Placental growth from the first to the second trimester of pregnancy in SGA-foetuses and pre-eclamptic pregnancies compared to normal foetuses

The aim of this study was to determine placental growth between 12-22 weeks in normal pregnancies compared to pregnancies complicated by foetal SGA and maternal pre-eclampsia (PE). The placentae of 1199 women were measured 3D sonographically at 12, 16 and 22 weeks of gestation. Placental volume growth was then calculated. Neonatal birthweight, birth centile and the occurrence of pre-eclampsia were recorded in every woman and correlated with placental growth (four groups: normals, SGA, PE, SGA+PE). SGA-placentae are already smaller at 12 weeks but then develop in a similar way to normal placentae. PE placentae are slightly, but significantly, larger at 12 weeks, grow rapidly until 16 weeks and then stop growing normally between 16 and 22 weeks. If SGA goes together with PE, both placental volume (PV) at 12 weeks as well as growth is reduced significantly. Nevertheless, placental growth between week 12 and 22 is too heterogeneous to justify using this method as a clinical tool, but it can provide new information on placental physiology underlying unfavourable obstetric outcomes.     

To ignore or not to ignore placental calcifications on prenatal ultrasound: a systematic review and meta-analysis

Objective: The human placenta is known to calcify with advancing gestational age, and, in fact, the presence of significant calcifications is one of the components of grade III placenta, typical of late gestation. As such, the presence of significant placental calcifications often prompts obstetric providers to expedite delivery. This practice has been attributed, in part, to the presumed association between grade III placenta and adverse pregnancy outcomes. Such approach, however, can be the source of major anxiety and may lead to unnecessary induction of labor, with its associated predisposition to cesarean delivery as well as a myriad of maternal and neonatal morbidities. The objective of this study was to examine the association between grade III placental calcifications and pregnancy outcomes.

Materials and methods: A systematic review of the literature was performed for studies evaluating the association between grade III placenta and a number of pregnancy outcomes, including labor induction, fetal distress (abnormal fetal heart tracing), low Apgar score (less than 7 at 5?min), need for neonatal resuscitation, admission to the Neonatal Intensive Care Unit, perinatal death, meconium liquor, and low birth weight.

Results: There was a five-fold increase in risk of labor induction with the presence of grade III placenta (OR 5.41; 95% CI 2.98–9.82). There was no association between grade III placenta and the incidence of abnormal fetal heart tracing (OR 1.62; 95% CI 0.94–2.78), low Apgar score of less than 7 at 5?min (OR 1.68; 95% CI 0.84–3.36), need for neonatal resuscitation (OR 1.08; 95% CI 0.67–1.75), and admission to the Neonatal Intensive Care Unit (OR 0.90; 95% CI 0.21–3.74). In turn, the incidence of meconium liquor was higher in the setting of grade III placentae (OR 1.68; 95% CI 1.17–2.39). Similarly, a positive association between grade III placental calcifications and low birth weight (OR 1.63; 95% CI 1.19–2.22) and perinatal death (OR 7.41; 95% CI 4.94–11.09) was identified.

Conclusion: The study alerts us to a significant association between grade 3 placental calcifications and labor induction, although it demonstrates that these sonographic findings do not appear to predispose to fetal distress, low Apgar score, need for neonatal resuscitation, or admission to the NICU.     

Placental grading with ultrasound in hypertensive and normotensive pregnancies. A prospective, consecutive study

Placental grading was studied prospectively with real-time ultrasound in 654 consecutive pregnancies. The placental maturation was clearly demonstrated in both unselected and hypertensive pregnancies. No differences in placental grading were found between normotensive and hypertensive pregnancies. Fetal outcome was not associated with different placental grades and a grade III placenta was not predictive of an adverse outcome. The value of antenatal placental grading in unselective and hypertensive pregnancies could not be demonstrated.     

The correlation of ultrasonic placental grading and fetal pulmonary maturation in five hundred sixty-three pregnancies

In a previous study, it was suggested that the presence of a grade III placenta correlates 100% with a mature lecithin/sphingomyelin (L/S) ratio and may replace amniocentesis in confirming fetal lung maturity. In this study that hypothesis was tested in 563 pregnancies. All patients underwent amniocentesis and simultaneously had placental grading. The correlations of placental grade with an L/S ration ≥2 were: grade 0, 17%; grade I, 68%; grade II, 91%; grade III, 93%. The correlations of placental grade with the presence of phosphatidylglycerol (PG) were: grade 0, 17; grade I, 41%; grade II, 79%; grade II, 75%. The false positive rates associated with grade III placenta were, therefore, 7% for mature L/S ratio and 25% for PG present; when combined with a biparietal diameter ≥9.0 cm, a grade III placenta incorrectly predicted lung maturity in 8.5%. We conclude that placental grading is not accurate enough to replace amniocentesis as the standard test of fetal pulmonary maturity.     

Novel placental ultrasound assessment: Potential role in pre-gestational diabetic pregnancy

Objectives

Management of women with pre-gestational diabetes continues to be challenging for clinicians. This study aims to determine if 3D power Doppler (3DPD) analysis of placental volume and flow, and calculation of placental calcification using a novel software method, differ between pregnancies with type 1 or type 2 diabetes and normal controls, and if there is a relationship between these ultrasound placental parameters and clinical measures in diabetics.

Methods

This was a prospective cohort study of 50 women with diabetes and 250 controls (12–40 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental calcification was calculated by computer analysis. Results in diabetics were compared with control values, and correlated with early pregnancy HbA1c, Doppler results and placental histology.

Results

Placental calcification and volume increased with advancing gestation in pre-gestational diabetic placentae. Volume was also found to be significantly higher than in normal placentae. VI and VFI were significantly lower in diabetic pregnancies between 35 and 40 weeks gestation. A strong relationship was seen between a larger placental volume and both increasing umbilical artery pulsatility index and decreasing middle cerebral artery pulsatility index. FI was significantly lower in cases which had a booking HbA1c level ≥6.5%. Ultrasound assessed placental calcification was reduced with a histology finding of delayed villous maturation. No other correlation with placental histology was found.

Conclusions

This study shows a potential role for 3D placental evaluation, and computer analysis of calcification, in monitoring pre-gestational diabetic pregnancies.     

The value of ultrasonic placental grading: no correlation with intrauterine growth retardation or with maternal smoking

In a prospective study the usefulness of placental grading in detecting IUGR has been evaluated. Those who were echoscopically examined within one week before delivery were taken into the study (n = 137). Changes in placental tissue increased clearly as pregnancy progressed and in 42% (57/137) the placentae reached Grade III. Increasing placental grading is associated with normal maturation of the placenta. Post partum examination of the placenta correlated well with the echoscopic picture (accuracy = 80.5%). No relationship was found in an unselected group between Grade III and IUGR at term. When a Grade III placenta was first seen before 36 weeks, in three out of five cases a growth retarded neonate was born. The effects of maternal smoking habits during pregnancy on birth weight and placenta were examined. There were no significant differences in mean placental weight, placental ratio and placental grading as the amount of cigarettes increased. The mean birth weight and birth weight percentile decreased significantly when the mother smoked more than 10 cigarettes per day.     

Reproducibility of placental maturity grade classification using a dynamic ultrasonography

Objective: To evaluate the agreement between ultrasonographers in classifying placental maturity grade using examination videos.

Methods: A prospective, cross-sectional study was conducted using 25 videos of ultrasonographic examinations of single, healthy pregnancies ≥?34?+?0 weeks. The Grannum (grades 0, I, II and III) and Julio (grades 0, 1, 2A, 2B and 3) classifications were used for placental maturity grade. The videos were evaluated on two occasions by 10 experienced ultrasonographers. Intra- and inter-observer agreements were evaluated using the Kappa (k) coefficient of agreement.

Results: According to the Grannum classification, the inter-observer agreement coefficients were good for grades III and 0 (k?=?0.69 and 0.738, respectively) and moderate for grades I and II (k?=?0.401 and 0.593, respectively) placentas. According to the Julio classification, the inter-observer agreement coefficients were good for grades 0 and 3 (k?=?0.738 and 0.651, respectively), moderate for grades 1 and 2A (0.401 and 0.413, respectively) and poor for grade 2B (k?=?0.161). Intra-observer coefficients for the Grannum and Julio classifications ranged from 0.567 to 0.890 and from 0.446 to 0.790, respectively.

Conclusion: Placental maturity grading using the Grannum and Julio classifications demonstrated moderate/good intra- and inter-observer agreements on examination videos evaluation.     

Correlation between grade III placenta and plasma antithrombin III activity in full term pregnancy

We evaluated whether the presence of a grade III placenta correlates with blood hypercoagulability in pregnancy between 37 and 39 weeks of gestation. The placenta was graded by ultrasound in 155 healthy full-term women and the plasma levels of antithrombin III (AT III) activity, thrombin-antithrombin complex (TAT) and D-dimer were correlated with each placental grade. AT III activity levels tended to decrease with advancing placental grade from I to III (p < 0.05). D-dimer showed the same tendency while TAT did not. The incidence of reduced AT III activity levels (<70%) in women with a grade III placenta was about twice those in women with a grade II or I placenta, and that of AT III <80% was 3-fold greater. We concluded that the presence of a grade III placenta in full-term pregnancies correlates with blood hypercoagulability.     

Raised maternal serum alpha-fetoprotein in the absence of fetal abnormality--placental findings. A quantitative morphometric study

Ten placentae from pregnancies proceeding to term from mothers who on routine screening at 16-18 weeks gestation were found to have raised serum AFP but no increase in amniotic fluid AFP and no fetal abnormality, were studied using morphometric techniques. The results were compared with 20 placentae from normal term pregnancies where the maternal serum AFP level was not elevated. The mean total placental volume, volume of parenchyma and villous surface area were increased in the placentae associated with a raised maternal serum AFP. More of these placentae were infarcted and the fetal-placental weight ratio was significantly lower. The hypothesis that elevation of maternal serum AFP level is related to the increase in placental size is addressed.     

Use of External Cephalic Version for Breech Pregnancy and Mode of Delivery for Breech and Twin Pregnancy: A Survey of Canadian Practitioners

Objectives: (1) To understand how external cephalic version (ECV) is used in the management of breech pregnancies; (2) to determine if Canadian practitioners have changed their recommendations regarding the mode of breech delivery since becoming aware of the findings of the Term Breech Trial; and (3) to establish a baseline of how twins are being delivered in Canada.Methods: In March 2001, a survey was mailed to 920 obstetrician/gynaecologists, 409 family physicians, and 62 midwives from the membership list of the Society of Obstetricians and Gynaecologists of Canada.Results: The response rate was 52% (476/920) for obstetrician/gynaecologists, 22% (90/409) for family physicians, and 53% (32/62) for midwives. Eighty-nine percent of practitioners routinely offered women ECV. The median self-estimated ECV success rate for nulliparous women was 30%, and for multiparous women, it was 58%. Forty-seven percent of practitioners used tocolytics 9% used analgesics, and 14% recommended repeat ECV when initial attempts failed. Eighty-four percent of practitioners recommended vaginal breech birth before learning the results of the Term Breech Trial, and 14% afterwards. When both twins present as vertex, most respondents planned vaginal delivery (100% for term, 95% for preterm > 32 weeks, and 73% for preterm ≤ 32 weeks). Vaginal birth was recommended for Twin A vertex, Twin B breech at term by 92% of practitioners for frank, 92% for complete, and 88% for footling breech at Preterm > 32 weeks by 84% of practitioners for frank, 81% for complete, and 78% for footling breech; and at preterm ≤ 32 weeks by 43% of practitioners for frank, 42% for complete, and 39% for footling breech pregnancies. When Twin A was non-footling breech and Twin B vertex 7%, 5% and 2% of practitioners recommended vaginal birth for term, preterm > 32 weeks, and preterm ≤ 32 weeks pregnancies, respectively. Sixty-four percent of respondents on twin births were interested in a randomized controlled trial to compare planned Caesarean section with planned vaginal birth for twin pregnancies.Conclusion: Although the use of ECV is high in Canada, the success rate is low. Increasing the use of tocolytics, considering epidural analgesic, and repeating the procedure when the initial attempt fails may increase success and decrease Caesarean section rates. The survey results reflect a dramatic shift toward recommending Caesarean section for management of term breech pregnancies. Vaginal birth is the method of delivery of choice for most twin pregnancies of 32 weeks’ gestation, especially for vertex/vertex presentations.     

Cellular growth of the placenta in twin pregnancy late in gestation

In order to establish the pattern of cellular growth in placentae from human twin pregnancy, the total placental concentrations of deoxyribonucleic acid (DNA) and protein were determined. Twin placentae from 31 to 40 weeks' gestation were analysed from 40 pregnancies whose precise gestational ages were known. The study has shown that nuclear multiplication continues until placental growth in weight itself comes to an end. Increase in placental weight was caused by cellular hyperplasia without hypertrophy.     

Maternal serum ferritin as a clinical tool at 34–36 weeks’ gestation for distinguishing subgroups of fetal growth restriction

Objective: To compare maternal ferritin levels across pregnancies with fetal growth restriction including SGA and IUGR compared to appropriate for gestational age (AGA). Methods: Three groups were enrolled: AGA, SGA (birth weight below 10th percentile for gestational age with no placental insufficiency findings), and IUGR (birth weight below 5th percentile for gestational age accompanied by abnormal umbilical artery Doppler waveforms and/or oligohydramnios). Maternal serum ferritin samples were obtained at gestational weeks 34 through 36, and delivery occurred at or beyond 36 weeks. Results: A total of 126 pregnancies with AGA (36%), SGA (40%), and IUGR (24%) were enrolled. The mean maternal serum ferritin level was higher in the IUGR group than in the AGA group (59?μg/l versus 32.5?μg/l, p?Conclusion: Maternal serum ferritin levels differ in pregnancies with IUGR. The role of maternal serum ferritin measurements as a clinical tool for distinguishing different forms of fetal growth restriction warrants further investigation.     

The relationship of placental grade, fetal lung maturity, and neonatal outcome in normal and complicated pregnancies

Ultrasonically diagnosed maturity changes in the placenta, Grades 0 to III, have been previously shown to correlate with fetal lung maturity. In a prospective study of 230 term and preterm complicated pregnancies, we compared the relationship between sonographic placental grading, amniotic fluid phospholipids, and neonatal outcome. The frequencies of gestational age less than 38 weeks, lecithin/sphingomyelin (L/S) ratio less than 2.0, negative phosphatidylglycerol, and neonatal hyaline membrane disease were found to decrease as placental grade advanced from 0 to III. Patients were divided into subgroups on the basis of maternal complications. In patients with Grade III placentas, the frequencies of gestational age less than 38 weeks and L/S ratio less than 2.0 were significantly increased when the subgroup of patients with chronic hypertension was compared individually to both of the subgroups, repeat cesarean section deliveries, and Classes A, B, and C diabetes mellitus (both with p less than 0.05) All three infants who developed hyaline membrane disease in association with Grade III placentas were from pregnancies of less than 38 weeks complicated by chronic hypertension. These findings suggest that the presence of a Grade III placenta is affected by both gestational age and pregnancy complications. Hence, when an elective cesarean section delivery is being planned near term gestation, a Grade III placenta is a reliable predictor of lung maturity. In preterm complicated pregnancies, an ultrasound-diagnosed Grade III placenta may still be associated with hyaline membrane disease.     

Rates of intrauterine fetal demise and neonatal morbidity at term: determining optimal timing of delivery

Objective: To examine rates of unexplained intrauterine fetal demise (IUFD) and neonatal morbidity in uncomplicated term pregnancies to identify the optimal gestational age for delivery.

Methods: A retrospective case control study was performed with singleton pregnancies delivered between 37 0/7 weeks and 42 6/7 weeks. Exclusion criteria were “complicated pregnancies”: emergency deliveries, maternal hypertension, diabetes, infection, fetal disease/malformations and placental abnormalities.

Results: Nineteen thousand two hundred and sixty-four maternal/infant pairs were examined. The overall rate of NICU admission was 2.7% and the rate of unexplained IUFD was 2.02 per 1000 births. The lowest rate of IUFD was found at 39 weeks (1.40 per 1000 births). Odds ratios adjusted for maternal smoking, ethnicity, age and mode of delivery showed 2.74 (95% CI 0.35–21.83) risk of IUFD at 42 versus 39 weeks, 2.09 (1.47–2.98) risk of NICU admission at 37 versus 38 weeks, 2.54 (1.62–3.97) risk of respiratory morbidity at 37 versus 38 weeks and 3.38 (1.84–6.18) risk of transient tachypnea of the newborn or respiratory distress syndrome at 37 versus 38 weeks.

Conclusions: Neonatal respiratory morbidity was lowest for deliveries at 38–39 weeks. IUFD was 2.74 times more likely at 42 weeks versus 39 weeks. Our findings support current guidelines advising clinicians when to deliver term pregnancies.     

Sonographic Maturation of the Placenta at 30 to 34 Weeks Is Not Associated With Second Trimester Markers of Placental Insufficiency in Low-risk Pregnancies

ObjectiveAdvanced placental maturation (Grannum [G] grade 3) before term is associated with adverse perinatal outcomes associated with placental insufficiency. The nature and timing of the underlying pathology of this process is presently unclear. We hypothesized that advanced placental maturation at 30 to 34 weeks’ gestation is not associated with established second trimester markers of severe placental dysfunction.MethodsIn a cohort study of 1238 low-risk Caucasian women with singleton pregnancies who had sonographic assessment of placental maturation and fetal growth at 34 weeks, the results of maternal serum screening (MSS) and uterine artery Doppler (UtAD) flow studies at 16 weeks were related to adverse perinatal outcomes associated with placental insufficiency: antepartum hemorrhage, preeclampsia, preterm birth < 37 weeks, small for gestational age (< 10th percentile), or postnatal evidence of intrauterine growth restriction (IUGR; ponderal index < 5th percentile).ResultsG1 was found in 127 women (10.3%), G2 was found in 18 women (1.5%), and no cases of G3 were observed. Advanced Grannum grading was significantly associated with IUGR (48 [4.4%] in G0, 9 [7.1%] in G1, 5 [27.8%] in G2; P < 0.001), but was dependent on smoking status. IUGR was not predicted by abnormal MSS or abnormal UtAD findings at either the second or third trimester ultrasounds.ConclusionG2 maturation at 30 to 34 weeks’ gestation is associated with mild IUGR at delivery in low-risk women and with smoking. IUGR was not predicted by either second or third trimester markers of severe placental dysfunction. Future studies directly observing the placenta in the late third trimester may aid the elusive diagnosis of “late-onset” mild IUGR.     

Placental apoptosis is increased in post-term pregnancies

Placentae were obtained at delivery in 14 pregnancies complicated by post maturity (gestational age ≥ 40 weeks and 10 days) and in 23 uncomplicated pregnancies (gestational age c 40 weeks). The incidence of apoptotic nuclei was significantly greater in the placentae from the postmature pregnancies.     

Pregnancy associated plasma protein-A2: A novel biomarker for down syndrome

IntroductionIn an effort to improve prenatal screening for Trisomy 21, we evaluated pregnancy associated plasma protein-A2 (PAPP-A2) as a potential novel second trimester biomarker for Trisomy 21.MethodsTrisomy 21 and normal control mid-trimester placental samples were subjected to quantitative rt PCR analysis of seven genes we had previously found to be differentially expressed in Trisomy 21 placentae. The localization and differential expression of PAPP-A2 in second trimester placentae from normal and Trisomy 21 pregnancies was determined by immunohistochemistry. PAPP-A2 maternal serum protein levels in ten Trisomy 21 and ten diploid pregnancies were compared by Western blotting. Maternal serum PAPP-A2 levels were measured in 30 Down syndrome cases and 142 normal controls, using ELISA. Regression analysis was used to determine the correlation of PAPP-A2 with other existing markers of Trisomy 21.ResultsPAPP-A2 (aka PLAC 3) mRNA and protein expression were both increased in Down syndrome placentae as compared to diploid placentae. PAPP-A2 was also increased in maternal serum from Down syndrome pregnancies as compared to diploid pregnancies. PAPP-A2 expression correlated weakly with established markers.DiscussionThis work takes advantage of our previously performed systematic approach to the discovery of novel maternal serum biomarkers for Trisomy 21, using cDNA microarray analysis. Beginning with the validation of the microarray results, we have tracked PAPP-A2 overexpression in Down syndrome from placental mRNA to maternal serum protein.ConclusionPAPP-A2 could serve as an additional maternal serum marker in prenatal screening for Trisomy 21.     

Morphological aspects of the placenta in HIV pregnancies

Forty-nine placentae from HIV-seropositive mothers were collected in various hospitals in France and Belgium. Twenty [corrected] placentae with seven fetuses from interrupted pregnancies and 29 [corrected] placentae from spontaneous deliveries, including two stillborns and a set of twins, were studied morphologically. No significant abnormalities were observed in the aborted material. The placentae corresponding to deliveries presented no significant gross abnormalities but the ratio of fetal to placental weight was significantly decreased in the study group compared with the control group (6.13 versus 7.41; P less than 0.001), associated with a congestive and mature aspect of the parenchyma. Histologically a high incidence of chorioamnionitis (43 per cent) was found, contrasting with the absence of villitis. A relative villous hypercellularity was observed in the study group compared with the control group. Ultrastructural studies of 13 placentae corresponding to gestations of 10 to 40 weeks are presented. In six cases, retrovirus-like particles were found at various sites, such as villous fibroblasts, syncytiotrophoblast and endothelial cells, and in the free membranes.     

Regulation of nitric oxide synthase activity by tetrahydrobiopterin in human placentae from normal and pre-eclamptic pregnancies

The possible regulatory role of tetrahydrobiopterin (BH(4)) in Type III nitric oxide synthase (NOS III) activity of human placentae from first trimester, term and pre-eclamptic pregnancies was investigated. In homogenates of first-trimester or term placentae, BH(4)stimulated NOS III activity up to 2.5-fold in a concentration dependent manner from 20 n m to 1 microm BH(4), and half-maximal stimulation (EC(50)) was observed at 100-110 n m. No significant further stimulation was detectable over an extended concentration range from 1 microm to 50 microm BH(4). NOS III present in microsomal and gel-filtered cytosol fractions exhibited similar BH(4)-activation patterns, with an identical EC(50)value of 50 n m. Remarkably, tissue concentrations of BH(4)showed a marked decrease in term placentae (57+/-23 n m, mean+/-s.d., n=26) relative to first-trimester placentae (189+/-79 n m, mean+/-s.d., n=17), suggesting that alterations in cellular BH(4)concentrations may play a more significant role in the regulation of NOS III activity in late pregnancy. Placental homogenates from 10 pre-eclamptic pregnancies exhibited two distinct types of response to BH(4). In seven placental homogenates, addition of physiological concentrations of BH(4)(20 n m to 1 microm) elicited no increase whatsoever in basal NOS III activity, and only high BH(4)concentrations (50 microm) caused notable stimulation (BH(4)resistant group). In contrast, in three of 10 placental homogenates both physiological and 50 microm BH(4)concentrations stimulated NOS III to levels similar to that of normal placentae (BH(4)responsive group). There were no appreciable differences in the clinical presentation of pre-eclampsia between the two groups. Importantly, BH(4)concentrations in pre-eclamptic placentae were comparable with those of normal, control placentae. Taken together, the observations suggest that BH(4)controls NOS III activity in the human placenta, and a defect in BH(4)regulation of NOS III may contribute to the development of pre-eclampsia. A model implicating the malfunction of placental NOS III rather than its actual tissue level in the pathogenesis of pre-eclampsia is discussed.