Introduction

Disorders of deep placentation are now recognized as a major mechanism of disease for several complications of pregnancy. The definition, classification, diagnostic criteria and mechanisms of disease responsible for disorders of deep placentation have been covered by other authors in this issue of the journal and elsewhere. Moreover, a recent review has examined the key concepts and proposed a classification of defective deep placentation.

The article “Defective deep placentation” by Khong and Brosens in this issue reviews the information about disorders of deep placentation in preeclampsia and intrauterine growth restriction (IUGR). The frequency of physiologic remodeling of the spiral arteries in normal pregnancy and in those with preeclampsia from 7 articles is summarized in Table 1 . The mechanisms proposed to be responsible for disorders of deep placentation are reviewed in detail by Pijnenborg et al.

It is now clear that disorders of deep placentation are present not only in preeclampsia and IUGR, but in other obstetrical syndromes. This article will review the evidence that failure of physiologic transformation of the spiral arteries is present in spontaneous abortion, preterm labor with intact membranes, preterm prelabor rupture of membranes (PROM) and abruptio placentae. We will also propose how such defects may play a role in the genesis of the different phenotypes of complications of pregnancy.

Spontaneous abortions in the first trimester

Khong et al. were the first to examine the morphology of the placental bed in idiopathic, sporadic and recurrent spontaneous abortion. In this pioneering study, twelve patients had spontaneous abortions, four composed the control group, three had elective terminations of pregnancy and one had a late spontaneous abortion with a live fetus (due to cervical insufficiency). All patients in the control group had physiologic transformation of the spiral arteries. In contrast, failure of physiologic transformation of the decidual segments was seen in 58% (7/12) of cases with spontaneous abortion. Among these cases, only 33% (4/12) of cases had myometrial segments of the spiral arteries in the biopsy material. None had evidence of physiologic transformation. Karyotype of the products of conception was performed in six of the spontaneous abortions, and there was no relationship between the karyotype results and the histology of the placental bed.

Similarly, Gun et al. reported a study in which the histology of the decidua was compared in women ( n = 25) with spontaneous abortion (5 to 12 weeks) and the decidua of 40 women undergoing elective terminations of pregnancy (between 5 and 11 weeks). The authors found that transformation of the spiral arteries occurred in 90% of elective abortions, whereas lack of physiologic transformation in the decidual segments was present in 48% of patients with spontaneous abortions ( p < 0.001).

Michel et al. examined the placental bed of patients who had an elective termination of pregnancy ( n = 12), women who had a history of recurrent spontaneous abortion (defined as 3 or more unexplained miscarriages with the same partner, and not more than one live birth; n = 10), and women who had a “mis-abortion”, diagnosed with ultrasound ( n = 6). Physiologic transformation in the decidual segments of the spiral arteries was observed in 91.6% (11/12) of patients who had an elective termination of pregnancy. In contrast, 83% (5/6) of women who had a spontaneous abortion had inadequate development of most spiral arteries in the decidua. In the group of patients with recurrent spontaneous abortions, physiologic transformation in the decidual segments of the spiral arteries was observed in 4 women, incomplete physiologic transformation was present in the other two, and poorly developed vasculature was observed in the remaining four. Moreover, the number of cells with large granules, probably corresponding to uterine natural killer cells, was reported in the study. The proportion of these cells was significantly higher in women undergoing elective terminations of pregnancy than in those who had spontaneous abortions (either sporadic or recurrent).

Hustin et al. evaluated 184 specimens of complete spontaneous abortions. A complete spontaneous abortion was defined as one in which the gestational sac was expelled “en bloc”. The control group consisted of 219 patients who underwent voluntary termination of pregnancy in the first trimester by uterine aspiration. In addition, there were three hysterectomy specimens with pregnancies in situ (before 10 weeks of gestation).

Limited trophoblastic infiltration and inadequate physiologic changes of the spiral arteries was observed in 64% of those with embryonic demise and 77% of abnormal conceptuses, while such findings were not observed in patients with normal pregnancies. The authors concluded that most cases of spontaneous abortion are associated with defective trophoblast invasion into the decidua and spiral arteries. They proposed if the trophoblast growth is reduced, intra-arterial plugs will be less well-formed. Therefore, untimely initiation of blood circulation in the intervillous space may be associated with pregnancy failure and complete abortion. Indeed, maternal blood was found with higher frequency in the intervillous space in pathologic cases than in normal pregnancy. This study is unique because it was based on the examination of the complete aborted material, rather than a biopsy of the placental bed. For further detail about pathophysiology we refer the readers to the article by Burton et al. in this issue of the journal.

In contrast to the conclusion of the previous studies, Ball et al. reported a large study in which placental bed biopsies were obtained under ultrasound visualization from 50 women who had a spontaneous abortion, and from 78 women who underwent elective terminations of pregnancy. Frozen sections were immunostained for cytokeratin, desmin and von Willebrand factor (to detect trophoblast, vascular and myometrial smooth muscle, and endothelium, respectively). Inclusion in the study required the presence of at least one spiral artery in the biopsy specimen. Trophoblast invasion of the decidua and physiologic transformation of spiral arteries did not differ between spontaneous abortion and elective terminations of pregnancy. Similarly, there were no differences in the histologic features between patients with euploidy and aneuploidy conceptuses.

The discrepancy among studies could be attributed to the nature of the specimens collected, the requirement for the presence of an embryo and gestational age. Further investigation is required to elucidate the role of trophoblast plugging of the spiral arteries and physiologic transformation of the decidual and myometrial segments in early spontaneous abortions. Since myometrial invasion of the spiral arteries does not occur until after 14 weeks of gestation, one may not expect that failure of transformation of this particular segment may be associated with spontaneous abortion. Systematic studies of the cell populations in the decidua are warranted. The difficulties in interpreting whether the changes in cell populations represent a causal shift or epiphenomenon resulting from pregnancy failure are acknowledged.

Spontaneous abortions in the first trimester

Khong et al. were the first to examine the morphology of the placental bed in idiopathic, sporadic and recurrent spontaneous abortion. In this pioneering study, twelve patients had spontaneous abortions, four composed the control group, three had elective terminations of pregnancy and one had a late spontaneous abortion with a live fetus (due to cervical insufficiency). All patients in the control group had physiologic transformation of the spiral arteries. In contrast, failure of physiologic transformation of the decidual segments was seen in 58% (7/12) of cases with spontaneous abortion. Among these cases, only 33% (4/12) of cases had myometrial segments of the spiral arteries in the biopsy material. None had evidence of physiologic transformation. Karyotype of the products of conception was performed in six of the spontaneous abortions, and there was no relationship between the karyotype results and the histology of the placental bed.

Similarly, Gun et al. reported a study in which the histology of the decidua was compared in women ( n = 25) with spontaneous abortion (5 to 12 weeks) and the decidua of 40 women undergoing elective terminations of pregnancy (between 5 and 11 weeks). The authors found that transformation of the spiral arteries occurred in 90% of elective abortions, whereas lack of physiologic transformation in the decidual segments was present in 48% of patients with spontaneous abortions ( p < 0.001).

Michel et al. examined the placental bed of patients who had an elective termination of pregnancy ( n = 12), women who had a history of recurrent spontaneous abortion (defined as 3 or more unexplained miscarriages with the same partner, and not more than one live birth; n = 10), and women who had a “mis-abortion”, diagnosed with ultrasound ( n = 6). Physiologic transformation in the decidual segments of the spiral arteries was observed in 91.6% (11/12) of patients who had an elective termination of pregnancy. In contrast, 83% (5/6) of women who had a spontaneous abortion had inadequate development of most spiral arteries in the decidua. In the group of patients with recurrent spontaneous abortions, physiologic transformation in the decidual segments of the spiral arteries was observed in 4 women, incomplete physiologic transformation was present in the other two, and poorly developed vasculature was observed in the remaining four. Moreover, the number of cells with large granules, probably corresponding to uterine natural killer cells, was reported in the study. The proportion of these cells was significantly higher in women undergoing elective terminations of pregnancy than in those who had spontaneous abortions (either sporadic or recurrent).

Hustin et al. evaluated 184 specimens of complete spontaneous abortions. A complete spontaneous abortion was defined as one in which the gestational sac was expelled “en bloc”. The control group consisted of 219 patients who underwent voluntary termination of pregnancy in the first trimester by uterine aspiration. In addition, there were three hysterectomy specimens with pregnancies in situ (before 10 weeks of gestation).

Limited trophoblastic infiltration and inadequate physiologic changes of the spiral arteries was observed in 64% of those with embryonic demise and 77% of abnormal conceptuses, while such findings were not observed in patients with normal pregnancies. The authors concluded that most cases of spontaneous abortion are associated with defective trophoblast invasion into the decidua and spiral arteries. They proposed if the trophoblast growth is reduced, intra-arterial plugs will be less well-formed. Therefore, untimely initiation of blood circulation in the intervillous space may be associated with pregnancy failure and complete abortion. Indeed, maternal blood was found with higher frequency in the intervillous space in pathologic cases than in normal pregnancy. This study is unique because it was based on the examination of the complete aborted material, rather than a biopsy of the placental bed. For further detail about pathophysiology we refer the readers to the article by Burton et al. in this issue of the journal.

In contrast to the conclusion of the previous studies, Ball et al. reported a large study in which placental bed biopsies were obtained under ultrasound visualization from 50 women who had a spontaneous abortion, and from 78 women who underwent elective terminations of pregnancy. Frozen sections were immunostained for cytokeratin, desmin and von Willebrand factor (to detect trophoblast, vascular and myometrial smooth muscle, and endothelium, respectively). Inclusion in the study required the presence of at least one spiral artery in the biopsy specimen. Trophoblast invasion of the decidua and physiologic transformation of spiral arteries did not differ between spontaneous abortion and elective terminations of pregnancy. Similarly, there were no differences in the histologic features between patients with euploidy and aneuploidy conceptuses.

The discrepancy among studies could be attributed to the nature of the specimens collected, the requirement for the presence of an embryo and gestational age. Further investigation is required to elucidate the role of trophoblast plugging of the spiral arteries and physiologic transformation of the decidual and myometrial segments in early spontaneous abortions. Since myometrial invasion of the spiral arteries does not occur until after 14 weeks of gestation, one may not expect that failure of transformation of this particular segment may be associated with spontaneous abortion. Systematic studies of the cell populations in the decidua are warranted. The difficulties in interpreting whether the changes in cell populations represent a causal shift or epiphenomenon resulting from pregnancy failure are acknowledged.

Spontaneous abortions in the second trimester

In addition to the study of Khong et al., a recent study by Ball et al. provides support for a relationship between failure of physiologic transformation of the spiral arteries and spontaneous abortion in the midtrimester. This study included 26 late spontaneous miscarriages between 13 and 23.9 gestational weeks and gestational age-matched normal pregnancies undergoing elective termination ( n = 74). Myometrial spiral arteries from patients with late miscarriage showed a lower number of endovascular trophoblasts (4% vs. 31%, p = 0.001), intramural trophoblasts (76% vs. 88%, p = 0.05), and less extensive fibrinoid change (4% vs. 18%, p = 0.01) compared to myometrial spiral arteries from women with normal pregnancies. In contrast, the number of endovascular trophoblasts in the decidual spiral arteries was higher in patients who had a spontaneous abortion than in the control group (66% vs. 40%, p = 0.04).

Preterm birth

Preterm birth is traditionally defined as delivery occurring before 37 weeks of gestation, and is the leading cause of perinatal morbidity and mortality worldwide. Spontaneous preterm labor (with intact membranes or following preterm PROM) accounts for 2/3 of preterm births. The remaining 1/3 is due to preeclampsia and intrauterine growth restriction, in which preterm delivery is accomplished for maternal or fetal indications.

Spontaneous preterm parturition is considered a syndrome whether it occurs with intact or ruptured membranes. The spectrum of the phenotype may range from cervical insufficiency, preterm labor with intact membranes or preterm PROM. The causes of spontaneous preterm parturition have been proposed to include infection/inflammation, ischemia due to vascular disease, cervical disease, uterine overdistension, abnormal allograft reaction, allergy, and endocrine disorders (deficient progesterone action). Growing evidence suggests that vascular disorders may play a role in a subset of patients who have preterm labor with intact membranes or preterm PROM.

Spontaneous preterm labor leading to preterm delivery

The most common lesions found in the placenta of patients with spontaneous preterm parturition are those of acute inflammation (acute chorioamnionitis and funisitis). Vascular lesions are the second most common pathology of the placenta in these patients. Arias et al. reported that 34.1% of women with spontaneous preterm labor and intact membranes had vascular lesions in decidual vessels attached to the placenta, while this only occurred in 11.8% of control women (term gestation without complications, p = 0.001). Placental vascular lesions in the decidual vessels of the placenta were more frequent in patients with preterm labor with intact membranes (odds ratio 3.8, 95% CI 1.3-11.1, p = 0.007). Moreover, abruptio placentae was more frequent in patients with preterm labor than in controls (9.5% vs. 0%, respectively; p = 0.001). Similarly, Germain et al. reported a higher frequency of ischemic lesions in placentas from patients with preterm labor who delivered preterm than in those with an episode of preterm labor who delivered at term (25.4% vs. 3.7%, p < 0.05).

Kim et al. reported the only systematic study of the placental bed of patients presenting with preterm labor who had a preterm delivery. Placental bed biopsies were obtained at the time of cesarean section under direct visualization. Specimens were immunostained for cytokeratin and counterstained with periodic acid Schiff (PAS) to detect trophoblasts and fibrinoid, respectively. Three groups of patients were studied: 1) patients who had a cesarean section at term; 2) patients who had spontaneous preterm labor/delivery with a cesarean section for obstetrical indications; and 3) patients with preeclampsia (positive control).

The rate of failure of physiologic transformation of the myometrial segment of the spiral arteries was significantly higher in patients with spontaneous preterm labor/delivery than in those who had a term delivery (30.9% vs. 13.6%, p = 0.004). The same was the case for the decidual segment in the placental bed (13.1% vs. 3.6%, p = 0.001), but not for the decidual segment in the basal plate of the placenta (10.4% vs. 7.4%, p > 0.05). Figure 1 describes the mean percentage of non-transformed spiral arteries in three different locations (myometrium, decidual segment of the placental bed, and decidua in the basal plate).

Mean percentage of non-transformed spiral arteries weighted by the number of vessels. Figure1a: The mean percentage of the spiral arteries that had failure of physiologic transformation in the myometrial segment was significantly higher in patients with preterm labor and those with preeclampsia than in normal pregnant women at term (preterm labor; mean ± SEM = 30.9% ± 5.8% vs. normal pregnant women; mean ± SEM = 13.6% ± 2.1%; p = 0.0004 and preeclampsia; mean ± SEM = 80.5% ± 3.8% vs. normal pregnant women; mean ± SEM = 13.6% ± 2.1%; p < 0.0001). Figure 1b: Patients with preterm labor and intact membranes, as well as patients with preeclampsia, had a significantly higher mean percentage of the spiral arteries that had failure of physiologic transformation in the decidual segment of the placental bed than normal pregnant women (preterm labor; mean ± SEM = 13.1% ± 4.4% vs. normal pregnant women; mean ± SEM = 3.6% ± 1.2%; p = 0.001 and preeclampsia; mean ± SEM = 33.1% ± 4.5% vs. normal pregnant women; mean ± SEM = 3.6% ± 1.2%; p < 0.0001). Figure 1c: The mean percentage of the spiral arteries that had failure of physiologic transformation in the decidual segments of the basal plate was not significantly different between patients with preterm labor and normal pregnant women at term (preterm labor; mean ± SEM = 10.4% ± 3.0% vs. normal pregnant women; mean ± SEM = 7.4% ± 1.3%; p > 0.05). Patients with preeclampsia had a significantly higher mean percentage of the spiral arteries that had failure of physiologic transformation in the decidual segments of the basal plate than patients with preterm labor and normal pregnant women (preeclampsia; mean ± SEM = 38.7% ± 4.0% vs. preterm labor; mean ± SEM = 10.4% ± 3.0%; p < 0.0001 and preeclampsia; mean ± SEM = 38.7% ± 4.0% vs. normal pregnant women; mean ± SEM = 7.4% ± 1.3%; p < 0.0001). Comparisons were performed with ANOVA, followed by student’s t tests; p value >0.017 became non-significant after adjusting for multiple comparisons. Reprinted with permission from Kim et al.

These observations indicate that patients with preterm labor and intact membranes who deliver a preterm neonate have a greater degree of failure of transformation of the spiral arteries in the myometrial and decidual segments than women who deliver at term. However, the extent of this defect was much greater in patients with preeclampsia than those in preterm labor with intact membranes. Of interest is that there was no difference in the frequency of lack of physiologic transformation between patients with and without histologic chorioamnionitis. The reasons why some women with failure of physiologic transformation develop preterm labor, or other obstetrical syndromes, are presently unknown. However, it is possible that the more extensive degree of vascular pathology in preeclampsia than in preterm labor may, in part, be responsible for the phenotype.

Preterm prelabor rupture of membranes

Preterm PROM accounts for one-third of all preterm births, and is often a leading cause of spontaneous preterm labor. Vascular lesions of the placental bed have been described in patients with preterm PROM, including failure of physiologic transformation of the decidual segment of the spiral arteries, thrombosis, and atherosis.

Only one study has examined the histology of the placental bed in patients with preterm PROM. Kim et al. determined the frequency of non-transformed spiral arteries in placental bed biopsies obtained under direct visualization at the time of cesarean section in three groups of patients: 1) normal pregnancies who delivered at term; 2) patients with preterm PROM who underwent cesarean section for obstetrical indications; and 3) patients with preeclampsia. Specimens were stained with cytokeratin and PAS. The study showed that the frequency of failure of physiologic transformation of the myometrial segment of the spiral arteries was higher in patients with preterm PROM than in patients who had a spontaneous delivery at term [completely transformed spiral arteries were observed in 59% of patients who delivered at term, 29% of those with preterm PROM, and 4.3% of patients with preeclampsia ( Table 2 )]. The lack of transformation of all vessels in the biopsy specimen was observed in only 6.8% of term deliveries, 52% of patients with preeclampsia, and in 19.4% of patients with preterm PROM. Notably, there was no difference in the rate of failure of physiologic transformation in the decidual or myometrial segments of the spiral arteries in patients with and without histologic chorioamnionitis ( Table 3 ).

Table 3

Comparison of number (count) of failure of physiologic transformation of the spiral arteries between patients with preterm PROM with and without histologic chorioamnionitis

	Preterm PROM		P value
	Without histologic chorioamnionitis	With histologic chorioamnionitis
Myometrial segment of the spiral arteries
Total No. of patients	11	20
Non-transformed vessels (mean ± SE)	0.91 ± 0.37	0.90 ± 0.28	NS
Completely or partially transformed vessels (mean ± SE)	1.91 ± 0.79	2.75 ± 0.63	NS
Decidual segment of the spiral arteries in the basal plate
Total No. of patients	11	19
Non-transformed vessels (mean ± SE)	0.09 ± 0.09	0.32 ± 0.22	NS
Completely or partially transformed vessels (mean ± SE)	3.18 ± 0.69	3.37 ± 0.45	NS

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