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The clinical significance of large placental lakes
European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 139–143
Contents lists available at SciVerse ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
The clinical significance of large placental lakes Han Sung Hwang, In Sook Sohn, Han Sung Kwon * Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Research Institute of Biomedical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 December 2011 Received in revised form 26 January 2012 Accepted 20 February 2012
Objective: The aim of our study was to establish whether there is a correlation between the size of placental lakes and adverse pregnancy outcome. Study design: Target ultrasonography for diagnosis of placental lake was performed in the 2nd trimester of pregnancy and followed up in the 3rd trimester. Placental lakes were defined as homogenous sonolucent avillous lesions greater than 2 cm 2 cm in diameter. The 109 pregnant women enrolled in this study were divided into four groups according to the size and change in size of placental lakes. Clinical characteristics and pregnancy outcomes in each group were compared. Results: Some placental lakes decreased and disappeared, whereas others persisted. There were no significant differences in clinical characteristics among the four investigated groups. Fetal small-forgestational-age status was significantly correlated with large placental lakes, compared to small. Conclusion: Large placental lakes were correlated with the fetal status of small for gestational age. Therefore, if a large placental lake is identified in the 2nd trimester of pregnancy, appropriate surveillance should be considered for the remainder of the pregnancy. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Placental lake Pregnancy outcome Small for gestational age
1. Introduction Advances in high resolution ultrasonography and dynamic imaging have expanded the role of these techniques in the diagnosis of pregnant women. Though sonographic evaluation of the placenta during pregnancy has some limitations, many studies have shown that various placental abnormalities detected by prenatal sonography could be danger signs for increased fetal risk and postpartum disorders [1,2]. Placental lakes are homogenous, anechoic, avillous vascular spaces in the placenta, surrounded by normal echogenic placental parenchyma [3]. Among pathological placental findings, the placental lake has been poorly examined. In addition, few studies or case reports have investigated whether placental lakes are correlated with pregnancy outcome, or examined the difference in pregnancy outcome according to different shapes of the placental lake. Two recent studies showed that a finding of placental lakes during pregnancy did not appear to be associated with adverse pregnancy outcome [4,5] but those studies did not show whether there was a difference in outcome according to the size of the placental lake. Harris et al. found that a large placental lake diagnosed at a gestational age of less than 25 weeks was associated with the worst possible prognosis [6]. Some
* Corresponding author at: Department of Obstetrics and Gynecology, Konkuk University Medical Center 4-12 Hwayang-dong, Gwangjin-gu, Seoul 143-729, Republic of Korea. Tel.: +82 2 2030 7747; fax: +82 2 2030 7748. E-mail address: [email protected] (H.S. Kwon). 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2012.02.015
case reports also revealed that a large placental lake seemed to be correlated with poor pregnancy outcome, especially with a smallfor-gestational-age (SGA) fetus [7–9]. Based on previous reports, it is possible to hypothesize that there may be an association between the size of the placental lake and adverse pregnancy outcome. The aim of our study, therefore, was to establish whether there is such a correlation. 2. Materials and methods This prospective observational study was conducted during routine target ultrasonography for fetal abnormality at 19 + 0– 23 + 6 weeks’ gestation in 1294 pregnancies, between January 2007 and December 2009. Enrolled pregnant women had singleton pregnancies. Women with multiple pregnancies, fetal malformation and chromosomal anomaly were excluded from the analysis. Imaging data of fetal biometry, morphology, amniotic fluid volume and placental morphology were obtained during ultrasonography. Gestational age was determined by menstrual history and confirmed in nearly all cases by an early ultrasound scan. During the ultrasound scanning, placental shapes were carefully examined. If a placental lake was present, it was followed up by ultrasonography at every 4 weeks until delivery. All pregnant women were examined by two sonographic experts (HSH and HSK). During ultrasonographic measurement, umbilical and uterine artery Doppler velocimetry was also evaluated in women with placental lakes. For the umbilical artery, Doppler velocimetry was considered abnormal when the pulsatility index (PI) was greater
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H.S. Hwang et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 139–143
Fig. 1. Large and small placental lakes. Large placental lake measuring 7.9 cm 5.2 cm 2.1 cm in the subchorionic area (A), and small placental lake measuring 3.2 cm 2.1 cm 2.5 cm in the intraplacental area (B) were detected during the anatomy scan (arrowheads). The placental lake extended through the full-thickness of placenta, was maintained during the 2nd and 3rd trimesters (C), and its gross finding was examined after placental delivery (D) (arrow).
than 1.0 or when end-diastolic flow was absent or reversed. For the uterine artery, a PI greater than 0.9 or the presence of an endsystolic notch were defined as abnormal. The system ACCUVIX XQ (MEDISON, Seoul, Korea) with a 3.5–5.0 MHz curvilinear transducer was used to obtain Doppler waveforms by two well-trained personnel at the time of ultrasonographic examination. During Doppler ultrasonography, the high-pass filter and sample gate were set at 100 MHz and 2 mm, respectively. Umbilical artery Doppler velocimetry was performed with the sample gate placed at the umbilical artery, near the placental insertion site. Uterine artery waveforms were measured from both sides of the uterus, with the patients in a semirecumbent position, and the transducers were placed in a longitudinal plane along the inguinal area. The quality of the flow velocity waveforms was maximized by use of the smallest possible angle of insonation and acceptance of only those with sharp and definite outline. When 5 consecutive uniform waveforms were obtained, the image was frozen and waveform evaluation was performed. A placental lake was defined as a homogenous, sonolucent avillous lesion greater than 2 cm 2 cm in diameter, with turbulent, swirling slow flow inside the lake on real-time color Doppler scanning with increasing the gain of the scanner [3]. Women with other placental pathologic findings, such as subchorionic fibrin deposition, perivillous fibrin deposition, intervillous thrombosis, subchorial thrombosis and placental infarcts, were excluded from this study. When a placental lake was found during the 2nd trimester target ultrasonography between 19 + 0 and 23 + 6 weeks’ gestation, the size of the lake was measured. The placental lake was identified in its longitudinal plane, and the probe was rotated to find the longest axis. Then, the maximum length of the placental lake was measured in a linear fashion. The perpendicular depth and width of the placental lake were measured, respectively. The longest linear length was defined
as the size of the placental lake. If the longest diameter of the lake was between 2 and 5 cm, it was regarded as small lake. When the maximum length was >5 cm, the placental lake was considered to be large. If a placental lake was found, it was followed up by ultrasonography every 4 weeks until delivery. After delivery, each placenta was evaluated and confirmed, both macroscopically and microscopically (Fig. 1). According to the change of the placental lake, the participants were divided into four groups, as follows: group I, small lake at 2nd trimester and disappearance at 3rd trimester; group II, large lake at 2nd trimester and disappearance or small lake at 3rd trimester; group III, small lake at 2nd trimester and persistence at 3rd trimester; and group IV, large lake at 2nd trimester and persistence at 3rd trimester. Adverse pregnancy outcomes included SGA (defined as birth weight < 10 percentile on fetal growth curve) [10], preterm birth, placental abruption, placenta previa, low Apgar score (<7 at 5 min), admission to the neonatal intensive care unit (NICU), and postpartum bleeding with transfusion. The protocol for this study was approved by the institutional internal review board, and informed consent was obtained from each participant. Data on clinical characteristics of patients were expressed as mean SD, and compared by Mann–Whitney U-test. Fisher’s exact test was used to compare pregnancy outcomes between two groups using SPSS software version 16.0 (SPSS Inc., Chicago, IL). A p-value of less than 0.05 was considered to be statistically significant. 3. Results A placental lake was found in 113 (8.7%) pregnant women at the time of routine 2nd trimester ultrasonography scan. Four pregnant women were excluded because of the absence of 3rd trimester ultrasonography data and pregnancy outcome by follow-up loss. A total 109 pregnant women with a placental lake at the 2nd
H.S. Hwang et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 139–143
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Table 1 Clinical characteristics of participants in groups I–IV.
Maternal age (years) Gestational age at delivery (weeks) Parity Birth weight (Kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Gestational age at diagnosis (weeks) Abnormal uterine artery Doppler (cases) Abnormal umbilical artery Doppler (cases) Abnormal cord insertion (cases)
Group I (n = 52)
Group II (n = 19)
Group III (n = 27)
Group IV (n = 11)
31.4 2.5 38.1 1.5 1.6 1.1 3.19 0.75 113 6 78 6 22.3 1.2 3 0 0
33.1 3.1 38.8 2.3 1.8 1.5 2.75 0.94* 117 5 75 5 21.9 1.4 1 0 0
32.3 2.9 38.6 1.9 1.7 1.1 3.24 0.84 114 4 76 3 21.6 1.4 1 0 0
33.6 3.6 37.7 2.1 1.8 1.3 2.69 0.60** 115 8 77 5 22.3 0.9 0 0 0
Data are presented as mean SD. * Between group I and II. ** Between group III and IV, Mann–Whitney U-test, p < 0.05; statistically significant.
trimester were enrolled in this study. During the observation of placental lakes in this study, the size of the lake decreased and it disappeared at the 3rd trimester evaluation in 52 of 79 pregnant women with a small placental lake, and in 19 of 30 cases with a large placental lake. The other placental lakes persisted in the 3rd trimester, but there were no cases in which the size of lake increased. Pregnant women with a large placental lake had only one lake. In the small placental lake cases, there were some patients with two or three small lakes, but there was no correlation between the number of placental lakes and adverse pregnancy outcome (data not shown). The clinical characteristics of the participants (groups I–IV) are compared in Table 1. There was no significant difference between the four groups in maternal age, gestational age at delivery, parity, systolic blood pressure, diastolic pressure, gestational age at diagnosis, abnormal uterine and umbilical artery Doppler velocimetry and abnormal cord insertion. After delivery, all placentas were pathologically reviewed. The cord insertion sites in the 113 placentas were all central, and there were no velamentous and marginal insertion cases. Birth weight, however, was significantly lower in groups II and IV (large placental lake group) than groups I
and III (small placental lake group). There was no significant difference in birth weight between groups II and IV. The incidence of SGA was higher in groups II and IV compared with groups I and III. The rate of NICU admissions was higher in group IV compared with the other groups. There was, however, no significant difference between the four groups in other pregnancy outcomes, such as preterm birth, placental abruption, placenta previa, low Apgar score, and postpartum bleeding with transfusion (Table 2). During 2nd trimester target ultrasonography scanning, different types of large placental lake were found. They were phenotypically classified as 4 types (retroplacental type, subchorionic type, full thickness type, and lake previa type) (Fig. 2). Clinical data in pregnancies with persistent large placental lakes (group IV) are presented in Table 3. After delivery, each placenta was examined. There were no definite pathologic lesions in the placentas obtained from groups I to III. In group IV, the size of placental lake was pathologically measured and compared with the sonographic one. There was no difference in size of placental lake between the pathological and sonographic measurements. Three cases were delivered by cesarean section because of placenta
Fig. 2. Four types of large placental lakes. Transabdominal and transvaginal ultrasonography for large placental lakes revealed several types of lakes (arrowheads): A. Retroplacental type, 5.6 cm 4.3 cm 1.5 cm; B. Subchorionic type, 7.7 cm 3.5 cm 1.8 cm; C. Full thickness type, 10.9 cm 8.0 cm 5.4 cm; D. Lake previa type, 6.3 cm 3.2 cm 2.5 cm.
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Table 2 Pregnancy outcomes in groups I–IV. I
Group Small for gestational age (<10 percentile) Preterm birth Placental abruption Placenta previa Low Apgar score (<7 at 5 min) Admission to the NICU Postpartum bleeding with transfusion
II *
3 1 0 1 0 1 1
7 1 0 1 0 1 1
III
IV
1 1 0 0 0 0 0
6* 2 0 2 1 3* 1
Data are presented as number of cases. NICU: neonatal intensive care unit. * Fisher’s exact test, p < 0.05; statistically significant.
Table 3 Clinical data in 11 pregnancies with persisted large placental lakes at 3rd semester follow up (group IV). Maternal age (years)
Placental lake Type
Sonographic size (cm)
Pathologic size (cm)
1 2 3 4 5 6
32 35 34 29 37 35
Subchorionic Lake previa Retroplacental Full thickness Retroplacental Full thickness
7.9 5.2 2.1 5.4 3.8 2.6 5.6 4.3 1.5 8.5 5.3 2.6 5.5 3.5 1.9 10.9 8.0 5.4
7 8
32 40
Full thickness Lake previa
9 10 11
37 30 29
Subchorionic Subchorionic Full thickness
No.
Birth weight (Kg)
5 min Apgar
Delivery weeks
Delivery mode
Pregnancy outcomes
8.3 4.9 2.3 6.5 3.9 2.2 5.5 5.3 2.1 8.9 6.4 2.1 6.4 4.3 3.5 9.5 8.9 3.4
3.11 2.25 3.18 2.54 3.23 1.41
8 9 9 8 9 6
39 37 39 38 38 33
SVD C/sec SVD SVD SVD C/sec
8.9 4.9 4.8 6.3 3.2 2.5
9.6 5.5 4.2 7.6 4.2 3.1
2.04 2.95
9 8
37 36
SVD C/sec
7.7 3.5 1.8 5.9 3.8 2.3 7.5 5.6 2.3
6.4 4.3 2.1 5.5 4.3 2.4 6.9 4.6 2.1
3.45 2.68 2.73
9 8 9
40 40 39
SVD SVD SVD
NS Placenta previa, SGA, NICU NS SGA NS Preterm labor, fetal distress, SGA, NICU SGA, NICU Placenta previa, postpartum bleeding NS SGA SGA
NS: no specific results, C/sec: cesarean section, SVD: spontaneous vaginal delivery, SGA: small for gestational age, NICU: neonatal intensive care unit admission.
previa and fetal distress. Eight pregnant women were delivered by normal spontaneous vaginal delivery. Unusually, case 8 with large lake previa had massive postpartum bleeding after cesarean section, and cesarean hysterectomy was performed. 4. Comment This study showed that the size of the placental lakes was related to adverse pregnancy outcome, especially small-forgestational-age status. Though there has been variation in detection rates due to unclear criteria for the diagnosis of placental lake, the detection rate in this study was 8.7%, which is within the previously range of 2.2–17.8% [4,5]. Previous studies have reported that placental lakes were not correlated with adverse pregnancy outcomes [4–6]. Although those studies were based on large unselected population samples, the size of the placental lake was not clearly defined and measured. Several case reports have shown that pregnancies with large placental lakes resulted in intrauterine growth restriction and sudden intrauterine death [7,8,11,12]. Though there has been no definition or explanation for a large placental lake, the placental lakes found in those case reports were at least over 5 cm in diameter. Therefore, in this study, when the maximum length of the lake was above 5 cm, we defined it as a large placental lake, and after the division of the patients into groups, we compared the outcomes between groups. To diagnose the placental lake and evaluate its effects, we had to consider the following criteria. First, it is essential to discriminate between the placental lake and other hypoechoic or anechoic lesions, such as subchorionic fibrin deposition, perivillous fibrin deposition, intervillous thrombosis, subchorial thrombosis, and placental infarcts. Second, it is crucial to confirm whether the placental lake exists at the 3rd trimester. In the current study, the
placental lakes of 71 cases shrank or disappeared at the 3rd trimester follow-up ultrasonography and this seemed to have little effect on pregnancy outcome. Villous vascularity in the placental bed is associated with various maternal–fetal conditions. Soma et al. reported that chorangiosis was frequently observed in the placenta of women from the Himalayas, suggesting that villus hypervascularization was caused by a chronic hypoxic state at extremely high altitude [13]. Chorangiosis or villous hypervascularization in the terminal villi might suggest the presence or a history of unidentified disturbances in feto-maternal oxygen exchange. Pre-eclampsia is a pregnancy disorder with hypertension and proteinuria associated with impoverished chorionic villous development and fetoplacental angiogenesis, when the fetus is growth restricted [14]. When fetal growth is normal, branching angiogenesis is increased and the villous capillary loops can be hyper-ramified with irregular and narrow lumina [15,16]. Placental lakes are known as homogenous, anechoic, avillous vascular space in the placenta [3]. Therefore, considering the effect of villous vascularity in the placental bed during pregnancy, it is possible to explain that the larger the avillous area is, the more the fetal-maternal exchange is disturbed and the fetal growth is restricted. Some studies have shown that umbilical artery Doppler values may be an indicator of SGA. In our studies, there was no correlation between the incidence of SGA and abnormal umbilical artery Doppler values. There is an explanation for this discordance. Following analysis of complicated pregnancies, fetal hypoxia has been classed as preplacental, uteroplacental or postplacental in origin [17]. In preplacental hypoxia (high altitude, maternal anemia), maternal blood entering the intervillous space is hypoxemic with potential consequences of hypoxia for the mother, placenta and fetus. In uteroplacental hypoxia (late-onset pre-eclampsia, SGA with persisting end diastolic flow in umbilical arteries), maternal blood is normoxic
H.S. Hwang et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 139–143
but flow into the intervillous space is heterogeneous and locally compromised. Postplacental hypoxia (pre-eclampsia with absent or reversed end diastolic flow, SGA with absent or reversed end diastolic flow) is characterized also by maternal normoxemia coupled with normal or reduced intervillous blood flow [18]. So, SGA cases enrolled in this study may have had uteroplacental hypoxia due to placental pathology. In cases of placental lakes, the mode of delivery has been usually determined according to a standard obstetrical care program, because of the rather good prognosis [4]. In some case reports, however, elective cesarean section was performed for huge placental lake, due to the risk of rupture during spontaneous vaginal delivery and uncontrollable massive bleeding after the separation of the placenta [9,19]. Though the size of placental lakes included in this study was a little smaller than in one of those case reports, most of the women enrolled in our study were delivered vaginally, except two cases of placenta previa and one of fetal distress. Of course, the results of this study do not mean that all pregnancies with large placental lakes should be delivered vaginally. It is necessary to consider elective cesarean section when a large placental lake is found. Although some previous studies showed that the placental lake was related to placental infarct, intervillous thrombosis, and decidual cysts, which may be the cause of the lake, its etiology is still uncertain [20,21]. In a very recent study, Cooley et al. showed that there was a significant association between placental lakes and threatened first trimester loss [22]. In our study, we found 113 pregnant women with placental lakes at the time of routine 2nd trimester ultrasonography scan. Among these cases, 27 (23.9%) had experienced vaginal bleeding in the first trimester and this result is statistically similar to results from the previous study [22]. Therefore, the current study supports the association between 2nd trimester placental lake and threatened miscarriage. For patients with significant intraplacental hemorrhage, it is reasonable to suggest that this could produce ‘holes’ in the placenta, which are naturally replaced by venous lakes persisting even after the hemorrhage resolves. This situation may reflect underlying placental or utero-placental abnormalities. A number of limitations of the present study should be noted. First, the definition of large placental lake used in this study has to be confirmed by further studies. Second, the incidence of admissions to the NICU was higher in group IV, compared with the other groups. Three cases of admission to NICU were SGAs, however, so admission to NICU was not an independent factor of pregnancy outcome. Third, the number of cases enrolled in this study was relatively small and more studies of the placental lake must be done. Despite the limitations of the this study, we were able to show an effect of size of placental lake on pregnancy outcome, which was different from previous studies that only compared pregnancy outcomes according to the existence of placental lake. In conclusion, this study showed that large placental lakes (>5 cm) were correlated with small-for-gestational-age status. Thus, if a large placental lake is identified in the 2nd trimester, a growth scan early in the 3rd trimester should be considered. If that scan shows the fetus to be in the small-for-gestational-age range, appropriate surveillance should be instituted for the remainder of the pregnancy. Further longitudinal studies on placental lake
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measured by 3D volume ultrasonography and MRI are under way to evaluate whether it is a clinically useful indicator of the adverse pregnancy outcome. Acknowledgement This work was supported by Konkuk University in 2012. References [1] Jauniaux E. Placental ultrasonographic measurement: what can be learn and is it worth doing routinely. Ultrasound Obstet Gynecol 1992;2:241–2. [2] Harris RD, Cho C, Wells A. Sonography of placenta with emphasis on pathological correlation. Semin Ultrasound CT MRI 1996;17:66–89. [3] Jauniaux E, Moscoso G, Campbell S, Gibb D, Driver M, Nicolaides KH. Correlation of ultrasound and pathologic findings of placental anomalies in pregnancies with elevated maternal serum alpha-fetoprotein. Eur J Obstet Gynecol Reprod Biol 1990;37:219–30. [4] Thompson MO, Vines SK, Aquilina J, Wathen NC, Harrington K. Are placental lakes of any clinical significance. Placenta 2002;23:685–90. [5] Reis NS, Brizot ML, Schultz R, Nomura RM, Zugaib M. Placental lakes on sonographic examination: correlation with obstetric outcome and pathologic findings. J Clin Ultrasound 2005;33:67–71. [6] Harris RD, Simpson WA, Pet LR, Marin-Padilla M, Crow HC. Placental hypoechoic–anechoic areas and infarction: sonographic–pathologic correlation. Radiology 1990;176:75–80. [7] Castaner JC, D’Alton ME. A large placental venous lake. Curr Opin Obstet Gynecol 1995;7:151–5. [8] Has R, Yu¨ksel A, Gu¨nay S, Aydinhan E, Ozgu¨n T. Antenatal sonographic detection of an unusual placental lake under the cord insertion. Arch Gynecol Obstet 2005;271:59–61. [9] Morikawa M, Cho K, Kataoka S, et al. Magnetic resonance image findings of placental lake: report of two cases. Prenat Diagn 2005;25:250–2. [10] Seo K, Park YW, Park TK. Birth weight distribution by gestational age and constructing cut-off value for fetal growth retardation: their statistical consideration. Korean J Obstet Gynecol 1989;32:530–40. [11] Kojima K, Suzuki Y, Makino A, Murakami I, Suzumori K. A case of massive subchorionic thrombohematoma diagnosed by ultrasonography and magnetic resonance imaging. Fetal Diagn Ther 2001;16:57–60. [12] Hong SC, Yoo SW, Kim T, et al. Prenatal diagnosis of a large subchorionic placental cyst with intracystic hematomas. A case report. Fetal Diagn Ther 2007;22:259–63. [13] Soma H, Hata T, Oguro T, Fujita K, Kudo M, Vaidya U. Characteristics of histopathological and ultrastructural features of placental villi in pregnant Nepalese women. Med Mol Morphol 2005;38:92–103. [14] Mayhew TM, Wijesekara J, Baker PN, Ong SS. Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia. Placenta 2004;25: 829–33. [15] Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis: III, changes in complicated pregnancies. Placenta 2004;25:127–39. [16] Resta L, Capobianco C, Marzullo A, et al. Confocal laser scanning microscope study of terminal villi vessels in normal term and pre-eclamptic placentas. Placenta 2006;27:735–9. [17] Kingdom JCP, Kaufmann P. Oxygen and placental villous development: origins of fetal hypoxia. Placenta 1997;18:613–21. [18] Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta 2004;25:127–39. [19] Muramatsu K, Itoh H, Yamasaki T, et al. A case of a huge placental lake; prenatal differential diagnosis and clinical management. J Obstet Gynaecol Res 2010;36:165–9. [20] Jauniaux E, Avni FE, Elkhazen N, Wilkin P, Hustin J. Morphologic study of ultrasonic placental anomalies in the second half of pregnancy. J Gynecol Obstet Biol Reprod 1989;18:601–13. [21] Spirt BA, Gordon LP, Kagan EH. Intervillous thrombosis: sonographic and pathologic correlation. Radiology 1983;147:197–200. [22] Cooley SM, Donnelly JC, Walsh T, McMahon C, Gillan J, Geary MP. The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population. J Matern Fetal Neonatal Med 2011;24:493–7.
Contents lists available at SciVerse ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
The clinical significance of large placental lakes Han Sung Hwang, In Sook Sohn, Han Sung Kwon * Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Research Institute of Biomedical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 December 2011 Received in revised form 26 January 2012 Accepted 20 February 2012
Objective: The aim of our study was to establish whether there is a correlation between the size of placental lakes and adverse pregnancy outcome. Study design: Target ultrasonography for diagnosis of placental lake was performed in the 2nd trimester of pregnancy and followed up in the 3rd trimester. Placental lakes were defined as homogenous sonolucent avillous lesions greater than 2 cm 2 cm in diameter. The 109 pregnant women enrolled in this study were divided into four groups according to the size and change in size of placental lakes. Clinical characteristics and pregnancy outcomes in each group were compared. Results: Some placental lakes decreased and disappeared, whereas others persisted. There were no significant differences in clinical characteristics among the four investigated groups. Fetal small-forgestational-age status was significantly correlated with large placental lakes, compared to small. Conclusion: Large placental lakes were correlated with the fetal status of small for gestational age. Therefore, if a large placental lake is identified in the 2nd trimester of pregnancy, appropriate surveillance should be considered for the remainder of the pregnancy. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Placental lake Pregnancy outcome Small for gestational age
1. Introduction Advances in high resolution ultrasonography and dynamic imaging have expanded the role of these techniques in the diagnosis of pregnant women. Though sonographic evaluation of the placenta during pregnancy has some limitations, many studies have shown that various placental abnormalities detected by prenatal sonography could be danger signs for increased fetal risk and postpartum disorders [1,2]. Placental lakes are homogenous, anechoic, avillous vascular spaces in the placenta, surrounded by normal echogenic placental parenchyma [3]. Among pathological placental findings, the placental lake has been poorly examined. In addition, few studies or case reports have investigated whether placental lakes are correlated with pregnancy outcome, or examined the difference in pregnancy outcome according to different shapes of the placental lake. Two recent studies showed that a finding of placental lakes during pregnancy did not appear to be associated with adverse pregnancy outcome [4,5] but those studies did not show whether there was a difference in outcome according to the size of the placental lake. Harris et al. found that a large placental lake diagnosed at a gestational age of less than 25 weeks was associated with the worst possible prognosis [6]. Some
* Corresponding author at: Department of Obstetrics and Gynecology, Konkuk University Medical Center 4-12 Hwayang-dong, Gwangjin-gu, Seoul 143-729, Republic of Korea. Tel.: +82 2 2030 7747; fax: +82 2 2030 7748. E-mail address: [email protected] (H.S. Kwon). 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2012.02.015
case reports also revealed that a large placental lake seemed to be correlated with poor pregnancy outcome, especially with a smallfor-gestational-age (SGA) fetus [7–9]. Based on previous reports, it is possible to hypothesize that there may be an association between the size of the placental lake and adverse pregnancy outcome. The aim of our study, therefore, was to establish whether there is such a correlation. 2. Materials and methods This prospective observational study was conducted during routine target ultrasonography for fetal abnormality at 19 + 0– 23 + 6 weeks’ gestation in 1294 pregnancies, between January 2007 and December 2009. Enrolled pregnant women had singleton pregnancies. Women with multiple pregnancies, fetal malformation and chromosomal anomaly were excluded from the analysis. Imaging data of fetal biometry, morphology, amniotic fluid volume and placental morphology were obtained during ultrasonography. Gestational age was determined by menstrual history and confirmed in nearly all cases by an early ultrasound scan. During the ultrasound scanning, placental shapes were carefully examined. If a placental lake was present, it was followed up by ultrasonography at every 4 weeks until delivery. All pregnant women were examined by two sonographic experts (HSH and HSK). During ultrasonographic measurement, umbilical and uterine artery Doppler velocimetry was also evaluated in women with placental lakes. For the umbilical artery, Doppler velocimetry was considered abnormal when the pulsatility index (PI) was greater
140
H.S. Hwang et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 162 (2012) 139–143
Fig. 1. Large and small placental lakes. Large placental lake measuring 7.9 cm 5.2 cm 2.1 cm in the subchorionic area (A), and small placental lake measuring 3.2 cm 2.1 cm 2.5 cm in the intraplacental area (B) were detected during the anatomy scan (arrowheads). The placental lake extended through the full-thickness of placenta, was maintained during the 2nd and 3rd trimesters (C), and its gross finding was examined after placental delivery (D) (arrow).
than 1.0 or when end-diastolic flow was absent or reversed. For the uterine artery, a PI greater than 0.9 or the presence of an endsystolic notch were defined as abnormal. The system ACCUVIX XQ (MEDISON, Seoul, Korea) with a 3.5–5.0 MHz curvilinear transducer was used to obtain Doppler waveforms by two well-trained personnel at the time of ultrasonographic examination. During Doppler ultrasonography, the high-pass filter and sample gate were set at 100 MHz and 2 mm, respectively. Umbilical artery Doppler velocimetry was performed with the sample gate placed at the umbilical artery, near the placental insertion site. Uterine artery waveforms were measured from both sides of the uterus, with the patients in a semirecumbent position, and the transducers were placed in a longitudinal plane along the inguinal area. The quality of the flow velocity waveforms was maximized by use of the smallest possible angle of insonation and acceptance of only those with sharp and definite outline. When 5 consecutive uniform waveforms were obtained, the image was frozen and waveform evaluation was performed. A placental lake was defined as a homogenous, sonolucent avillous lesion greater than 2 cm 2 cm in diameter, with turbulent, swirling slow flow inside the lake on real-time color Doppler scanning with increasing the gain of the scanner [3]. Women with other placental pathologic findings, such as subchorionic fibrin deposition, perivillous fibrin deposition, intervillous thrombosis, subchorial thrombosis and placental infarcts, were excluded from this study. When a placental lake was found during the 2nd trimester target ultrasonography between 19 + 0 and 23 + 6 weeks’ gestation, the size of the lake was measured. The placental lake was identified in its longitudinal plane, and the probe was rotated to find the longest axis. Then, the maximum length of the placental lake was measured in a linear fashion. The perpendicular depth and width of the placental lake were measured, respectively. The longest linear length was defined
as the size of the placental lake. If the longest diameter of the lake was between 2 and 5 cm, it was regarded as small lake. When the maximum length was >5 cm, the placental lake was considered to be large. If a placental lake was found, it was followed up by ultrasonography every 4 weeks until delivery. After delivery, each placenta was evaluated and confirmed, both macroscopically and microscopically (Fig. 1). According to the change of the placental lake, the participants were divided into four groups, as follows: group I, small lake at 2nd trimester and disappearance at 3rd trimester; group II, large lake at 2nd trimester and disappearance or small lake at 3rd trimester; group III, small lake at 2nd trimester and persistence at 3rd trimester; and group IV, large lake at 2nd trimester and persistence at 3rd trimester. Adverse pregnancy outcomes included SGA (defined as birth weight < 10 percentile on fetal growth curve) [10], preterm birth, placental abruption, placenta previa, low Apgar score (<7 at 5 min), admission to the neonatal intensive care unit (NICU), and postpartum bleeding with transfusion. The protocol for this study was approved by the institutional internal review board, and informed consent was obtained from each participant. Data on clinical characteristics of patients were expressed as mean SD, and compared by Mann–Whitney U-test. Fisher’s exact test was used to compare pregnancy outcomes between two groups using SPSS software version 16.0 (SPSS Inc., Chicago, IL). A p-value of less than 0.05 was considered to be statistically significant. 3. Results A placental lake was found in 113 (8.7%) pregnant women at the time of routine 2nd trimester ultrasonography scan. Four pregnant women were excluded because of the absence of 3rd trimester ultrasonography data and pregnancy outcome by follow-up loss. A total 109 pregnant women with a placental lake at the 2nd
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Table 1 Clinical characteristics of participants in groups I–IV.
Maternal age (years) Gestational age at delivery (weeks) Parity Birth weight (Kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Gestational age at diagnosis (weeks) Abnormal uterine artery Doppler (cases) Abnormal umbilical artery Doppler (cases) Abnormal cord insertion (cases)
Group I (n = 52)
Group II (n = 19)
Group III (n = 27)
Group IV (n = 11)
31.4 2.5 38.1 1.5 1.6 1.1 3.19 0.75 113 6 78 6 22.3 1.2 3 0 0
33.1 3.1 38.8 2.3 1.8 1.5 2.75 0.94* 117 5 75 5 21.9 1.4 1 0 0
32.3 2.9 38.6 1.9 1.7 1.1 3.24 0.84 114 4 76 3 21.6 1.4 1 0 0
33.6 3.6 37.7 2.1 1.8 1.3 2.69 0.60** 115 8 77 5 22.3 0.9 0 0 0
Data are presented as mean SD. * Between group I and II. ** Between group III and IV, Mann–Whitney U-test, p < 0.05; statistically significant.
trimester were enrolled in this study. During the observation of placental lakes in this study, the size of the lake decreased and it disappeared at the 3rd trimester evaluation in 52 of 79 pregnant women with a small placental lake, and in 19 of 30 cases with a large placental lake. The other placental lakes persisted in the 3rd trimester, but there were no cases in which the size of lake increased. Pregnant women with a large placental lake had only one lake. In the small placental lake cases, there were some patients with two or three small lakes, but there was no correlation between the number of placental lakes and adverse pregnancy outcome (data not shown). The clinical characteristics of the participants (groups I–IV) are compared in Table 1. There was no significant difference between the four groups in maternal age, gestational age at delivery, parity, systolic blood pressure, diastolic pressure, gestational age at diagnosis, abnormal uterine and umbilical artery Doppler velocimetry and abnormal cord insertion. After delivery, all placentas were pathologically reviewed. The cord insertion sites in the 113 placentas were all central, and there were no velamentous and marginal insertion cases. Birth weight, however, was significantly lower in groups II and IV (large placental lake group) than groups I
and III (small placental lake group). There was no significant difference in birth weight between groups II and IV. The incidence of SGA was higher in groups II and IV compared with groups I and III. The rate of NICU admissions was higher in group IV compared with the other groups. There was, however, no significant difference between the four groups in other pregnancy outcomes, such as preterm birth, placental abruption, placenta previa, low Apgar score, and postpartum bleeding with transfusion (Table 2). During 2nd trimester target ultrasonography scanning, different types of large placental lake were found. They were phenotypically classified as 4 types (retroplacental type, subchorionic type, full thickness type, and lake previa type) (Fig. 2). Clinical data in pregnancies with persistent large placental lakes (group IV) are presented in Table 3. After delivery, each placenta was examined. There were no definite pathologic lesions in the placentas obtained from groups I to III. In group IV, the size of placental lake was pathologically measured and compared with the sonographic one. There was no difference in size of placental lake between the pathological and sonographic measurements. Three cases were delivered by cesarean section because of placenta
Fig. 2. Four types of large placental lakes. Transabdominal and transvaginal ultrasonography for large placental lakes revealed several types of lakes (arrowheads): A. Retroplacental type, 5.6 cm 4.3 cm 1.5 cm; B. Subchorionic type, 7.7 cm 3.5 cm 1.8 cm; C. Full thickness type, 10.9 cm 8.0 cm 5.4 cm; D. Lake previa type, 6.3 cm 3.2 cm 2.5 cm.
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Table 2 Pregnancy outcomes in groups I–IV. I
Group Small for gestational age (<10 percentile) Preterm birth Placental abruption Placenta previa Low Apgar score (<7 at 5 min) Admission to the NICU Postpartum bleeding with transfusion
II *
3 1 0 1 0 1 1
7 1 0 1 0 1 1
III
IV
1 1 0 0 0 0 0
6* 2 0 2 1 3* 1
Data are presented as number of cases. NICU: neonatal intensive care unit. * Fisher’s exact test, p < 0.05; statistically significant.
Table 3 Clinical data in 11 pregnancies with persisted large placental lakes at 3rd semester follow up (group IV). Maternal age (years)
Placental lake Type
Sonographic size (cm)
Pathologic size (cm)
1 2 3 4 5 6
32 35 34 29 37 35
Subchorionic Lake previa Retroplacental Full thickness Retroplacental Full thickness
7.9 5.2 2.1 5.4 3.8 2.6 5.6 4.3 1.5 8.5 5.3 2.6 5.5 3.5 1.9 10.9 8.0 5.4
7 8
32 40
Full thickness Lake previa
9 10 11
37 30 29
Subchorionic Subchorionic Full thickness
No.
Birth weight (Kg)
5 min Apgar
Delivery weeks
Delivery mode
Pregnancy outcomes
8.3 4.9 2.3 6.5 3.9 2.2 5.5 5.3 2.1 8.9 6.4 2.1 6.4 4.3 3.5 9.5 8.9 3.4
3.11 2.25 3.18 2.54 3.23 1.41
8 9 9 8 9 6
39 37 39 38 38 33
SVD C/sec SVD SVD SVD C/sec
8.9 4.9 4.8 6.3 3.2 2.5
9.6 5.5 4.2 7.6 4.2 3.1
2.04 2.95
9 8
37 36
SVD C/sec
7.7 3.5 1.8 5.9 3.8 2.3 7.5 5.6 2.3
6.4 4.3 2.1 5.5 4.3 2.4 6.9 4.6 2.1
3.45 2.68 2.73
9 8 9
40 40 39
SVD SVD SVD
NS Placenta previa, SGA, NICU NS SGA NS Preterm labor, fetal distress, SGA, NICU SGA, NICU Placenta previa, postpartum bleeding NS SGA SGA
NS: no specific results, C/sec: cesarean section, SVD: spontaneous vaginal delivery, SGA: small for gestational age, NICU: neonatal intensive care unit admission.
previa and fetal distress. Eight pregnant women were delivered by normal spontaneous vaginal delivery. Unusually, case 8 with large lake previa had massive postpartum bleeding after cesarean section, and cesarean hysterectomy was performed. 4. Comment This study showed that the size of the placental lakes was related to adverse pregnancy outcome, especially small-forgestational-age status. Though there has been variation in detection rates due to unclear criteria for the diagnosis of placental lake, the detection rate in this study was 8.7%, which is within the previously range of 2.2–17.8% [4,5]. Previous studies have reported that placental lakes were not correlated with adverse pregnancy outcomes [4–6]. Although those studies were based on large unselected population samples, the size of the placental lake was not clearly defined and measured. Several case reports have shown that pregnancies with large placental lakes resulted in intrauterine growth restriction and sudden intrauterine death [7,8,11,12]. Though there has been no definition or explanation for a large placental lake, the placental lakes found in those case reports were at least over 5 cm in diameter. Therefore, in this study, when the maximum length of the lake was above 5 cm, we defined it as a large placental lake, and after the division of the patients into groups, we compared the outcomes between groups. To diagnose the placental lake and evaluate its effects, we had to consider the following criteria. First, it is essential to discriminate between the placental lake and other hypoechoic or anechoic lesions, such as subchorionic fibrin deposition, perivillous fibrin deposition, intervillous thrombosis, subchorial thrombosis, and placental infarcts. Second, it is crucial to confirm whether the placental lake exists at the 3rd trimester. In the current study, the
placental lakes of 71 cases shrank or disappeared at the 3rd trimester follow-up ultrasonography and this seemed to have little effect on pregnancy outcome. Villous vascularity in the placental bed is associated with various maternal–fetal conditions. Soma et al. reported that chorangiosis was frequently observed in the placenta of women from the Himalayas, suggesting that villus hypervascularization was caused by a chronic hypoxic state at extremely high altitude [13]. Chorangiosis or villous hypervascularization in the terminal villi might suggest the presence or a history of unidentified disturbances in feto-maternal oxygen exchange. Pre-eclampsia is a pregnancy disorder with hypertension and proteinuria associated with impoverished chorionic villous development and fetoplacental angiogenesis, when the fetus is growth restricted [14]. When fetal growth is normal, branching angiogenesis is increased and the villous capillary loops can be hyper-ramified with irregular and narrow lumina [15,16]. Placental lakes are known as homogenous, anechoic, avillous vascular space in the placenta [3]. Therefore, considering the effect of villous vascularity in the placental bed during pregnancy, it is possible to explain that the larger the avillous area is, the more the fetal-maternal exchange is disturbed and the fetal growth is restricted. Some studies have shown that umbilical artery Doppler values may be an indicator of SGA. In our studies, there was no correlation between the incidence of SGA and abnormal umbilical artery Doppler values. There is an explanation for this discordance. Following analysis of complicated pregnancies, fetal hypoxia has been classed as preplacental, uteroplacental or postplacental in origin [17]. In preplacental hypoxia (high altitude, maternal anemia), maternal blood entering the intervillous space is hypoxemic with potential consequences of hypoxia for the mother, placenta and fetus. In uteroplacental hypoxia (late-onset pre-eclampsia, SGA with persisting end diastolic flow in umbilical arteries), maternal blood is normoxic
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but flow into the intervillous space is heterogeneous and locally compromised. Postplacental hypoxia (pre-eclampsia with absent or reversed end diastolic flow, SGA with absent or reversed end diastolic flow) is characterized also by maternal normoxemia coupled with normal or reduced intervillous blood flow [18]. So, SGA cases enrolled in this study may have had uteroplacental hypoxia due to placental pathology. In cases of placental lakes, the mode of delivery has been usually determined according to a standard obstetrical care program, because of the rather good prognosis [4]. In some case reports, however, elective cesarean section was performed for huge placental lake, due to the risk of rupture during spontaneous vaginal delivery and uncontrollable massive bleeding after the separation of the placenta [9,19]. Though the size of placental lakes included in this study was a little smaller than in one of those case reports, most of the women enrolled in our study were delivered vaginally, except two cases of placenta previa and one of fetal distress. Of course, the results of this study do not mean that all pregnancies with large placental lakes should be delivered vaginally. It is necessary to consider elective cesarean section when a large placental lake is found. Although some previous studies showed that the placental lake was related to placental infarct, intervillous thrombosis, and decidual cysts, which may be the cause of the lake, its etiology is still uncertain [20,21]. In a very recent study, Cooley et al. showed that there was a significant association between placental lakes and threatened first trimester loss [22]. In our study, we found 113 pregnant women with placental lakes at the time of routine 2nd trimester ultrasonography scan. Among these cases, 27 (23.9%) had experienced vaginal bleeding in the first trimester and this result is statistically similar to results from the previous study [22]. Therefore, the current study supports the association between 2nd trimester placental lake and threatened miscarriage. For patients with significant intraplacental hemorrhage, it is reasonable to suggest that this could produce ‘holes’ in the placenta, which are naturally replaced by venous lakes persisting even after the hemorrhage resolves. This situation may reflect underlying placental or utero-placental abnormalities. A number of limitations of the present study should be noted. First, the definition of large placental lake used in this study has to be confirmed by further studies. Second, the incidence of admissions to the NICU was higher in group IV, compared with the other groups. Three cases of admission to NICU were SGAs, however, so admission to NICU was not an independent factor of pregnancy outcome. Third, the number of cases enrolled in this study was relatively small and more studies of the placental lake must be done. Despite the limitations of the this study, we were able to show an effect of size of placental lake on pregnancy outcome, which was different from previous studies that only compared pregnancy outcomes according to the existence of placental lake. In conclusion, this study showed that large placental lakes (>5 cm) were correlated with small-for-gestational-age status. Thus, if a large placental lake is identified in the 2nd trimester, a growth scan early in the 3rd trimester should be considered. If that scan shows the fetus to be in the small-for-gestational-age range, appropriate surveillance should be instituted for the remainder of the pregnancy. Further longitudinal studies on placental lake
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measured by 3D volume ultrasonography and MRI are under way to evaluate whether it is a clinically useful indicator of the adverse pregnancy outcome. Acknowledgement This work was supported by Konkuk University in 2012. References [1] Jauniaux E. Placental ultrasonographic measurement: what can be learn and is it worth doing routinely. Ultrasound Obstet Gynecol 1992;2:241–2. [2] Harris RD, Cho C, Wells A. Sonography of placenta with emphasis on pathological correlation. Semin Ultrasound CT MRI 1996;17:66–89. [3] Jauniaux E, Moscoso G, Campbell S, Gibb D, Driver M, Nicolaides KH. Correlation of ultrasound and pathologic findings of placental anomalies in pregnancies with elevated maternal serum alpha-fetoprotein. Eur J Obstet Gynecol Reprod Biol 1990;37:219–30. [4] Thompson MO, Vines SK, Aquilina J, Wathen NC, Harrington K. Are placental lakes of any clinical significance. Placenta 2002;23:685–90. [5] Reis NS, Brizot ML, Schultz R, Nomura RM, Zugaib M. Placental lakes on sonographic examination: correlation with obstetric outcome and pathologic findings. J Clin Ultrasound 2005;33:67–71. [6] Harris RD, Simpson WA, Pet LR, Marin-Padilla M, Crow HC. Placental hypoechoic–anechoic areas and infarction: sonographic–pathologic correlation. Radiology 1990;176:75–80. [7] Castaner JC, D’Alton ME. A large placental venous lake. Curr Opin Obstet Gynecol 1995;7:151–5. [8] Has R, Yu¨ksel A, Gu¨nay S, Aydinhan E, Ozgu¨n T. Antenatal sonographic detection of an unusual placental lake under the cord insertion. Arch Gynecol Obstet 2005;271:59–61. [9] Morikawa M, Cho K, Kataoka S, et al. Magnetic resonance image findings of placental lake: report of two cases. Prenat Diagn 2005;25:250–2. [10] Seo K, Park YW, Park TK. Birth weight distribution by gestational age and constructing cut-off value for fetal growth retardation: their statistical consideration. Korean J Obstet Gynecol 1989;32:530–40. [11] Kojima K, Suzuki Y, Makino A, Murakami I, Suzumori K. A case of massive subchorionic thrombohematoma diagnosed by ultrasonography and magnetic resonance imaging. Fetal Diagn Ther 2001;16:57–60. [12] Hong SC, Yoo SW, Kim T, et al. Prenatal diagnosis of a large subchorionic placental cyst with intracystic hematomas. A case report. Fetal Diagn Ther 2007;22:259–63. [13] Soma H, Hata T, Oguro T, Fujita K, Kudo M, Vaidya U. Characteristics of histopathological and ultrastructural features of placental villi in pregnant Nepalese women. Med Mol Morphol 2005;38:92–103. [14] Mayhew TM, Wijesekara J, Baker PN, Ong SS. Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia. Placenta 2004;25: 829–33. [15] Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis: III, changes in complicated pregnancies. Placenta 2004;25:127–39. [16] Resta L, Capobianco C, Marzullo A, et al. Confocal laser scanning microscope study of terminal villi vessels in normal term and pre-eclamptic placentas. Placenta 2006;27:735–9. [17] Kingdom JCP, Kaufmann P. Oxygen and placental villous development: origins of fetal hypoxia. Placenta 1997;18:613–21. [18] Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta 2004;25:127–39. [19] Muramatsu K, Itoh H, Yamasaki T, et al. A case of a huge placental lake; prenatal differential diagnosis and clinical management. J Obstet Gynaecol Res 2010;36:165–9. [20] Jauniaux E, Avni FE, Elkhazen N, Wilkin P, Hustin J. Morphologic study of ultrasonic placental anomalies in the second half of pregnancy. J Gynecol Obstet Biol Reprod 1989;18:601–13. [21] Spirt BA, Gordon LP, Kagan EH. Intervillous thrombosis: sonographic and pathologic correlation. Radiology 1983;147:197–200. [22] Cooley SM, Donnelly JC, Walsh T, McMahon C, Gillan J, Geary MP. The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population. J Matern Fetal Neonatal Med 2011;24:493–7.