The Placental Distal Villous Hypoplasia Pattern: Interobserver Agreement and Automated Fractal Dimension as an Objective Metric.

The distal villous hypoplasia (DVH) pattern is a placental correlate of fetal growth restriction. Because the pattern seems to involve less complexity than do appropriately developed placental villi, we postulated that it may be associated with lower fractal dimension-a mathematical measure of complexity. Our study objectives were to evaluate interobserver agreement related to the DVH pattern among expert pathologists and to determine whether pathologist classification of DVH correlates with fractal dimension. A study set of 30 images of placental parenchyma at ×4 magnification was created by a single pathologist from a digital slide archive. The images were graded for the DVH pattern according to pre-specified definitions and included 10 images graded as "no DVH" (grade  =  0), 10 with mild to moderate DVH (grade  =  1), and 10 with severe DVH (grade  =  2). The images were randomly sorted and shown to a panel of 4 international experts who similarly graded the images for DVH. Weighted kappas were calculated. For each image, fractal dimension was calculated by the Box Counting method. The correlation coefficient between (1) the averaged DVH scores obtained by the 5 pathologists and (2) fractal dimension was calculated. The mean weighted kappa score among the observers was 0.59 (range: 0.42-0.70). The correlation coefficient between fractal dimension and the averaged DVH score was -0.915 (P < 0.001). Expert pathologists achieve fair to substantial agreement in grading DVH, indicating consensus on the definition of DVH. Distal villous hypoplasia correlates extremely well with fractal dimension and represents an objective measure for DVH.

Funisitis and chorionic vasculitis: relation to chorioamnionitis, timing and scoring.

Five hundred consecutive cases with histologic chorioamnionitis and umbilical cord inflammation were analyzed to develop a staging system for funisitis and to correlate stage of funisitis with stage of chorioamnionitis in order to estimate the timing of various stages of funisitis. Funisitis progresses through venous involvement (with or without Wharton's jelly inflammation) to arterial involvement without Wharton's jelly and then full involvement of all three vessels and surrounding Wharton's jelly. Arterial involvement and full funisitis are strongly associated with stage III/IV chorioamnionitis, and imply a significant time interval following the onset of amniotic cavity inflammation.

Guide wire assisted catheterization and colored dye injection for vascular mapping of monochorionic twin placentas.

Monochorionic (MC) twin pregnancies are associated with significantly higher morbidity and mortality rates than dichorionic twins. Approximately 50% of MC twin pregnancies develop complications arising from the shared placenta and associated vascular connections. Severe twin-to-twin syndrome (TTTS) is reported to account for approximately 20% of these complications. Inter-twin vascular connections occur in almost all MC placentas and are related to the prognosis and outcome of these high-risk twin pregnancies. The number, size and type of connections have been implicated in the development of TTTS and other MC twin conditions. Three types of inter-twin vascular connections occur: 1) artery to vein connections (AVs) in which a branch artery carrying deoxygenated blood from one twin courses along the fetal surface of the placenta and dives into a placental cotyledon. Blood flows via a deep intraparenchymal capillary network into a draining vein that emerges at the fetal surface of the placenta and brings oxygenated blood toward the other twin. There is unidirectional flow from the twin supplying the afferent artery toward the twin receiving the efferent vein; 2) artery to artery connections (AAs) in which a branch artery from each twin meets directly on the superficial placental surface resulting in a vessel with pulsatile bidirectional flow, and 3) vein to vein connections (VVs) in which a branch vein from each twin meets directly on the superficial placental surface allowing low pressure bidirectional flow. In utero obstetric sonography with targeted Doppler interrogation has been used to identify the presence of AV and AA connections. Prenatally detected AAs that have been confirmed by postnatal placental injection studies have been shown to be associated with an improved prognosis for both twins. Furthermore, fetoscopic laser ablation of inter-twin vascular connections on the fetal surface of the shared placenta is now the preferred treatment for early, severe TTTS. Postnatal placental injection studies provide a valuable method to confirm the accuracy of prenatal Doppler ultrasound findings and the efficacy of fetal laser therapy. Using colored dyes separately hand-injected into the arterial and venous circulations of each twin, the technique highlights and delineates AVs, AAs, and VVs. This definitive demonstration of MC placental vascular anatomy may then be correlated with Doppler ultrasound findings and neonatal outcome to enhance our understanding of the pathophysiology of MC twinning and its sequelae. Here we demonstrate our placental injection technique.

Third-trimester stillbirths: correlative neuropathology and placental pathology.

Although in recent years placental pathology has been the subject of a wealth of detailed descriptions and diagnostic categorization, systematic correlation of these conditions with the pathology of stillbirth has not been attempted. We examine the relationship between specific inflammatory, maternal, and fetal vascular pathologies and the central nervous system pathology and histological indicators of fetal compromise. Our design was a retrospective case series of 37 3rd-trimester intrauterine fetal deaths. In general, mixed placental pathologies were the rule, with three quarters of the placentas demonstrating combinations of maternal vascular pathology, fetal vascular pathologies, umbilical cord abnormalities, or inflammatory lesions. The range of brain pathology was limited to acute, severe congestion, white matter edema, and neuronal karyorrhexis (pontosubicular necrosis with or without neuronal karyorrhexis at other sites). Established periventricular leukomalacia was present in only 2 cases. The presence of neuronal karyorrhexis or white matter gliosis was correlated with the presence of a high-grade inflammatory lesion and with fetal thymic involution. Neuronal karyorrhexis, but not white matter gliosis, correlated as well with histologically established fetal vascular lesions in the placenta, even once the effect of inflammation was accounted for. Gliosis also correlated with inflammation, meconium staining, and thymic involution. Central nervous system injury may be the end result of complex placental pathologies, and neuronal injury may be a consequence of the fetal inflammatory response. The correspondence between the time courses of histological features of chorioamnionitis, neuronal karyorrhexis, and thymic involution points to irreversible central nervous system injury being common 12-48 hours prior to in utero demise.

Familial monozygotic twinning: a report of seven pedigrees.

Seven families contained 19 MZ twin pairs (2.7 pairs/family), diagnosed by low-stringency variable number tandem repeats in DNA from placental tissue or blood. Chorion status was known in 10 pairs, 6 dichorionic, 4 monochorionic. Sex ratio was equal. Autosomal dominant inheritance is apparent.

Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: a review.

Monozygotic twins (MZ) are rarely absolutely "identical." This review discusses the types of genetic/epigenetic and prenatal environmental post-zygotic mechanisms that cause discordance within such twin pairs. Some of these mechanisms--ranging from heterokaryotypia to skewed X-chromosome inactivation--may cause extreme discordance, but these extremes are merely the more emphatic examples of discordance that, to some degree, underlies the majority of MZ twin pairs. Because of the entrenched misconception that MZ twins are necessarily identical, many MZ twin pairs are mistakenly designated as dizygotic (DZ). Clinical benefits to accurate zygosity determination include correct solid organ transplantation matching, if one twin requires donation for a non-genetically mediated disease; the opportunity of preventive management for disorders that do not manifest synchronously; and better counseling to parents regarding their individually unique, and often psychologically puzzling, twin offspring. In twin pairs with complex and confusing biological origins, more detailed zygosity testing may be required. For example, intermediate trigametic and tetragametic chimeric dizygotic twins are reviewed, some of whom are, nevertheless, monochorionic (MC). Because of inter-fetal vascular anastomoses in MC twins, genetic results from blood samples may not accurately reflect discordance in solid organs. Previously, it was thought that MZ twinning was some sort of embryological fluke. However, familial monozygotic twinning is more common than suggested by the literature. Seven new families are presented in an accompanying paper. Despite the difficulties and dangers of twin pregnancy (especially so for MC twins), human twinning persists, and continues to both challenge and fascinate parents, clinicians and geneticists.

The prevalence of chronic deciduitis in cases of preterm labor without clinical chorioamnionitis.

Preterm labor is a major cause of perinatal mortality and morbidity, and in approximately 30% of cases a clinical cause is not identified. Acute chorioamnionitis is found histologically in a significant percentage of placentas from preterm deliveries, and the mother is often asymptomatic. Although such subclinical acute chorioamnionitis is known to play a role in preterm labor, this study explores the hypothesis that chronic deciduitis with plasma cells is seen more frequently in cases of preterm labor than in control placentas. Thirty-nine singleton placentas from patients with idiopathic preterm labor were examined microscopically and compared in a blinded fashion with 39 gestational age-matched control placentas. Cases of clinical acute chorioamnionitis and known chronic maternal diseases were excluded. Thirty-nine control singleton placentas were obtained from patients undergoing induction of labor for fetal structural abnormalities, excluding aneuploidy. The presence or absence of acute chorioamnionitis, acute fetal inflammatory response, chronic deciduitis, chronic villitis, infarction, and decidual vasculopathy was noted. Immunohistochemical staining was undertaken to further define leukocyte subtypes. Forty-one percent of cases and 15% of controls showed chronic deciduitis (P = 0.022). Forty-six percent of cases and 18% of controls showed histologic acute chorioamnionitis (P = 0.015). There were 8 cases demonstrating acute fetal inflammatory response but only 1 control (P = 0.029). Little difference was seen in the distribution of lymphocyte subsets between cases and control placentas. Our findings suggest that chronic deciduitis plays a role in the etiology of some cases of preterm labor.

Maternal thrombophilias are associated with specific placental lesions.

Maternal floor infarction (MFI), massive perivillous fibrin deposition (MPVFD), and fetal thrombotic vasculopathy (FTV) are specific placental lesions with associations to recurrent adverse fetal outcomes and with maternal thrombophilia. We studied the frequency of a range of acquired and genetic maternal thrombophilias in MFI (40 cases), MPVFD (87 cases), FTV (7 cases), and FTV+MPVFD (4 cases). Thrombophilias were identified in 16 (40%), 20 (23%), 5 (71%), and 2 (50%) of these lesions, respectively. Seventy-seven percent of the identified thrombophilias were genetic, and 23% were acquired. The most common genetic thrombophilia was protein S deficiency, which constituted 14 of the 36 genetic thrombophilias (39%). We advocate full maternal thrombophilia testing when the diagnosis of MFI, MPVFD, and FTV is made by placental pathology examination. Because of the possible contribution of paternal thrombophilic mutations to the fetal genotype, it would be desirable to test the whole family as well.

Unequal placental sharing and birth weight discordance in monochorionic diamniotic twins.

OBJECTIVE: The purpose of this study was to define the association between unequal placental sharing and birth weight discordance in monochorionic/diamniotic twin pregnancies. STUDY DESIGN: The study comprised a prospective cohort of monochorionic/diamniotic twin pregnancies who were delivered in Kaiser Permanente-Northern California, 1997-2003. Dye injection studies of fresh postpartum placentas were performed. Placental sharing, cord insertion combinations, vascular anastomoses, gestational age, and birth weights were recorded. Statistical comparisons of birth weight and gestational age were made with the Student t test. Rates of birth weight discordance were compared with the chi-square test. Multivariate logistic regression models analyzed the relationship between variables of interest. RESULTS: Mean birth weights for larger and smaller twins were 2400 g and 2109 g, respectively. Twenty-two percent of the monochorionic/diamniotic twin pairs had birth weight discordance > or = 20%, and 8% of these pairs had twin-twin transfusion syndrome. Monochorionic/diamniotic twin pairs with unequal placental sharing had a 9.8 times greater likelihood of birth weight discordance (95% CI, 5.4-17.9) as compared with those pairs with equal placental sharing. CONCLUSION: Unequal placental sharing is a significant risk factor for birth weight discordance in monochorionic/diamniotic twins. Antenatal diagnosis of unequal placental sharing would enable improved counseling in the setting of monochorionic/diamniotic twins.

Why zygosity of multiple births is not always obvious: an examination of zygosity testing requests from twins or their parents.

This paper examines why parents of twins or adult twins themselves request zygosity testing. Of 405 multiples including 8 sets of triplets, the majority (93%) were monozygotic. Age of testing ranged from 0 days to 73 years. About 50% of requests came from parents or twins who were curious about, or expressed a need to be certain of, their zygosity. Other reasons included health concerns (current or future), other twins in the family, and misinformation about zygosity, frequently because of the erroneous assumption that all dichorionic twins are dizygotic. Parents of monozygotic twins may expect their twins to be 'identical' and believe their twins to be dizygotic because of minor phenotypic differences between them. Dizygotic twins like other siblings may share a phenotypic resemblance. Health professionals should be aware that zygosity of multiples may not always be obvious to parents and that accurate knowledge of zygosity may be justified.

Why is it important to diagnose chorionicity and how do we do it?

Because the monochorionic (MC) placenta is designed for a singleton fetus, and might not provide adequate physiological support for twins, obstetric problems are more frequent in MC than dichorionic (DC) twins. Problems arise because asymmetric cord insertions cause growth discordance as a result of unequal sharing of placental tissue. Approximately 95% of MC twin placentas contain interfetal vascular connections of some kind, sometimes in several combinations. Such connections can cause twin-twin transfusion syndrome and twin reversed arterial perfusion. The survivor can also suffer damage if the co-twin dies spontaneously or from inappropriate methods of selective termination. These complications are progressive and often advanced by 18 weeks gestation. Monoamniotic twins carry greater risks than diamniotic twins, especially entangled cords. MC twins are often discordant for congenital anomalies. Diagnosis of MC twinning is optimal in the first trimester. Optimal management of these MC twin disorders is not yet established; long-term follow-up studies are unsatisfactory. In clinical practice, chorionicity is not always determined in the first trimester.

Fetal therapy for giant hepatic cysts.

Cystic mesenchymal hamartoma is an extremely rare, benign tumor. Rapid growth to a giant size can pose a threat not only in early childhood but also during fetal life. The experience with 2 antenatally diagnosed giant hepatic cysts with widely disparate approaches to management, treatment, and outcome is presented. A giant hepatic cyst was diagnosed on routine screening ultrasound scan. Because of its extremely massive size, the cyst was treated in utero with repeated aspirations, primarily for obstetric considerations. The infant did well, and the lesion was excised laparoscopically during the neonatal period. A second fetus with a giant hepatic cyst was not treated in utero, and the pregnancy continued to term. Nonimmune hydrops fetalis developed, and the fetus was delivered prematurely at 34 weeks. At birth, the infant was noted to have diffuse neurologic injury and no urine output despite normal-appearing kidneys. The lesion was excised during the neonatal period by open laparotomy. Observations at the time of surgery and pathologic studies of the placenta showed aneurysmal dilatation of the placental veins suggesting in utero compression of the fetal intraabdominal umbilical vein. The infant died shortly after birth. The experience with these 2 cases suggests the possibility that giant mesenchymal hamartoma diagnosed in utero may cause umbilical venous obstruction leading to ischemia during fetal life. Decompression of giant hepatic cysts may reverse this phenomenon and allow normal fetal development.

The Northwestern Twin Chorionicity Study: I. Discordant inflammatory findings that are related to chorionicity in presenting versus nonpresenting twins.

OBJECTIVE: The purpose of this study was to evaluate the association between chorionicity and discordant chorioamnionitis and funisitis in twin gestations. STUDY DESIGN: This was a retrospective analysis of 1156 twin placentas with a standardized diagnosis of chorionicity, chorioamnionitis, and funisitis for comparison between presenting and nonpresenting twins with dichorionic-separate, dichorionic-fused, and monochorionic placentas. RESULTS: Frequencies of chorioamnionitis in the nonpresenting twin were significantly lower in dichorionic placentas (odds ratio, 0.4; 95% CI, 0.3, 0.6, in dichorionic-separate placentas; odds ratio, 0.5; 95% CI, 0.3, 0.8, in dichorionic-fused placentas) compared with monochorionic placentas. The frequency of advanced inflammation (ie, chorioamnionitis with funisitis) was significantly lower in the nonpresenting twin than in the presenting twin, but only in dichorionic-separate placentas (odds ratio, 0.2; 95% CI, 0.1, 0.4). CONCLUSION: Dichorionic placentas confer significant protection against the spread of chorioamnionitis from the presenting to the nonpresenting gestational sac. In the more advanced process that involves the umbilical cord, only the subset of separate dichorionic placentas confers this protective effect against the spread of inflammation.

Rapid onset of severe twin-twin transfusion syndrome caused by placental venous thrombosis.

We report a case of rapid onset of severe twin-twin transfusion syndrome (TTTS) at 25 weeks gestation in a monochorionic twin pregnancy that was uneventful before that time. Thrombosis of a main venous branch draining several arteriovenous (AV) anastomoses to the donor changed the previous hemodynamic balance that existed between multiple bidirectional AV anastomoses. The opposing AVs became hemodynamically uncompensated and, despite amnioreductions, severe TTTS developed. At 27 weeks a cesarean section was performed because of worsening cardiotocography parameters of both fetuses. Birth weights were 750 and 1840 g, and initial hemoglobin concentrations were 9.2 and 13.4 mmol/liter for donor and recipient, respectively. The recipient twin died 5 months later of an ischemic, necrotic, and perforated small intestine due to a thrombosed superior mesenteric artery. The donor is well at 2.5 years. No abnormalities in several factors associated with thrombophilia, including factor V Leiden mutations, were found in the parents.

Rejoinder to meta-analysis of twin-twin transfusion by Skupski et al.

Assessment of treatment options in twin-twin transfusion should involve a detailed interrogation of the placenta and fetuses prior to treatment, stratification according to response to amnioreduction and careful analysis of quality of survival. Amnioreduction and laser coagulation are not alternative and equivalent modalities for the treatment of twin-twin transfusion. Randomized trials may not be ethical without prior therapeutic/diagnostic amnioreduction.