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The association between isolated oligohydramnios at term and placental pathology in correlation with pregnancy outcomes
Placenta 90 (2020) 37–41
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Placenta journal homepage: http://www.elsevier.com/locate/placenta
The association between isolated oligohydramnios at term and placental pathology in correlation with pregnancy outcomes Hadas Miremberg a, c, *, Ehud Grinstein a, c, Hadas Ganer Herman a, c, Cindy Marelly a, c, Elad Barber a, c, Letizia Schreiber b, c, Jacob Bar a, c, Michal Kovo a, c, Eran Weiner a, c a b c
Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, Holon, Israel and Sackler School of Medicine, Israel Pathology, The Edith Wolfson Medical Center, Holon, Israel and Sackler School of Medicine, Israel Tel-Aviv University, Israel
A R T I C L E I N F O
A B S T R A C T
Keywords: Isolated term oligohydramnios Placental pathology Placental insufficiency
Introduction: Isolated term oligohydramnios (ITO) is an obstetrical complication of which the etiology, man agement, and clinical importance are controversial. In attempt to deepen our understanding, we aimed to study placental pathology and pregnancy outcomes in pregnancies complicated by ITO. Materials and methods: – Maternal demographics, neonatal outcomes, and placental histopathology reports of all pregnancies complicated by ITO at 370/7 to 410/7 weeks were reviewed. Excluded were cases complicated by hypertensive disorders, intrauterine fetal growth restriction, placental abruption, and deliveries of undiagnosed small for gestational age neonates. Results were compared between the ITO group and a control group matched for gestational age and mode of delivery. Placental lesions were classified according to the current “Amsterdam” criteria. Composite adverse neonatal outcome was defined as one or more of the following early complications: neonatal intensive care unit admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis, or death. Results: The study group included 108 patients with ITO that were compared to matched controls. Placentas from the ITO group were characterized by higher rates of placental weights <10th centile (p < 0.001), abnormal cord insertion (p < 0.001), and maternal vascular malperfusion (MVM) lesions (p < 0.001). Neonates from the ITO group had lower birth weights (p < 0.002), and worse composite adverse neonatal outcome (p ¼ 0.028) compared to controls. Conclusion: – The current study demonstrates higher rates of placental MVM lesions, and worse neonatal outcome in pregnancies complicated by ITO. These novel findings suggest that ITO should be seen as part of the “placental insufficiency” spectrum.
1. Introduction Oligohydramnios is an obstetric complication with several defini tions: amniotic fluid index (AFI) measurement of less than 5 cm, or less than the 5th centile for gestational age, or a single deepest pocket (SDP) of less than 2 cm [1–3]. SDP is considered in some studies to be a better way to diagnose oligohydramnios [4,5]. Isolated term oligohydramnios (ITO) [6,7] is defined as the new appearance of reduced amniotic fluid at term in the absence of fetal growth restriction (FGR), structural or chromosomal abnormalities, or maternal morbidities such as preeclampsia. Some studies [7,8] demon strated that ITO is associated with adverse neonatal outcomes including
neonatal intensive care unit (NICU) admissions, meconium staining of the amniotic fluid, meconium aspiration syndrome (MAS), and low Apgar scores, while other studies [6,9] failed to demonstrate this asso ciation. In addition, there are numerous studies that demonstrate that ITO is associated with a higher rate of interventions such as labor in duction and cesarean deliveries [6,8,10]. The recommended manage ment of ITO is controversial and there are no uniform recommendations regarding the appropriate management [11]. In pregnancies complicated by FGR, the presence of oligohydramnios is a significant risk factor for adverse neonatal outcomes [12,13]. Moreover, in the setting of FGR, placental pathology [12] directly cor relates with histological features of placental under-perfusion and fetal
* Corresponding author. Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, P.O Box 5, Holon, 58100, Israel. E-mail address: [email protected] (H. Miremberg). https://doi.org/10.1016/j.placenta.2019.12.004 Received 16 September 2019; Received in revised form 22 November 2019; Accepted 3 December 2019 Available online 4 December 2019 0143-4004/© 2019 Elsevier Ltd. All rights reserved.
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smoking, pregnancies achieved by assisted reproductive techniques, gestational age at delivery, mode of delivery (Cesarean delivery vs. vaginal delivery), meconium stained amniotic fluid, postpartum hem orrhage (PPH), and length of maternal hospitalization. Immediately after birth, all neonates were examined by pediatri cians. Birth weight percentiles for gestational age were assigned using the updated local growth charts [14]. The following data were collected from the neonatal records: APGAR scores, cord blood pH, neonatal intensive care unit (NICU) admissions, sepsis (positive blood or cere brospinal fluid culture), need for blood transfusion, need for photo therapy, respiratory distress syndrome, need for mechanical ventilation or support, necrotizing enterocolitis, intraventricular hemorrhage (all grades), hypoxic ischemic encephalopathy, seizures, and death.
vascular damage. According to our knowledge, there are no studies published with the aim to investigate placental pathology in pregnancies complicated by ITO, in the absence of FGR, preeclampsia, and other obstetric complications. Thus, our aim in this study was to deepen our understanding of pregnancies complicated by this entity, by comparing pregnancy outcomes and placental pathology in pregnancies compli cated by ITO vs. matched controls. We hypothesized that ITO would be associated with a higher rate of placental maternal vascular malperfu sion lesions reflecting the position of ITO as part of the “placental insufficiency” spectrum. 2. Material and methods Retrospective review was performed of the medical records of all pregnancies complicated by ITO in a single tertiary center between January 2009 to December 2017. In our current study oligohydramnios was defined as AFI<5 cm [3]. In our institutional protocol we recom mend induction of labor only after 40 gestational weeks in cases of ITO. After the diagnosis of ITO close surveillance is recommended with an ultrasound for fetal wellbeing and a non-stress test twice a week. Mode of delivery is determined as per routine obstetrical indications. In all cases, the placentas were sent to histopathology for evaluation, in accordance with our departmental policy that routinely performs placental analyses in all complicated pregnancies, and randomly also in women with uncomplicated pregnancies for research purposes. Our study group included pregnancies complicated by ITO that were randomly matched, in a 1:1 ratio, to the control group. In attempt to isolate the effect of ITO, the control group was matched for year of de livery, gestational age at delivery, and mode of delivery, which could each potentially affect placental pathology. Excluded were all cases of membrane rupture or suspected amniotic fluid leakage. In addition, we excluded all cases complicated by preeclampsia or other hypertensive disorders, FGR, placental abruption, thrombophilia, and deliveries of undiagnosed small for gestational age (SGA) neonates defined as neonatal birthweight � 10th percentile. For the purpose of this study pregnancy outcome and placental pathology reports were compared between pregnancies with ITO and the control group. Approval was obtained from the local ethics committee (decision number 0042-10WOMC).
2.2. Placental examination All placental full histopathological evaluations were performed by a single pathologist (author L.S) using our standard protocol as previously reported by us [15–18]. Placental lesions were classified according to the “Amsterdam” criteria [19,20]. Briefly, placental weight was deter mined 24 h after delivery, and the percentile was determined according to placental weight charts [21]. Each placenta was fixed in formalin, and at least 5 samples were embedded in paraffin blocks for microscopic assessment. Maternal vascular malperfusion (MVM) included: placental hemor rhages (marginal, and retro-placental hematoma), placental weight <10th percentile, vascular changes associated with maternal malper fusion (acute atherosis and mural hypertrophy), and villous changes associated with maternal malperfusion (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, distal villous hypoplasia, and villous infarcts). Fetal vascular malperfusion (FVM) lesions are consistent with vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (villi with stromal vascular karyorrhexis and avascular villi). Findings consistent with chorioamnionitis were defined by the presence of an inflammatory neutrophil infiltrate at two or more sites on the chorionic plate and extra-placental membranes. Maternal inflam matory response (MIR), and fetal inflammatory response (FIR) were each divided into 3 stages according to the criteria adopted by the So ciety for Pediatric Pathology [20]. The umbilical cord was examined for the detection of abnormal coiling (hyper-coiling and under-coiling), and abnormal cord insertion. Coiling index was calculated as described by Strong et al. [22]. Abnormal cord insertion was defined as either vela mentous, or marginal insertion.
2.1. Data collection We collected the following data from the patient’s computerized medical records: age, gravidity, parity, body mass index (BMI kg/m2),
2.3. Statistical analysis
Table 1 Maternal characteristics of the study groups.
Maternal age (years) Maternal age > 35 Gestational age at delivery (weeks) Nulliparity BMI (kg/m2) ART Smoking Bleeding during pregnancy Antenatal corticosteroids Meconium in labor PPH, n (%) Maternal hospitalization (days)
ITO group (n ¼ 108)
Control group (n ¼ 108)
pvalue
30.6 � 5.4 20 (18.5) 39.5 � 1.3
�5.730.5 18 (16.6) 39.3 � 1.1
0.894 0.858 0.223
50 (46.3) 24.4 � 4.4 8 (7.4) 5 (4.6) 5 (4.6) 2 (1.8) 28 (25.9) 12 (11.1) 4.8 � 1.5
30 (27.8) 25.1 � 6.3 5 (4.6) 4 (3.7) 2 (1.8) 3 (2.8) 10 (9.3) 5 (4.6) 4.5 � 1.6
0.007 0.345 0.568 >.99 0.445 >.99 0.002 0.127 0.156
Data were analyzed with SPSS software, version 21.0 (SPSS Inc; Chicago, Illinois). Continuous variables are presented as median � standard deviation. Categorical variables are presented as rate (%). Continuous parameters were compared by Mann–Whitney’s U test and categorical variables by chi-square test or by Fisher exact test, as appropriate. P-value of <0.05 was considered statistically significant. Composite placental MVM lesions was defined as the presence of one or more of maternal vascular or villous lesions related to MVM including placental weight <10th percentile. Composite placental FVM lesions was defined as the presence of one or more fetal vascular or villous abnormalities related to FVM. Composite adverse neonatal outcome was defined as one or more of the following: NICU admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, NEC, or death. A multivariable regression analysis was performed to identify inde pendent associations with composite MVM lesions which served as the dependent variable while the study groups (ITO vs. controls), maternal age, gestational age at delivery, mode of delivery, smoking, and
All data are shown as number (%), mean � standard deviation or median (range), as appropriate. BMI- body mass index; ART-assisted reproductive technology; Antenatal corticosteroid treatment administrated between 24 and 34 weeks of gestation; PPH- post-partum hemorrhage. 38
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Table 2 Placental lesions in the study groups.
Placental weight (grams) Hypercoiled cord Hypocoiled cord Abnormal cord insertion Maternal vascular supply lesions Retro-placental hemorrhage Placental weight <10% percentile Vascular lesions related to maternal malperfusion Villous changes related to maternal malperfusion Composite maternal vascular supply lesions Fetal vascular supply lesions Vascular lesions consistent with FTOD Villous lesions consistent with FTOD Composite fetal vascular supply lesions Inflammatory lesions MIR stages 1–3 FIR stages 1–3
Table 3 Neonatal outcomes in the study groups.
ITO group (n ¼ 108)
Control group (n ¼ 108)
p-value
477 � 100 28 (25.9) 14 (12.9) 24 (22.2)
512 � 111 21 (19.4) 5 (4.6) 4 (3.7)
<0.001 0.329 0.052 <0.001
3 (2.8) 69 (63.8)
7 (6.5) 41 (37.9)
0.332 <0.001
3 (2.8)
2 (1.8)
<.99
31 (28.7)
18 (16.6)
0.050
75 (69.4)
42 (38.8)
<0.001
6 (5.5)
5 (4.6)
>.99
4 (3.7)
9 (8.3)
0.251
10 (9.3)
13 (12)
0.659
24 (22.2) 10 (9.3)
14 (12.9) 6 (5.5)
0.197 0.437
Neonatal hospitalization (days) Birth weight (grams) NICU admission 5 min Apgar � 7 Umbilical Ph � 7.1 Respiratory morbidity * Cerebral morbidity ** Neonatal sepsis Necrotizing enterocolitis Phototherapy Neonatal death Composite adverse neonatal outcome
ITO group (n ¼ 108)
Control group (n ¼ 108)
pvalue
4.67 � 1.6
4.4 � 1.6
0.169
3180 � 435.7 25 (23.1) 0 0 7 (6.5) 0 0 0 4 (3.7) 0 29 (26.8)
3395 � 551.4 11 (10.2) 0 0 5 (4.6) 0 0 0 3 (2.8) 0 15 (13.9)
0.002 0.016 >.99 >.99 0.767 >.99 >.99 >.99 >.99 >.99 0.028
All data are shown as number (%), mean � standard deviation, or median (range), as appropriate. NICU- neonatal intensive care unit. Respiratory morbidity includes-presence of respiratory distress syndrome, or mechanical ventilation or need for respiratory support. Cerebral morbidity includespresence of intra-ventricular hemorrhage (all grades), or seizures or hypoxicischemic encephalopathy.
ITO group had a significantly lower birthweight (3180 � 435.7 vs. 3395 � 551.4 g, p ¼ 0.002), as compared to the control group. Composite adverse neonatal outcome was also significantly higher in the ITO group as compared to control group (26.8% vs 13.9% p ¼ 0.028). In multi variate analysis composite adverse neonatal outcome was associated with ITO (aOR ¼ 1.4, 95% CI 1.2–3.6) and the combination of MVM and abnormal cord insertion (aOR ¼ 1.2, 95% CI 1.1–4.0) independent of background confounders.
Continuous variables are presented as mean � SD and categorical variables as n (%). FTOD-fetal thrombo-occlusive disease; MIR - maternal inflammatory response; FIR - fetal inflammatory response.
nulliparity served as independent variables. Another multivariable regression analysis was performed to identify independent associations with composite adverse neonatal outcome which served as the dependent variable while the study groups (ITO vs. controls), maternal age, gestational age at delivery, mode of delivery, smoking, nulliparity, placental MVM lesions, and cord abnormalities served as independent variables.
4. Discussion ITO is an obstetrical challenge that obstetricians encounter every day worldwide due to controversial and conflicting data [6–8,23–25]. This confusion arises from differences between studies in definitions of oli gohydramnios, the definition of “isolated”, the definition of adverse neonatal outcomes, and small sample sizes. We believe that part of this confusion is the lack of understanding whether ITO is part of the “placental insufficiency” spectrum, as some believe or whether it should be perceived as part of the physiological manifestations of term preg nancy, as others believe. In attempt to deepen our understanding of this entity, in the current study we aimed to investigate the association between ITO and different placental histopathological lesions and neonatal outcomes. Our study has several important findings: 1) Maternal background characteristics did not significantly differ in cases of ITO vs. controls. 2) Placental from the ITO group were associated with higher rates of placental weights <10th percentile, MVM lesions, and abnormal cord insertion, compared to controls. Importantly, ITO was associated with composite MVM le sions independent of background confounders. 3) Despite matched gestational age at delivery and despite that by definition we excluded all cases with SGA/FGR, neonates from the ITO group had significantly lower birthweights (approximately 200 g difference) and a higher rate of composite adverse neonatal outcome. Importantly, adverse neonatal outcome was associated with ITO and with the combination of MVM and abnormal cord insertion, independent of background confounders. Additionally, a recent study [26] demonstrated that placental MVM le sions correlated inversely with birthweight even in appropriate for age (AGA) neonates, this subgroup of normal weight neonates (similar to our study group) are in a higher risk of adverse outcome. Placental insufficiency and pregnancy complications such as hyper tensive diseases and fetal growth restriction correlate well with the presence of placental MVM lesions [27,28]. The most probable mecha nism of placental insufficiency is defective placentation and the
3. Results In total 108 pregnancies with ITO were included and were matched in a 1:1 ratio to the control group based on year of delivery, gestational age at delivery, and mode of delivery. As per study design (matching for mode of delivery) the rate of normal vaginal deliveries (33.3%), planned Cesarean deliveries (25.0%), and laboring Cesarean deliveries (41.7%) were similar between the groups. The maternal demographics, pregnancy, and delivery characteristics are presented in Table 1. The ITO group was characterized by a higher rate of nulliparity (46.3% vs. 27.8%, p ¼ 0.007). The rate of meconium stained amniotic fluid was also significantly higher in the ITO group as compared to the control group (25.9% vs 9.3%, p ¼ 0.002). There were no other significant differences between the groups. Placental characteristics are summarized in Table 2. Mean placental weight was significantly lower in the ITO group than the control group (p < 0.001). In addition, the ITO group had a higher rate of placental weight <10th percentile (p < 0.001). The ITO group had also a higher rate of composite MVM lesions as compared to the control group (69.1% vs. 38.8%, p < 0.001). Inflam matory lesions did not differ between the ITO group and the control group, both MIR and FIR, as well as the different stages and grades of the inflammatory responses. There were also no differences between the groups in the rate of FVM lesions. The ITO group had s significantly higher prevalence of abnormal cord insertion as compared to control group (22.2% vs. 3.7%, p < 0.001, respectively). In multivariate analysis ITO was associated with composite MVM lesions (aOR ¼ 1.8 95% CI 1.3–4.1) independent of background confounders. Table 3 present the neonatal outcome parameters. Neonates in the 39
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Fig. 1. Rates of placental maternal vascular malperfusion (MVM) lesions in different pregnancy complications related to “Placental insufficiency”.
inadequate remodeling of the spiral arteries causing placental malper fusion lesions. Spinillo A et al. [12] have shown that placentas from pregnancies with FGR in the presence of oligohydramnios had higher rates of placental MVM lesions as compared to growth restricted preg nancies without oligohydramnios. We designed the current study to investigate the “pure” association between oligohydramnios and placental lesions after excluding cases with other presentations of placental insufficiency (hypertensive disor ders, fetal growth restriction, placental abruptions) of which the man agement is usually more straightforward and well defined in the literature. Our study was carefully designed in the aim of identifying associations between ITO and histological manifestations of placental insufficiency. Our findings of a higher rate of placental MVM lesions, higher rate of placentas weight below the 10th percentile, and higher rates of abnormal cord insertion support our hypothesis that ITO is part of the “placental insufficiency spectrum” (Fig. 1). Our findings are in concordance with previous studies [7,8,29] that have shown a correla tion between oligohydramnios and adverse neonatal outcomes- and suggest placental malperfusion as a possible explanation. Our study is unique in several aspects. First, it is to the best of our knowledge, the first study that compared placental pathology in cases of ITO to controls. Second, we designed a study that “purifies” the association of ITO with placental pathological lesions. Third, this is a relatively large cohort study. Finally, a single pathologist (author L.S) performed all placental histopathology evaluations using the validated placental pathological criteria [20] and was blinded to the outcomes. The current study is not without limitations. First, due to its retro spective design, which allowed us to study only cases whose placentas were initially sent for pathological examination, unintended selection bias may have occurred. Second, a recent study published by Erez O. et al. [30] studied the occurrence of histopathological lesions from a large series of placentas of women with a normal pregnancy outcome. The rate of placental lesions (both vascular and inflammatory) was significantly higher in this study than in our control group. This differ ence can be attributed to population differences such as maternal obesity, ethnicity, maternal age, and Cesarean delivery rate, as well as the definition of “uncomplicated pregnancies”. Third, in attempt to isolate the effect of ITO on placental pathology, the study group and control group were matched to the mode of de livery, as mode of delivery itself is associated with differences in
placental pathology [30,31]. This design did not allow us to investigate whether ITO is associated with Cesarean delivery during trial of labor vs. controls. Lastly, even though the use of a composite outcome may be seemed as a limitation of this study, we believe that the use was required due to the rarity of the individual components of the composite. In conclusion, as we hypothesized, isolated oligohydramnios at term was associated with placental vascular malperfusion lesions as well as adverse neonatal outcome. We believe that ITO should be seen as part of the “placental insufficiency” spectrum (probably in a milder form than preeclampsia and fetal growth restriction-Fig. 1). Our ongoing research focuses on demonstrating characteristic Doppler studies in the umbilical artery and middle cerebral artery in cases of ITO vs. controls and we will publish the results as they become available. Importantly, our study did not aim to suggest the optimal management of ITO and obviously large randomized trials are needed to study the appropriate management of this obstetric complication. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest I declare there is not any financial relationship with any organization or any conflict of interest to report. References [1] T.R. Moore, J.E. Cayle, The amniotic fluid index in normal human pregnancy, Am. J. Obstet. Gynecol. 162 (1990) 1168–1173, https://doi.org/10.1016/0002-9378 (90)90009-V. [2] E.F. Magann, M. Sanderson, J.N. Martin, S. Chauhan, The amniotic fluid index, single deepest pocket, and two-diameter pocket in normal human pregnancy, Am. J. Obstet. Gynecol. 182 (2000) 1581–1588, https://doi.org/10.1067/ mob.2000.107325. [3] C.R. Harman, Amniotic fluid abnormalities, Semin. Perinatol. 32 (2008) 288–294, https://doi.org/10.1053/j.semperi.2008.04.012. [4] N. Af, A. Ya, Amniotic fluid index versus single deepest vertical pocket as a screening test for preventing adverse pregnancy outcome ( Review ) summary of findings for the main comparison, Cochrane Database Syst. Rev. (2009), https:// doi.org/10.1002/14651858.CD006593.pub2. www.cochranelibrary.com. [5] S. Kehl, A. Schelkle, A. Thomas, A. Puhl, K. Meqdad, B. Tuschy, S. Berlit, C. Weiss, C. Bayer, J. Heimrich, U. Dammer, E. Raabe, M. Winkler, F. Faschingbauer, M.
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Contents lists available at ScienceDirect
Placenta journal homepage: http://www.elsevier.com/locate/placenta
The association between isolated oligohydramnios at term and placental pathology in correlation with pregnancy outcomes Hadas Miremberg a, c, *, Ehud Grinstein a, c, Hadas Ganer Herman a, c, Cindy Marelly a, c, Elad Barber a, c, Letizia Schreiber b, c, Jacob Bar a, c, Michal Kovo a, c, Eran Weiner a, c a b c
Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, Holon, Israel and Sackler School of Medicine, Israel Pathology, The Edith Wolfson Medical Center, Holon, Israel and Sackler School of Medicine, Israel Tel-Aviv University, Israel
A R T I C L E I N F O
A B S T R A C T
Keywords: Isolated term oligohydramnios Placental pathology Placental insufficiency
Introduction: Isolated term oligohydramnios (ITO) is an obstetrical complication of which the etiology, man agement, and clinical importance are controversial. In attempt to deepen our understanding, we aimed to study placental pathology and pregnancy outcomes in pregnancies complicated by ITO. Materials and methods: – Maternal demographics, neonatal outcomes, and placental histopathology reports of all pregnancies complicated by ITO at 370/7 to 410/7 weeks were reviewed. Excluded were cases complicated by hypertensive disorders, intrauterine fetal growth restriction, placental abruption, and deliveries of undiagnosed small for gestational age neonates. Results were compared between the ITO group and a control group matched for gestational age and mode of delivery. Placental lesions were classified according to the current “Amsterdam” criteria. Composite adverse neonatal outcome was defined as one or more of the following early complications: neonatal intensive care unit admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis, or death. Results: The study group included 108 patients with ITO that were compared to matched controls. Placentas from the ITO group were characterized by higher rates of placental weights <10th centile (p < 0.001), abnormal cord insertion (p < 0.001), and maternal vascular malperfusion (MVM) lesions (p < 0.001). Neonates from the ITO group had lower birth weights (p < 0.002), and worse composite adverse neonatal outcome (p ¼ 0.028) compared to controls. Conclusion: – The current study demonstrates higher rates of placental MVM lesions, and worse neonatal outcome in pregnancies complicated by ITO. These novel findings suggest that ITO should be seen as part of the “placental insufficiency” spectrum.
1. Introduction Oligohydramnios is an obstetric complication with several defini tions: amniotic fluid index (AFI) measurement of less than 5 cm, or less than the 5th centile for gestational age, or a single deepest pocket (SDP) of less than 2 cm [1–3]. SDP is considered in some studies to be a better way to diagnose oligohydramnios [4,5]. Isolated term oligohydramnios (ITO) [6,7] is defined as the new appearance of reduced amniotic fluid at term in the absence of fetal growth restriction (FGR), structural or chromosomal abnormalities, or maternal morbidities such as preeclampsia. Some studies [7,8] demon strated that ITO is associated with adverse neonatal outcomes including
neonatal intensive care unit (NICU) admissions, meconium staining of the amniotic fluid, meconium aspiration syndrome (MAS), and low Apgar scores, while other studies [6,9] failed to demonstrate this asso ciation. In addition, there are numerous studies that demonstrate that ITO is associated with a higher rate of interventions such as labor in duction and cesarean deliveries [6,8,10]. The recommended manage ment of ITO is controversial and there are no uniform recommendations regarding the appropriate management [11]. In pregnancies complicated by FGR, the presence of oligohydramnios is a significant risk factor for adverse neonatal outcomes [12,13]. Moreover, in the setting of FGR, placental pathology [12] directly cor relates with histological features of placental under-perfusion and fetal
* Corresponding author. Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, P.O Box 5, Holon, 58100, Israel. E-mail address: [email protected] (H. Miremberg). https://doi.org/10.1016/j.placenta.2019.12.004 Received 16 September 2019; Received in revised form 22 November 2019; Accepted 3 December 2019 Available online 4 December 2019 0143-4004/© 2019 Elsevier Ltd. All rights reserved.
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smoking, pregnancies achieved by assisted reproductive techniques, gestational age at delivery, mode of delivery (Cesarean delivery vs. vaginal delivery), meconium stained amniotic fluid, postpartum hem orrhage (PPH), and length of maternal hospitalization. Immediately after birth, all neonates were examined by pediatri cians. Birth weight percentiles for gestational age were assigned using the updated local growth charts [14]. The following data were collected from the neonatal records: APGAR scores, cord blood pH, neonatal intensive care unit (NICU) admissions, sepsis (positive blood or cere brospinal fluid culture), need for blood transfusion, need for photo therapy, respiratory distress syndrome, need for mechanical ventilation or support, necrotizing enterocolitis, intraventricular hemorrhage (all grades), hypoxic ischemic encephalopathy, seizures, and death.
vascular damage. According to our knowledge, there are no studies published with the aim to investigate placental pathology in pregnancies complicated by ITO, in the absence of FGR, preeclampsia, and other obstetric complications. Thus, our aim in this study was to deepen our understanding of pregnancies complicated by this entity, by comparing pregnancy outcomes and placental pathology in pregnancies compli cated by ITO vs. matched controls. We hypothesized that ITO would be associated with a higher rate of placental maternal vascular malperfu sion lesions reflecting the position of ITO as part of the “placental insufficiency” spectrum. 2. Material and methods Retrospective review was performed of the medical records of all pregnancies complicated by ITO in a single tertiary center between January 2009 to December 2017. In our current study oligohydramnios was defined as AFI<5 cm [3]. In our institutional protocol we recom mend induction of labor only after 40 gestational weeks in cases of ITO. After the diagnosis of ITO close surveillance is recommended with an ultrasound for fetal wellbeing and a non-stress test twice a week. Mode of delivery is determined as per routine obstetrical indications. In all cases, the placentas were sent to histopathology for evaluation, in accordance with our departmental policy that routinely performs placental analyses in all complicated pregnancies, and randomly also in women with uncomplicated pregnancies for research purposes. Our study group included pregnancies complicated by ITO that were randomly matched, in a 1:1 ratio, to the control group. In attempt to isolate the effect of ITO, the control group was matched for year of de livery, gestational age at delivery, and mode of delivery, which could each potentially affect placental pathology. Excluded were all cases of membrane rupture or suspected amniotic fluid leakage. In addition, we excluded all cases complicated by preeclampsia or other hypertensive disorders, FGR, placental abruption, thrombophilia, and deliveries of undiagnosed small for gestational age (SGA) neonates defined as neonatal birthweight � 10th percentile. For the purpose of this study pregnancy outcome and placental pathology reports were compared between pregnancies with ITO and the control group. Approval was obtained from the local ethics committee (decision number 0042-10WOMC).
2.2. Placental examination All placental full histopathological evaluations were performed by a single pathologist (author L.S) using our standard protocol as previously reported by us [15–18]. Placental lesions were classified according to the “Amsterdam” criteria [19,20]. Briefly, placental weight was deter mined 24 h after delivery, and the percentile was determined according to placental weight charts [21]. Each placenta was fixed in formalin, and at least 5 samples were embedded in paraffin blocks for microscopic assessment. Maternal vascular malperfusion (MVM) included: placental hemor rhages (marginal, and retro-placental hematoma), placental weight <10th percentile, vascular changes associated with maternal malper fusion (acute atherosis and mural hypertrophy), and villous changes associated with maternal malperfusion (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, distal villous hypoplasia, and villous infarcts). Fetal vascular malperfusion (FVM) lesions are consistent with vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (villi with stromal vascular karyorrhexis and avascular villi). Findings consistent with chorioamnionitis were defined by the presence of an inflammatory neutrophil infiltrate at two or more sites on the chorionic plate and extra-placental membranes. Maternal inflam matory response (MIR), and fetal inflammatory response (FIR) were each divided into 3 stages according to the criteria adopted by the So ciety for Pediatric Pathology [20]. The umbilical cord was examined for the detection of abnormal coiling (hyper-coiling and under-coiling), and abnormal cord insertion. Coiling index was calculated as described by Strong et al. [22]. Abnormal cord insertion was defined as either vela mentous, or marginal insertion.
2.1. Data collection We collected the following data from the patient’s computerized medical records: age, gravidity, parity, body mass index (BMI kg/m2),
2.3. Statistical analysis
Table 1 Maternal characteristics of the study groups.
Maternal age (years) Maternal age > 35 Gestational age at delivery (weeks) Nulliparity BMI (kg/m2) ART Smoking Bleeding during pregnancy Antenatal corticosteroids Meconium in labor PPH, n (%) Maternal hospitalization (days)
ITO group (n ¼ 108)
Control group (n ¼ 108)
pvalue
30.6 � 5.4 20 (18.5) 39.5 � 1.3
�5.730.5 18 (16.6) 39.3 � 1.1
0.894 0.858 0.223
50 (46.3) 24.4 � 4.4 8 (7.4) 5 (4.6) 5 (4.6) 2 (1.8) 28 (25.9) 12 (11.1) 4.8 � 1.5
30 (27.8) 25.1 � 6.3 5 (4.6) 4 (3.7) 2 (1.8) 3 (2.8) 10 (9.3) 5 (4.6) 4.5 � 1.6
0.007 0.345 0.568 >.99 0.445 >.99 0.002 0.127 0.156
Data were analyzed with SPSS software, version 21.0 (SPSS Inc; Chicago, Illinois). Continuous variables are presented as median � standard deviation. Categorical variables are presented as rate (%). Continuous parameters were compared by Mann–Whitney’s U test and categorical variables by chi-square test or by Fisher exact test, as appropriate. P-value of <0.05 was considered statistically significant. Composite placental MVM lesions was defined as the presence of one or more of maternal vascular or villous lesions related to MVM including placental weight <10th percentile. Composite placental FVM lesions was defined as the presence of one or more fetal vascular or villous abnormalities related to FVM. Composite adverse neonatal outcome was defined as one or more of the following: NICU admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, NEC, or death. A multivariable regression analysis was performed to identify inde pendent associations with composite MVM lesions which served as the dependent variable while the study groups (ITO vs. controls), maternal age, gestational age at delivery, mode of delivery, smoking, and
All data are shown as number (%), mean � standard deviation or median (range), as appropriate. BMI- body mass index; ART-assisted reproductive technology; Antenatal corticosteroid treatment administrated between 24 and 34 weeks of gestation; PPH- post-partum hemorrhage. 38
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Table 2 Placental lesions in the study groups.
Placental weight (grams) Hypercoiled cord Hypocoiled cord Abnormal cord insertion Maternal vascular supply lesions Retro-placental hemorrhage Placental weight <10% percentile Vascular lesions related to maternal malperfusion Villous changes related to maternal malperfusion Composite maternal vascular supply lesions Fetal vascular supply lesions Vascular lesions consistent with FTOD Villous lesions consistent with FTOD Composite fetal vascular supply lesions Inflammatory lesions MIR stages 1–3 FIR stages 1–3
Table 3 Neonatal outcomes in the study groups.
ITO group (n ¼ 108)
Control group (n ¼ 108)
p-value
477 � 100 28 (25.9) 14 (12.9) 24 (22.2)
512 � 111 21 (19.4) 5 (4.6) 4 (3.7)
<0.001 0.329 0.052 <0.001
3 (2.8) 69 (63.8)
7 (6.5) 41 (37.9)
0.332 <0.001
3 (2.8)
2 (1.8)
<.99
31 (28.7)
18 (16.6)
0.050
75 (69.4)
42 (38.8)
<0.001
6 (5.5)
5 (4.6)
>.99
4 (3.7)
9 (8.3)
0.251
10 (9.3)
13 (12)
0.659
24 (22.2) 10 (9.3)
14 (12.9) 6 (5.5)
0.197 0.437
Neonatal hospitalization (days) Birth weight (grams) NICU admission 5 min Apgar � 7 Umbilical Ph � 7.1 Respiratory morbidity * Cerebral morbidity ** Neonatal sepsis Necrotizing enterocolitis Phototherapy Neonatal death Composite adverse neonatal outcome
ITO group (n ¼ 108)
Control group (n ¼ 108)
pvalue
4.67 � 1.6
4.4 � 1.6
0.169
3180 � 435.7 25 (23.1) 0 0 7 (6.5) 0 0 0 4 (3.7) 0 29 (26.8)
3395 � 551.4 11 (10.2) 0 0 5 (4.6) 0 0 0 3 (2.8) 0 15 (13.9)
0.002 0.016 >.99 >.99 0.767 >.99 >.99 >.99 >.99 >.99 0.028
All data are shown as number (%), mean � standard deviation, or median (range), as appropriate. NICU- neonatal intensive care unit. Respiratory morbidity includes-presence of respiratory distress syndrome, or mechanical ventilation or need for respiratory support. Cerebral morbidity includespresence of intra-ventricular hemorrhage (all grades), or seizures or hypoxicischemic encephalopathy.
ITO group had a significantly lower birthweight (3180 � 435.7 vs. 3395 � 551.4 g, p ¼ 0.002), as compared to the control group. Composite adverse neonatal outcome was also significantly higher in the ITO group as compared to control group (26.8% vs 13.9% p ¼ 0.028). In multi variate analysis composite adverse neonatal outcome was associated with ITO (aOR ¼ 1.4, 95% CI 1.2–3.6) and the combination of MVM and abnormal cord insertion (aOR ¼ 1.2, 95% CI 1.1–4.0) independent of background confounders.
Continuous variables are presented as mean � SD and categorical variables as n (%). FTOD-fetal thrombo-occlusive disease; MIR - maternal inflammatory response; FIR - fetal inflammatory response.
nulliparity served as independent variables. Another multivariable regression analysis was performed to identify independent associations with composite adverse neonatal outcome which served as the dependent variable while the study groups (ITO vs. controls), maternal age, gestational age at delivery, mode of delivery, smoking, nulliparity, placental MVM lesions, and cord abnormalities served as independent variables.
4. Discussion ITO is an obstetrical challenge that obstetricians encounter every day worldwide due to controversial and conflicting data [6–8,23–25]. This confusion arises from differences between studies in definitions of oli gohydramnios, the definition of “isolated”, the definition of adverse neonatal outcomes, and small sample sizes. We believe that part of this confusion is the lack of understanding whether ITO is part of the “placental insufficiency” spectrum, as some believe or whether it should be perceived as part of the physiological manifestations of term preg nancy, as others believe. In attempt to deepen our understanding of this entity, in the current study we aimed to investigate the association between ITO and different placental histopathological lesions and neonatal outcomes. Our study has several important findings: 1) Maternal background characteristics did not significantly differ in cases of ITO vs. controls. 2) Placental from the ITO group were associated with higher rates of placental weights <10th percentile, MVM lesions, and abnormal cord insertion, compared to controls. Importantly, ITO was associated with composite MVM le sions independent of background confounders. 3) Despite matched gestational age at delivery and despite that by definition we excluded all cases with SGA/FGR, neonates from the ITO group had significantly lower birthweights (approximately 200 g difference) and a higher rate of composite adverse neonatal outcome. Importantly, adverse neonatal outcome was associated with ITO and with the combination of MVM and abnormal cord insertion, independent of background confounders. Additionally, a recent study [26] demonstrated that placental MVM le sions correlated inversely with birthweight even in appropriate for age (AGA) neonates, this subgroup of normal weight neonates (similar to our study group) are in a higher risk of adverse outcome. Placental insufficiency and pregnancy complications such as hyper tensive diseases and fetal growth restriction correlate well with the presence of placental MVM lesions [27,28]. The most probable mecha nism of placental insufficiency is defective placentation and the
3. Results In total 108 pregnancies with ITO were included and were matched in a 1:1 ratio to the control group based on year of delivery, gestational age at delivery, and mode of delivery. As per study design (matching for mode of delivery) the rate of normal vaginal deliveries (33.3%), planned Cesarean deliveries (25.0%), and laboring Cesarean deliveries (41.7%) were similar between the groups. The maternal demographics, pregnancy, and delivery characteristics are presented in Table 1. The ITO group was characterized by a higher rate of nulliparity (46.3% vs. 27.8%, p ¼ 0.007). The rate of meconium stained amniotic fluid was also significantly higher in the ITO group as compared to the control group (25.9% vs 9.3%, p ¼ 0.002). There were no other significant differences between the groups. Placental characteristics are summarized in Table 2. Mean placental weight was significantly lower in the ITO group than the control group (p < 0.001). In addition, the ITO group had a higher rate of placental weight <10th percentile (p < 0.001). The ITO group had also a higher rate of composite MVM lesions as compared to the control group (69.1% vs. 38.8%, p < 0.001). Inflam matory lesions did not differ between the ITO group and the control group, both MIR and FIR, as well as the different stages and grades of the inflammatory responses. There were also no differences between the groups in the rate of FVM lesions. The ITO group had s significantly higher prevalence of abnormal cord insertion as compared to control group (22.2% vs. 3.7%, p < 0.001, respectively). In multivariate analysis ITO was associated with composite MVM lesions (aOR ¼ 1.8 95% CI 1.3–4.1) independent of background confounders. Table 3 present the neonatal outcome parameters. Neonates in the 39
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Fig. 1. Rates of placental maternal vascular malperfusion (MVM) lesions in different pregnancy complications related to “Placental insufficiency”.
inadequate remodeling of the spiral arteries causing placental malper fusion lesions. Spinillo A et al. [12] have shown that placentas from pregnancies with FGR in the presence of oligohydramnios had higher rates of placental MVM lesions as compared to growth restricted preg nancies without oligohydramnios. We designed the current study to investigate the “pure” association between oligohydramnios and placental lesions after excluding cases with other presentations of placental insufficiency (hypertensive disor ders, fetal growth restriction, placental abruptions) of which the man agement is usually more straightforward and well defined in the literature. Our study was carefully designed in the aim of identifying associations between ITO and histological manifestations of placental insufficiency. Our findings of a higher rate of placental MVM lesions, higher rate of placentas weight below the 10th percentile, and higher rates of abnormal cord insertion support our hypothesis that ITO is part of the “placental insufficiency spectrum” (Fig. 1). Our findings are in concordance with previous studies [7,8,29] that have shown a correla tion between oligohydramnios and adverse neonatal outcomes- and suggest placental malperfusion as a possible explanation. Our study is unique in several aspects. First, it is to the best of our knowledge, the first study that compared placental pathology in cases of ITO to controls. Second, we designed a study that “purifies” the association of ITO with placental pathological lesions. Third, this is a relatively large cohort study. Finally, a single pathologist (author L.S) performed all placental histopathology evaluations using the validated placental pathological criteria [20] and was blinded to the outcomes. The current study is not without limitations. First, due to its retro spective design, which allowed us to study only cases whose placentas were initially sent for pathological examination, unintended selection bias may have occurred. Second, a recent study published by Erez O. et al. [30] studied the occurrence of histopathological lesions from a large series of placentas of women with a normal pregnancy outcome. The rate of placental lesions (both vascular and inflammatory) was significantly higher in this study than in our control group. This differ ence can be attributed to population differences such as maternal obesity, ethnicity, maternal age, and Cesarean delivery rate, as well as the definition of “uncomplicated pregnancies”. Third, in attempt to isolate the effect of ITO on placental pathology, the study group and control group were matched to the mode of de livery, as mode of delivery itself is associated with differences in
placental pathology [30,31]. This design did not allow us to investigate whether ITO is associated with Cesarean delivery during trial of labor vs. controls. Lastly, even though the use of a composite outcome may be seemed as a limitation of this study, we believe that the use was required due to the rarity of the individual components of the composite. In conclusion, as we hypothesized, isolated oligohydramnios at term was associated with placental vascular malperfusion lesions as well as adverse neonatal outcome. We believe that ITO should be seen as part of the “placental insufficiency” spectrum (probably in a milder form than preeclampsia and fetal growth restriction-Fig. 1). Our ongoing research focuses on demonstrating characteristic Doppler studies in the umbilical artery and middle cerebral artery in cases of ITO vs. controls and we will publish the results as they become available. Importantly, our study did not aim to suggest the optimal management of ITO and obviously large randomized trials are needed to study the appropriate management of this obstetric complication. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest I declare there is not any financial relationship with any organization or any conflict of interest to report. References [1] T.R. Moore, J.E. Cayle, The amniotic fluid index in normal human pregnancy, Am. J. Obstet. Gynecol. 162 (1990) 1168–1173, https://doi.org/10.1016/0002-9378 (90)90009-V. [2] E.F. Magann, M. Sanderson, J.N. Martin, S. Chauhan, The amniotic fluid index, single deepest pocket, and two-diameter pocket in normal human pregnancy, Am. J. Obstet. Gynecol. 182 (2000) 1581–1588, https://doi.org/10.1067/ mob.2000.107325. [3] C.R. Harman, Amniotic fluid abnormalities, Semin. Perinatol. 32 (2008) 288–294, https://doi.org/10.1053/j.semperi.2008.04.012. [4] N. Af, A. Ya, Amniotic fluid index versus single deepest vertical pocket as a screening test for preventing adverse pregnancy outcome ( Review ) summary of findings for the main comparison, Cochrane Database Syst. Rev. (2009), https:// doi.org/10.1002/14651858.CD006593.pub2. www.cochranelibrary.com. [5] S. Kehl, A. Schelkle, A. Thomas, A. Puhl, K. Meqdad, B. Tuschy, S. Berlit, C. Weiss, C. Bayer, J. Heimrich, U. Dammer, E. Raabe, M. Winkler, F. Faschingbauer, M.
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