CV, Prasad V, Vintzileos AM: Diagnosis of placental abruption: relationship between clinical and histopathological findings. Eur J Obstet Gynecol Reprod Biol, 148:125-130.

109.     Snyder FF: The experimental production of toxemia of pregnancy. Am J Obstet Gynecol 1943:1091-1106.

110.     Church MW, Dintcheff BA, Gessner PK: Dose-dependent consequences of cocaine on pregnancy outcome in the Long-Evans rat. Neurotoxicol Teratol 1988, 10:51-58.

111.     Powers SR, Jr., Nesbitt RE, Jr., Boba A, Stein A: Mechanism and prevention of distal tubular necrosis in dogs following experimental placental abruption. Surg Gynecol Obstet 1958, 107:469-473.







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