Lack of Association between Unexplained Elevated Maternal Serum Alpha Fetoprotein and/or Human Chorionic Gonadotropin and the Occurrence of Placental Thrombotic Lesions

Article Outline

• Abstract
• 1. Introduction
• 2. Methods
  • 2.1. Histological examination
  • 2.2. Statistical analysis
• 3. Results
• 4. Discussion
• 5. Authors' contributions
• Competing interests
• References
• Copyright

Abstract 

Objective

To investigate the significance of unexplained elevated maternal serum alpha fetoprotein (MSAFP) and/or human chorionic gonadotropin (HCG) on the occurrence of placental thrombotic changes.

Study design

Between January 2007 to April 2009, placentas of all women who delivered and had unexplained elevated MSAFP and/or HCG (above 2 MOM) were sent to histological examination. Women were divided into 2 groups. Group A included women who had uneventful pregnancies and delivered at term. Group B included women with antepartum complications attributed to thrombosis. Women in both groups (A and B) had elevated MSAFP and/or HCG. Group C was a frequency matched group of women who had normal MSAFP and HCG levels with uneventful pregnancies and delivered at term.

Main outcome measure

Incidence of placental thrombotic lesions in each group.

Results

Of 9695 women who delivered during the study period there were 76 women with elevated MSAFP and or HCG, 48 in group A and 28 in Group B. Group C, included 30 women. The number of placentas in which any thrombotic lesion was identified was 22 (45.8%), 19 (67.9%) and 10 (33%) respectively. Changes differed significantly only between group B and C (p = 0.03). Although the rate of changes in group A was higher than in group C it did not reach statistical significance even when considering only women with two abnormal results (MSAFP and HCG) or when a cutoff of 2.5 MOM or more was set.

Conclusion

Placental histopathological changes are associated with pregnancy complications and can only marginally be attributed to unexplained elevated MSAFP and/or HCG.

Keywords: Alpha fetoprotein, Human chorionic gonadotropin, Placental thrombotic lesions

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1. Introduction 

Unexplained elevated maternal serum alpha fetoprotein (MSAFP) and/or human chorionic gonadotropin (HCG) have been considered risk factors and linked with placenta mediated pregnancy complications [1], [2], [3]. Although there is limited evidence, so far, as to the optimal management of women with an elevated MSAFP and/or HCG, these women are considered to have an increased risk of an adverse maternal or fetal outcome, thus close monitoring and fetal surveillance have been suggested [1], [2].

Management is according to the complication, should one arise. Complications may present or appear in the third trimester [4] and women with elevated second trimester markers are at an increased risk of fetal death, and the risk remains relatively high even at term [5].

Placenta mediated pregnancy complications, including severe preeclampsia, still birth, fetal growth restriction and placental abruption affect 8% of pregnant women and contribute to the largest proportion of maternal and fetal mortality and morbidity [6]. Evidence has accumulated to suggest that placenta mediated pregnancy complications could have a common thrombogenic basis that manifests in the placenta as placental infarction, increased intervillous fibrin, intervillous thrombosis and placental floor infarction [6], [7]. In this study we examined the association of elevated second trimester MSAFP and/or HCG levels with the occurrence of placental thrombotic lesions. While induction of labor, frequently preterm, is mandated if complications develop, we checked whether the occurrence of these changes among women who had an uneventful pregnancy might conceal an impending event and thus justify induction of labor at least at term.

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2. Methods 

Between January 2007 to April 2009, placentas of all women with elevated second trimester (between 16 and 18 weeks of gestation) MSAFP and/or HCG were sent to histological examination. Values of MSAFP and/or HCG were adjusted for gestational age by using multiples of the median (MOM). For both MSAFP and HCG, an abnormal elevation was defined as a value equal or greater than 2 MOM. Patients with incorrect dating, structural or chromosomal abnormalities, and multiple gestations were excluded.

Relevant patient history, demographic data, and obstetric history were collected. Other parameters collected were neonatal birth weight and Apgar score. Placentas from women with elevated MSAFP and/or HCG were divided into two groups. Group A included placentas from women who had uneventful pregnancies and delivered at term (37–41 completed weeks). Group B included placentas from women with antepartum complications.

Complications that were considered relevant were intrauterine fetal death (above 22 weeks), intrauterine growth restriction (IUGR), defined as birth weight below the 10th percentile according to Israeli standards [8], severe preeclampsia and placental abruption. Severe preeclampsia was defined as blood pressure measuring above 140/90 combined with proteinuria (300 mg/24 h) and accompanied with one or more of the following complications: worsening blood pressure to a level above 160/110, HELLP syndrome (hemolysis, low platelet count and elevated liver enzymes), persistent severe headache or visual disturbances, persistent severe epigastric pain, nausea and vomiting, eclampsia, pulmonary edema, oligouria (urine output less than 500 cc/24 h), proteinuria of 5 g or more per 24 h and IUGR (below the 5th percentile).

In addition, selected placentas (Group C) from women with normal MSAFP and normal HCG levels and with uneventful pregnancies, who delivered at term, were also examined. Women in Group C were matched for age, gestational age (term pregnancy) and parity to group A. The local Institutional Review Board approved the study.

2.1. Histological examination 

The placenta was formalin fixed after trimming of the cord and the membranes. The placenta was examined macroscopically and placental measurements and trimmed weight were recorded. Histological samples were taken to include eight to ten blocks of placenta with both fetal and maternal surfaces. Blocks and slides from the placenta were submitted for review by the same pathologist (M.O.) who was blinded to the group allocation. Thrombotic lesions identified within the placenta were categorized as fetal stem vessel thrombosis, avascular villi, placental infarction, increased intervillous fibrin, intervillous thrombosis and placental floor infarction.

Fetal stem vessel thrombosis was diagnosed when a major placental vessel was completely or partially occluded by a thrombus. Avascular villi was diagnosed by foci of terminal villi showing total loss of villous capillaries and bland hyaline fibrosis of the villous stroma in a distribution consistent with obstructed flow in large supplying or draining vessels. We included foci of more than five terminal villi showing these changes. Placental villous infarction was diagnosed in the presence of an area of ischemic necrosis of the placental villi with collapse of the intervillous space and tight clustering of the villous tree. Increased intervillous fibrin was diagnosed in the presence of abnormal amounts of intervillous fibrin either coating the proximal stem villi or eccentrically adherentent to the distal villi.

Intervillous thrombosis was diagnosed when a villous free nodular thrombus was found in the intervillous space. Placental floor infarction was diagnosed when the maternal surface of the placenta was extensively thickened and stiffened due to accumulation of excessive fibrinoid material which expands the basal plate, envelops anchoring villi and surround large numbers of basal and periseptal villi [9], [10], [11].

2.2. Statistical analysis 

The analysis compared placental findings among patients who had abnormal serum marker levels and among those for whom the specific serum marker levels were within the normal range. Continuous data were analyzed using the Kruskal Wallis test because most of the parameters were not normally distributed. Categorical data were analyzed using Chi square tests. Fisher exact p values were computed where warranted. Comparison of two group's continuous data was analyzed by the Wilcoxon two independent sample tests. Spearman Correlations between placental characteristics and continuous variables were performed.

The reported incidence of thrombotic lesions among women in group B is about 70% [9]. The reported incidence of thrombotic lesions among women in group C is about 30% [12]. To justify induction of labor among women in group A, we believe that the incidence of placental lesions needs to be close to the incidence reported among group B. A sample size of 29 subjects in group A and group C were needed to demonstrate this difference with an alpha of 0.05 and a power of 80%.

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3. Results 

Of the 9695 women who delivered during the study period, there were 76 (0.8%) women with elevated MSAFP and/or HCG; 48 in group A and 28 in group B. Group C, included 30 women. Maternal characteristic of the three groups were similar (Table 1). Delivery mode differed significantly between the groups (p < 0.0001). Post hoc testing revealed that there were more cesarean sections in group B than either of the other groups (p < 0.001). Group B delivered earlier than either group A (p < 0.001) or C (p < 0.001); Post hoc testing revealed that group B had a lower mean birth weight and a lower mean 5 min Apgar score than both group A (p < 0.001) or group C (p < 0.001) (Table 2).

Table 1. Maternal characteristics of the three groups.^a

Table 2. Neonatal characteristics of the three groups.^a

The number of placentas in which any thrombotic lesion was identified was 22 (45.8%), 19 (67.9%) and 10 (33.3%) in group A, B and C respectively (Table 3).

Table 3. Placental histology and measurements of the three groups.^a

The incidence of women with any placental lesion differed among the 3 groups (p = 0.03). Post hoc testing revealed that group B had a significantly greater percentage of placental lesions than group C while the differences between group A and B, and between group A and C were not statistically different. The difference between group A and C did not reach statistical significance even when considering only women with two abnormal results (AFP and HCG) or when a cutoff of 2.5 MOM or more was set. Intervillous thrombosis (Fig. 1) was the most common lesion found among the thrombotic lesions described (Table 3). There was a significant difference in the incidence of avascular villi (Fig. 2). The difference was significant only between groups A and B (p = 0.01). There was a significant difference in the incidence of increased intervillous fibrin (Fig. 3). The difference was significant only between groups B and C (p = 0.03).

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• Fig. 1 

  Intervillous thrombosis: The thrombus in the intervillous space is composed of fibrin arranged in strands and of erythrocytes. Haematoxylin and Eosin stained.

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• Fig. 2 

  Avascular villi: Clusters of Hyalinized avascular villi at center. Haematoxylin and Eosin stained.

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• Fig. 3 

  Perivillous fibrin: The villi are separated by an amorphous accumulation of fibrillar material. Haematoxylin and Eosin stained.

Placental weight (p = 0.002) and both placental diameters were significantly different (diameter 1: p = 0.0001; diameter 2: p = 0.005) between the groups. Post hoc testing revealed that placentas of group B weighed significantly less than the other two groups (group C: p = 0.01; group A: p = 0.001) and had smaller diameters than the other two groups (diameter 1 of both groups: p = 0.001; diameter 2: group C: p = 0.002; group A: p = 0.02). Placental weight was positively correlated with gestational week (r = 0.343; p = 0.001), neonatal weight (r = 0.604, p = 0.0001) and 5 min Apgar score (r = 0.332; p = 0.001) as well as with placental diameters (and placental area and volume). Similarly, placental diameters one and two were positively correlated with gestational week (r = 0.350, p = 0.0001; r = 0.306; p = 0.002), neonatal weight (r = 0.558, r = 0.534, p = 0.0001) and 5 min Apgar score (r = 0.311; p = 0.001; r = 0.264, p = 0.007). Placental thickness was not correlated with any maternal or neonatal characteristic.

Forward stepwise logistic regression using the three groups, maternal age, body mass index (BMI) equal to or greater than 35 kg/m², AFP equal to or greater than 2.5 MOM, HCG equal to or greater than 2.5 MOM, gestational age, gender, neonatal weight and 5 min Apgar score as potential predictors for placental thrombotic lesions found that BMI was the best predictor (OR = 9.6, 95% CI: 1.13–81.14; p = 0.038). This model correctly identified 60.2% of the women; it correctly identified 15.6% of those with placental lesions and 98.1% of those without placental lesions. A cutoff equal to or greater than 35 kg/m² produced a sensitivity of 17.4% and a specificity of 96.3%. The addition of AFP or HCG greater than 2 or 2.5 MOM, did not statistically improve the prediction rate. A model with only AFP equal to or greater than 2.5 MOM correctly identified 57.5% of the women; it correctly identified 13.7% of those with placental lesions and 98.2% of those without placental lesions. Women with AFP 2.5 or more had an 8.6 fold risk of having a placental thrombotic lesion than women with AFP less than 2.5 MOM (OR: 8.6; 95% CI:1.02–72.49; p = 0.048). A cutoff equal to or greater than 2.5 MOM produced a sensitivity of 13.7% and a specificity of 98.2%.

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4. Discussion 

Approximately 1% of pregnant women have an elevated MSAFP and/or HCG levels that cannot be accounted for by incorrect dates, structural or chromosomal abnormalities, or multiple gestation [13]. Evidence has accumulated to suggest that antepartum complications accompanied with elevated MSAFP and/or HCG levels could have a common placental thrombogenic basis [6], [7]. In this study we aimed to investigate whether the unexplained elevation of MSAFP and/or HCG are associated with placental thrombotic lesions and to compare their occurrence in the presence or absence of antepartum complications. Of the 76 women identified with unexplained elevated MSAFP and/or HCG in the study period, 28 (37%) had one or more of the adverse pregnancy outcomes studied. This is close to the incidence of 35% reported in the literature among women with unexplained elevated maternal serum markers who had at least one adverse event during the course of pregnancy [14].

The incidence of any placental pathology was highest among women with both elevated maternal serum markers and antepartum complications (group B), and, significant differences were found only between this group of women and women who had normal MSAFP and HCG levels with uneventful pregnancies (group C). Although the rate of placental pathology among women with elevated maternal serum markers and uneventful pregnancies (group A) was higher than in group C it did not reach statistical significance even when considering only women with two abnormal results (MSAFP and HCG) or when a cutoff of 2.5 MOM or more was set.

Women who had MSAFP equal to or greater than 2.5 MOM had an 8.6 fold risk of having a placental lesion, however, sensitivity was only 13.7%. These findings suggest that placental histopathological changes may be associated with pregnancy complications and can only be marginally linked to an unexplained elevation of maternal serum markers solely.

BMI was found as another predictor for placental thrombotic lesions. Women with a BMI equal to or greater than 35 kg/m² had a 9.6 fold risk of having a placental lesion. Although BMI equal to or greater than 35 kg/m² had also a low sensitivity, this finding may explain the association between the higher incidence of preeclampsia and still birth reported among obese women [15].

In this study we selected six types of placental lesions to investigate, based on previous reports suggesting that these lesions are common among women with adverse pregnancy outcomes [9], [16]. Moreover, similar placental abnormalities have been found in association with increased levels of maternal serum markers [17], [18], [19]. Salafia et al. [17] found that an increased MSAFP level in the presence of intrauterine growth restriction was associated with either intervillous thrombosis or placental vascular infarction. Purdie et al. [18] found that increased MSAFP was associated with IUGR and placental abruption. They hypothesized that increased MSAFP levels in such patients are caused by maternal clearance of fetal hemorrhage as a result of chronic placental separation that led to chorionic villous damage. Nelson et al. [19] found that some patients with increased MSAFP levels have an increased placental mass and thickness. They hypothesized that as the placental size increases, as does the surface area through which AFP can pass from fetal to maternal circulation. Abnormally increased levels of HCG have been explained by decreased placental perfusion with subsequent reduced oxygenation of the cytotrophoblast, leading to increased HCG production [20]. This hypoxia induced cytotrophoblast proliferation has also been demonstrated in histologic studies [21].

In contrast to Nelson et al. [19], who linked the increased levels of MSAFP with the increased placental measurements through which AFP can pass from the fetal to the maternal circulation, we were unable to demonstrate a similar correlation between the levels of MSAFP and placental mass, thickness or area. Placental weight and diameters were positively correlated with gestational age at delivery and neonatal weight and were not correlated to serum marker levels. This may explain the finding of smaller placental weight and diameters among group B who delivered earlier and had smaller neonates. Furthermore, we showed that placental histopathological changes cannot be solely responsible for the unexplained elevation of MSAFP and/or HCG. This finding is supported by normal serum markers found among 33% of women in group C who had placental lesions.

In this study, only 68% of the women with adverse pregnancy outcomes (group B) had placental lesions. Similar proportions of placental lesions have been also reported by Mousa et al. among a group of women with similar antepartum complications [9]. Moreover, we did not find a correlation between any of the pregnancy complications studied and the chance of finding a specific placental lesion. The finding that 32% of women who had antepartum complications had normal placentas may be explained by the existence of placental lesions other than those examined in this study that may also be responsible for the development of adverse pregnancy outcomes, or to random sampling error. Otherwise, this may suggest that placental changes may not be the only factor responsible for the emergence of clinical antepartum complications. In fact, Zhang et al. [22] reported a poor correlation between the histological findings of the placenta and clinical preeclampsia.

It is noteworthy that of all uneventful low risk pregnancies that had normal levels of MSAFP and HCG (group C), 33% were found to have placental thrombotic lesions. It has been suggested that thrombogenic lesions that manifest in the placenta do not necessarily lead to adverse effects on fetal well being [23]. Similar results have been reported by Jauniaux et al. [12]. This means that some placental changes may be nonspecific and represent a nonsignificant phenomenon in term placentas.

Prospective studies looking at the association between increased maternal serum markers and poor obstetric outcomes have reported conflicting results [1], [2], [21], [24], [25], Waller et al. demonstrated that the risk of fetal death in women with elevated serum markers remained increased until term [5]. Consequently, it has been reported that having unexplained abnormal serum markers has subsequently led to iatrogenic preterm inductions [2]. Given the substantial increase in the risk of adverse pregnancy outcomes associated with abnormal serum markers, close monitoring of maternal blood pressure and fetal surveillance have been suggested [1], [2]. However, a retrospective study found that increased antenatal surveillance for women with unexplained elevated MSAFP did not achieve earlier or improved detection of adverse events [26]. This finding differs with the view taken by other authors who recommend increased fetal surveillance [27], [28].

In conclusion, we showed that placental histopathological changes may be associated with pregnancy complications and can only marginally be attributed to unexplained elevated MSAFP and/or HCG.

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5. Authors' contributions 

RS conceived and designed the study, supervised the data collection, assisted in the analysis and drafted the manuscript; MO reviewed and examined placental Blocks and slides; GG, ZN and NZ assisted in collection and maintenance of the data; ES assisted in conceiving, designing and analysis, and edited the manuscript. All authors declare that they have seen and approved the final manuscript.

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Competing interests 

The authors declare that they have no competing interests.

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