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Keywords:

  • Blood pressure;
  • placenta praevia;
  • pre-eclampsia;
  • trophoblast;
  • umbilical cord

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

Please cite this paper as: Hasegawa J, Sekizawa A, Farina A, Nakamura M, Matsuoka R, Ichizuka K, Okai T. Location of the placenta or the umbilical cord insertion site in the lowest uterine segment is associated with low maternal blood pressure. BJOG 2011;118:1464–1469.

Objective  To evaluate whether placental abnormalities and umbilical cord insertion site affect the occurrence of pre-eclampsia and maternal blood pressure.

Design  Case–control study.

Setting  Showa University Hospital, Tokyo, Japan.

Population  A total of 5722 consecutive women who delivered singleton infants were included in the study.

Methods  The associations of placental abnormalities, the location of the placenta, the location of the cord insertion site, and maternal background with the occurrence of pre-eclampsia and maternal blood pressure at the term of pregnancy were analysed.

Main outcome measure  Pre-eclampsia and maternal blood pressure at the term of pregnancy.

Results  Pre-eclampsia was observed in 236 women (4.1%). Pre-eclampsia was frequently observed in women with placental form abnormalities (odds ratio 3.0) and infarction of the placenta (odds ratio 5.3). Pre-eclampsia was observed in 0 and 4.1% of women with and without placenta praevia, respectively (P = 0.004), and in 0 and 2.5% of women with and without low cord insertion during the first trimester, respectively (P = 0.018). After adjustment for confounding variables, the multivariate regression analyses revealed reductions of 8.4 and 5.0 mmHg in systolic and diastolic blood pressure, respectively, in women with placenta praevia compared with women without placenta praevia, and reductions of 4.3 and 3.1 mmHg in systolic and diastolic blood pressure, respectively, in women with low cord insertion during the first trimester compared with women without low cord insertion.

Conclusion  Not only placenta praevia but also low cord insertion are associated with low frequencies of pre-eclampsia and low maternal blood pressure.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

There is an inverse association between lower placental implantation in the uterus and hypertension later in pregnancy.1–3 It has been suggested that hypoxia, the renin–aldosterone–angiotensin II axis, excessive oxidative stress and syncytiotrophoblast debris, immune maladaptation, and genetic susceptibility may play roles in the pathogenesis of pre-eclampsia.4 Many investigators have suggested that pre-eclampsia originates in the placenta, starting with inadequate cytotrophoblast invasion and ending with widespread maternal endothelial dysfunction.4,5 Extravillous cytotrophoblasts of fetal origin invade the uterine spiral arteries of the decidua and myometrium early in normal placental development. These invasive cytotrophoblasts replace the endothelial layer of the maternal spiral arteries, transforming them from small, high-resistance vessels into high-calibre capacitance vessels capable of providing adequate placental perfusion to sustain the growing fetus.6 This transformation is often incomplete in pre-eclampsia, and cytotrophoblast invasion of the spiral arteries is limited in the superficial decidua, and the myometrial segments remain narrow,7 creating a physiologically hypoxic environment in the intervillous space.8–10 Leiberman et al.3 speculated that the blood supply and oxygenation of a placenta implanted in the lower uterine segment are increased compared with those in a placenta implanted in the upper uterine segment because the blood flow to the lower uterine segment is less affected by the pressure of the myometrium. The improved blood supply and oxygenation of the placenta may play a role in the prevention of pregnancy-induced hypertensive disorders.

Disruption of the placenta during prenatal development, such as focal haemorrhage and subsequent inflammation, could also theoretically inhibit spiral arteriolar widening, contributing to reduced placental hypoperfusion and initiating a cascade of additional effects that include oxidative stress and endothelial cell dysfunction.11–13 The umbilical cord insertion site is determined before placental growth. Abnormal placental shape and velamentous cord insertions frequently develop when the site of umbilical placental insertion in the uterus is low, because the early placenta develops with advancing gestation to ensure a better blood supply to the more richly vascularised area such as the uterine body.14 In addition, placental disruptions, such as velamentous cord insertions and placental abnormalities, and placenta praevia are associated with cord insertion in the lower segment of the uterus.15–17

An abnormal cord insertion site is secondary to an oblique orientation of the blastocyst, so that the embryo does not face the implantation base at nidation.18,19 Huppertz6 noted that an insult occurring very early during trophoblast development, either before or at the blastocyst stage, may affect the villous as well as the extravillous pathways of trophoblast differentiation, leading to a combination of pre-eclampsia and intrauterine fetal growth restriction.

We therefore hypothesised that early abnormal placental implantation may be associated with the location of the umbilical placental cord insertion, and so an abnormal polarity of the blastocyst, and may affect maternal blood pressure later in pregnancy. The purpose of the present study was to evaluate whether placental abnormalities and umbilical cord insertion site affect the occurrence of pre-eclampsia and maternal blood pressure.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

Consecutive women who delivered viable singleton infants at Showa University Hospital between October 2006 and September 2010 were included in this study. The associations of the presence of placental abnormalities, the location of the placenta and the location of the umbilical placental cord insertion site, based on pathological and ultrasonographic evaluations, with the occurrence of pre-eclampsia and maternal blood pressure at the term of pregnancy, were analysed.

Data on placental abnormalities and maternal demographics, history and habits were collected. Placental findings evaluated in the present study included abnormalities in placental form (bi-lobed, succenturiate and accessory placentas), apparent placental infarction, velamentous cord insertion, placenta praevia, and umbilical cord insertion site at the end of the first trimester.

The presence of placenta praevia was confirmed by transvaginal ultrasonography just before delivery. Placenta praevia included complete, partial and marginal praevia and low-lying placenta. Apparent placental infarction was diagnosed on the basis of a macroscopic examination. The umbilical cord insertion site was examined by ultrasound at between 9 and 13 weeks of gestation, because we previously demonstrated associations between the low placental cord insertion during the first trimester and various placental and umbilical cord abnormalities later in pregnancy.16 Low cord insertion was detected by examination of the positional relationship between the uterine cavity and the cord insertion site using transvaginal and transabdominal ultrasonography. The internal os (the end of the cervical canal) and the fundus (the top of the uterine cavity) were visualised, and the distance between the internal os and the fundus was divided into three equal parts. Cord insertions located in the lowest of the three parts were defined as low cord insertions, regardless of their relationship to the chorion villosum, as we previously reported.16 We routinely performed ultrasound for cord insertion and recorded a ‘low cord insertion’ when it was present.

Pre-eclampsia was defined as the onset of hypertension after 20 weeks of gestation (defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) and proteinuria (≥0.3 g in a 24-hour urine specimen or a protein to creatinine ratio of >0.30). The maternal blood pressure (systolic and diastolic) was measured when the women visited the hospital for their deliveries at the onset of labour or when their membranes ruptured, or on the day before an elective caesarean section. Blood pressure was measured using a cuff size selected according to the woman’s upper arm diameter by well-trained midwives in a quiet room with the woman seated at a table and her arm supported at heart level after the woman had been seated for 15–30 minutes. Korotkoff phase V was used to measure diastolic blood pressure.

Continuous variables were compared using Student’s t test for parametric data and the Mann–Whitney U test for nonparametric data. Categorical variables were reported as percentages and compared using Fisher’s exact test. Multiple comparisons were performed using analysis of variance and post hoc paired tests, with P-values adjusted using a Bonferroni correction. A generalised linear model was used in the multivariate regression analysis to adjust for confounding variables of interest. Adjusted blood pressure values were estimated for each of the populations of interest. The presence or absence of placenta praevia, low cord insertion in the first trimester, placental form abnormalities, infarction of the placenta and elective caesarean section, weeks of gestation at delivery, and maternal age, body mass index and parity were used in this analysis as independent variables. Statistical significance was defined as a P-value <0.05. The Statistical Package for the Social Sciences (SPSS; Windows version 16.0J; SPSS, Chicago, IL, USA) was used for analyses.

This study was approved by the local ethical board of our institution. The analysis was retrospective, using clinical records and ultrasonography that had been performed in a normal clinical setting. Therefore, the confidentiality of the women involved was protected and no personal data were required for the present study.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

This study included 5722 mothers, for whom demographic data are shown in Table 1. Pre-eclampsia was observed in 236 (4.1%) of these women.

Table 1.   Demographics of the women
 Women with pre-eclampsiaWomen without pre-eclampsiaP-value
  1. IVF, in vitro fertilisation.

  2. Values are mean ± standard deviation, unless otherwise stated. Statistical analyses were performed using Student’s t test, the Mann–Whitney U test and Fisher’s exact test.

n (%)236 (4.1)5486 (95.9) 
Maternal age at delivery (years)34.0 ± 4.932.6 ± 4.7<0.001
Gravida, median (range)0 (0–6)1 (0–8)<0.001
Parity, median (range)0 (0–3)0 (0–7)<0.001
Height (cm)158.8 ± 5.8158.8 ± 5.30.793
Weight before pregnancy (kg)55.3 ± 9.951.9 ± 7.8<0.001
Weight at delivery (kg)64.9 ± 10.261.3 ± 8.1<0.001
Body mass index21.9 ± 3.820.5 ± 2.9<0.001
Pregnancy after IVF (%)7.23.50.007
Weeks of gestation at delivery36.5 ± 3.638.3 ± 2.5<0.001
Neonatal birthweight (g)2417 ± 8162908 ± 537<0.001
Stillbirth (%)1.30.60.205

The frequency of pre-eclampsia stratified by maternal characteristics is shown in Table 2. Pre-eclampsia was associated with maternal age ≥40 years [odds ratio (OR) 2.8; 95% confidence interval (95% CI) 1.9–4.1; P < 0.001], body mass index ≥25 (OR 3.0; 95% CI 2.1–4.3; P < 0.001) and nulliparity (OR 2.5; 95% CI 1.8–3.4; P < 0.001).

Table 2.   Frequency of pre-eclampsia stratified by maternal characteristics
 Yes % (n/total)No % (n/total)P-valueOR (95% CI)
  1. OR, crude odds ratio; 95% CI, 95% confidence intervals.

  2. Frequencies of pre-eclampsia were compared using Fisher’s exact test.

Nulliparity5.5 (56/2641)2.3 (177/3223)<0.0012.5 (1.8–3.4)
Maternal age ≥40 years9.7 (36/371)3.7 (200/5351)<0.0012.8 (1.9–4.1)
Body mass index ≥2510.3 (39/378)3.7 (194/5292)<0.0013.0 (2.1–4.3)
Maternal weight gain ≥30%4.5 (16/353)4.1 (213/5206)0.677 
Smoking3.1 (11/351)4.3 (203/4727)0.337 

The frequencies of pre-eclampsia in the presence and absence of placental abnormalities are reported in Table 3. Pathological investigations of the placenta were performed for all women, but ultrasonography of the umbilical cord during the first trimester was performed in only 1607 women, because referred women who were seen after their second trimester were included in the study. Pre-eclampsia was frequently observed in women with placental form abnormalities (OR 3.0; 95% CI 1.6–5.7; P = 0.002) and infarction of the placenta (OR 5.3; 95% CI 3.0–9.2; P < 0.001). Pre-eclampsia was observed in 0 and 4.1% of women with and without placenta praevia, respectively (P = 0.004), and in 0 and 2.5% of women with and without low cord insertion, respectively (P = 0.018).

Table 3.   Frequency of pre-eclampsia in the presence and absence of placental abnormalities
 Presence % (n/total)Absence % (n/total)P-valueOR (95% CI)
  1. OR, crude odds ratio; 95% CI, 95% confidence interval; n/a, not applicable.

  2. Frequencies of pre-eclampsia were compared using Fisher’s exact test.

Placental form abnormalities11.1 (11/99)4.0 (225/5623)0.0023.0 (1.6–5.7)
Infarction of the placenta17.6 (16/91)3.9 (220/5631)<0.0015.3 (3.0–9.2)
Velamentous cord insertion5.8 (4/69)4.1 (232/5653)0.532 
Placenta praevia0 (0/140)4.1 (236/5582)0.004n/a
Low cord insertion in first trimester0 (0/170)2.5 (40/1437)0.018n/a

Maternal blood pressure stratified by the severity of placenta praevia is shown in Table 4. Mean systolic and diastolic blood pressures (±SD) in control women and in women with low-lying, partial/marginal and complete placenta praevia were 115.9 ± 14.1, 110.4 ± 10.7, 108.2 ± 10.7 and 107.6 ± 11.1 mmHg and 75.7 ± 11.6, 70.4 ± 9.0, 68.2 ± 9.4 and 68.8 ± 0.4 mmHg, respectively. Both systolic and diastolic blood pressures in women with each category of severity of placenta praevia were significantly lower than in control women.

Table 4.   Maternal blood pressure stratified by the severity of placenta praevia
 Control (n = 5582)Placenta praevia
Low-lying (n = 64)Partial/marginal (n = 38)Complete (n = 38)
  1. Values are mean ± standard deviation (mmHg). Statistical analyses were performed using analysis of variance and Bonferroni correction.

  2. *P < 0.05, compared with controls.

Systolic115.9 ± 14.1110.4 ± 10.7*108.2 ± 10.7*107.6 ± 11.1*
Diastolic75.7 ± 11.670.4 ± 9.0*68.2 ± 9.4*68.8 ± 10.4*

The results of the multivariate regression analysis are shown in Table 5. Placenta praevia and low cord insertion in the first trimester were associated with low maternal blood pressure at the term of pregnancy. After adjustment for confounding variables, reductions of 8.4 and 5.0 mmHg in systolic and diastolic blood pressures, respectively, in women with placenta praevia compared with women without it, and reductions of 4.3 and 3.1 mmHg in systolic and diastolic blood pressures, respectively, in women with low cord insertion in the first trimester compared with women without low cord insertion, were observed.

Table 5.   Results of a multivariate regression analysis (generalised linear model) evaluating the coefficients of the regressions of maternal systolic and diastolic blood pressures on the independent variables respectively
 Coefficient (95% CI)SEP-value
  1. BMI, body mass index; CI, confidence interval; SE, standard error.

Systolic blood pressure
Placenta praevia−8.4 (−12.5, −4.3)2.1<0.001
Low cord insertion in first trimester−4.3 (−6.4, −2.2)1.1<0.001
Elective caesarean section−3.2 (−5.1, −1.2)1.00.002
Weeks of gestation (each 1-week increase)−0.7 (−1.1, −0.3)0.2<0.001
Maternal age (each 1-year increase)0.3 (0.1, 0.4)0.1<0.001
Maternal BMI (each increase of 1)0.7 (0.5, 0.9)0.1<0.001
Nulliparity2.4 (1.1, 3.7)0.7<0.001
Diastolic blood pressure
Placenta praevia−5.0 (−8.4, −1.5)1.80.005
Low cord insertion in first trimester−3.1 (−4.9, −1.4)0.9<0.001
Elective caesarean section−5.9 (−7.5, −4.3)0.8<0.001
Weeks of gestation (each 1-week increase)−0.6 (−0.9, −0.2)0.2<0.001
Maternal age (each 1-year increase)0.2 (0.0, 0.3)0.10.013
Maternal BMI (each increase of 1)0.5 (0.4, 0.7)0.1<0.001
Nulliparity2.2 (1.1, 3.3)0.6<0.001

Of the women who were followed up at our hospital from the first trimester, 13 (7.6%) of 170 women with low cord insertion in the first trimester had placenta praevia later in pregnancy. Maternal blood pressure in women who did not have low cord insertion or placenta praevia, who had low cord insertion without placenta praevia and who had placenta praevia regardless of the cord insertion site is shown in Table 6. Compared with women who had neither low cord insertion nor placenta praevia, lower maternal blood pressure was observed in women who had placenta praevia, and also in those who had low cord insertion but who did not have placenta praevia.

Table 6.   Maternal blood pressures in women who did not have low cord insertion or placenta praevia, who had low cord insertion without placenta praevia, and who had placenta praevia regardless of cord insertion site
 Without low cord insertion or placenta praevia (n = 1405)With low cord insertion without placenta praevia (n = 157)With placenta praevia (n = 45)
  1. Values are mean ± standard deviation (mmHg). Statistical analysis was using analysis of variance and post hoc paired tests, with P-values adjusted using a Bonferroni correction. *, † and ¶; compared each group (P < 0.05).

Systolic116.2 ± 13.0†¶111.6 ± 12.6*†106.4 ± 9.5*¶
Diastolic76.2 ± 10.9†¶72.7 ± 10.9*†67.6 ± 9.4*¶

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

As in previous reports,1–3 the present study found that placenta praevia was associated with lower average maternal blood pressure and a lower incidence of pre-eclampsia compared with normally situated placentas. Furthermore, we found that low cord insertion during the first trimester reduced the occurrence of pre-eclampsia and was associated with lower maternal blood pressure at term. Even in women with low cord insertion in the first trimester who did not have placenta praevia later in pregnancy, an association with low maternal blood pressure was observed.

During trophoblast invasion, the environment experienced by the trophoblasts is hypoxic and they need to find oxygen; they therefore invade the endometrium down to the deciduo–myometrial junction to locate arteries and an oxygen supply. This promotes angiogenesis, which enables the trophoblasts to obtain enough oxygen from the surrounding tissue. Rodesch et al.20 measured placental and endometrial partial pressures of oxygen (Po2) and found placental Po2 levels to be significantly lower than endometrial Po2 levels at between 8 and 10 weeks of gestation, with a peak at 12–13 weeks of gestation. There is little endovascular invasion during much of the first trimester, so maternal blood flow to the placenta is minimal. This creates a hypoxic environment in which placental development occurs.8–10 In addition, Farina et al.21 showed that gene expression relating to angiogenesis or oxidative stress is altered in the first trimester trophoblasts of women who develop pre-eclampsia later in pregnancy.

Biswas et al.22 demonstrated pathologically that trophoblastic cell invasion of the myometrial spiral arterioles is significantly more extensive in women with placenta praevia than in other women. As the lower uterine segment has more connective tissue and less muscle, it may be more hypoxic than the uterine body as a result of its poorer blood supply from the uterine arterioles during the first trimester. This hypoxic environment and the thinner endometrium in the lower part of the uterus may allow the trophoblast to invade the endometrium more easily and more deeply, resulting in more extensive remodelling of the spiral arteries. In fact, we found that complete placenta praevia was more likely to decrease maternal blood pressure compared with partial or marginal placenta praevia or a low-lying placenta, although the differences were not statistically significant.

Infarction of the placenta is frequently observed in pre-eclampsia. Tranquilli and Landi10 mentioned that the hypoxic placenta described in pre-eclampsia would only be a late result of the defective trophoblast tissue that had initially failed to progress, having no need to seek oxygen at the very beginning of the implantation process. However, infarction of the placenta is also often observed in placenta praevia. This is at odds with the observations of a low frequency of pre-eclampsia in women with placenta praevia. However, we believe that this contradiction may be explained by other factors. For example, placenta praevia may coexist with bleeding caused by detachment of the placenta near the cervical os. It was previously demonstrated that basal-plate decidual haemosiderin was related to villous infarction.23 Therefore, bleeding associated with placenta praevia might affect the occurrence of a placental infarct. Chorioamnionitis is also associated with placental infarction.24 Pathological studies have reported an excess of histological chorioamnionitis in women with placenta praevia.25,26 Chorioamnionitis in women with placenta praevia could therefore be associated with the frequency of placental infarction. We speculated that uteroplacental changes and the subsequent reduction in maternal blood pressure in women with placenta praevia may occur before these disruptive changes to the placenta.

It is still unclear why a low frequency of pre-eclampsia and low maternal blood pressure were observed even in women with low cord insertion who did not have placenta praevia later in pregnancy. As there is a very close relationship between the cord insertion site and early placental development, the umbilical cord insertion site may play a role in trophoblast invasion during the first trimester. We also believe that the placenta tends to be located in the lower uterine body when the umbilical cord insertion site is located in the lower uterine segment during the first trimester, even if a diagnosis of placenta praevia is not made, because our previous study showed that the distance between the lowest placental edge and the internal os at 18–20 weeks of gestation correlated with the distance between the cord insertion site and the internal os during the first trimester.17 In the current study, because accurate placental locations were not determined in women without placenta praevia, we were not able to ascertain whether low maternal blood pressure in women with low cord insertion was dependent on lower placentation or other factors related to the cord insertion site.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

This study showed that placenta praevia and an umbilical cord insertion site located in the lower uterine segment at the end of the first trimester were associated with a low frequency of pre-eclampsia and had a favourable effect on maternal blood pressure.

Disclosure of interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

The authors have no conflict of interest to declare. They receive no financial support from nor do they own stock in any company.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

JH, AS and TO were responsible for the study design. JH, MN, AS, RM and KI collected, analysed and interpreted the data. JH, AS and AF drafted the manuscript and JH and AF performed the statistical analyses.

Details of ethics approval

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References

This study was approved by the local ethical board of our institution. The study was a retrospective analysis based on clinical records. The confidentiality of the women involved was protected and no personal data were needed for the present study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. References