Umbilical cord characteristics and their association with adverse pregnancy outcomes: A systematic review and meta-analysis.

OBJECTIVE: Current data on the role of the umbilical cord in pregnancy complications are conflicting; estimates of the proportion of stillbirths due to cord problems range from 3.4 to 26.7%. A systematic review and meta-analysis were undertaken to determine which umbilical cord abnormalities are associated with stillbirth and related adverse pregnancy outcomes. METHODS: MEDLINE, EMBASE, CINAHL and Google Scholar were searched from 1960 to present day. Reference lists of included studies and grey literature were also searched. Cohort, cross-sectional, or case-control studies of singleton pregnancies after 20 weeks' gestation that reported the frequency of umbilical cord characteristics or cord abnormalities and their relationship to stillbirth or other adverse outcomes were included. Quality of included studies was assessed using NIH quality assessment tools. Analyses were performed in STATA. RESULTS: This review included 145 studies. Nuchal cords were present in 22% of births (95% CI 19, 25); multiple loops of cord were present in 4% (95% CI 3, 5) and true knots of the cord in 1% (95% CI 0, 1) of births. There was no evidence for an association between stillbirth and any nuchal cord (OR 1.11, 95% CI 0.62, 1.98). Comparing multiple loops of nuchal cord to single loops or no loop gave an OR of 2.36 (95% CI 0.99, 5.62). We were not able to look at the effect of tight or loose nuchal loops. The likelihood of stillbirth was significantly higher with a true cord knot (OR 4.65, 95% CI 2.09, 10.37). CONCLUSIONS: True umbilical cord knots are associated with increased risk of stillbirth; the incidence of stillbirth is higher with multiple nuchal loops compared to single nuchal cords. No studies reported the combined effects of multiple umbilical cord abnormalities. Our analyses suggest specific avenues for future research.

Significance of C4d Immunostaining in Placental Chronic Intervillositis.

Deposition of the complement split product C4d is a phenomenon studied extensively as a marker for complement activation in antibody-mediated transplant rejection. C4d also is observed in placental disease processes including spontaneous abortion, infarct, and villitis of unknown origins. Massive chronic intervillositis is a rare placental abnormality associated with increased risk of growth restriction, fetal death, and recurrent fetal loss. In this study, we evaluated C4d immunostaining in placentas with accumulation of intervillous monocytes with and without villitis. Archived placentas from Kosair Children's Hospital (Louisville, KY) and Seattle Children's Hospital (Seattle, WA) were selected and divided into 4 groups, 16 cases of intervillositis with complicated pregnancy, 15 cases of uncomplicated intervillositis, 20 cases of complicated villitis, and 13 cases of uncomplicated villitis, all with varying degrees of monocytic cells in the intervillous space. Representative specimen blocks were immunohistochemically stained for C4d. The percentage of positive staining of the microvillous surface of the syncytiotrophoblast was scored by five pathologists, and the following consensus score was determined: 0  =  0% to 5%; 1  =  5% to 25%; 2  =  25% to 75%; and 3 ≥ 75%. C4d immunostain localized to the microvillous border of syncytiotrophoblast in many of the placentas. C4d staining was more strongly associated with intervillositis than with villitis (odds ratio: 6.3; confidence interval: 2.1-18.7; P  =  0.001).

In vitro umbilical cord wrapping and torsion: possible cause of umbilical blood flow occlusion.

OBJECTIVE: Intrapartum fetal heart rate decelerations and bradycardia are often attributed to umbilical cord occlusion without knowing the anatomic basis of that occlusion. We hypothesized that umbilical cord twisting while looped around fetal parts could occlude blood flow. METHODS: Using an in vitro preparation, human umbilical cord veins were perfused at one end with water at approximately 40 cm H2O. The cords were looped around pipes that approximated the diameter of fetal body or limb parts, after which the perfused segment of cord was twisted until water flow stopped. The number of rotations needed to stop perfusion was recorded for each length of twisted cord (4, 6 and 8 cm) and for each pipe diameter. RESULTS: There were 21 completed studies. All cords demonstrated that a decreasing number of twists were needed to stop venous flow as the segment twisted became shorter (from 8 to 4 cm). For each segment length, the number of twists required to stop flow decreased as the pipe diameter narrowed. CONCLUSION: This model demonstrates that a wrapped umbilical cord, particularly with a short segment between the placental insertion and the fetal body part, may be predisposed to cord occlusion in response to fetal rotation.

Maternal cigarette smoking and the development of necrotizing enterocolitis.

BACKGROUND: The maternal variables that affect fetal development and correlate with necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in premature infants, are not well defined. We hypothesized that maternal risk factors were the primary determinant of future development of NEC. METHODS: Patients with NEC were identified from an established NICU database and were control-matched with 2 neonates treated at the same institution. The medical records of each patient during the NICU admission as well as the prenatal and delivery record of the patient's mother were reviewed. Perinatal data, including maternal smoking, maternal hypertension, maternal BMI, maternal gestational diabetes, conduct of labor and type of delivery, Apgar scores, types of feedings, and placental pathology, were examined, with P < .05 deemed significant. RESULTS: A total of 73 neonates diagnosed with NEC and 146 matched controls were identified. Medical records for each subject and their mothers were reviewed (438 records total). Maternal cigarette smoking was significantly associated with the future development of NEC (P = .02). Maternal gestational diabetes, maternal hypertension, formula feeding, and pathologic chorioamnionitis or uteroplacental insufficiency did not correlate with NEC. CONCLUSIONS: These data identified maternal cigarette smoking as the only risk factor that is associated with the development of NEC in premature infants. Our data imply that smoking delivers toxins and nicotine to the uterine microenvironment that can affect microvascular development and may predispose the fetus to future NEC.

Reassessing the clinical significance of chorionic membrane microcysts and linear necrosis.

Recent studies have suggested that 2 lesions of the fetal membranes, linear necrosis at the choriodecidual junction and chorionic membrane microcysts, are markers of uteroplacental ischemia. To evaluate this hypothesis, we examined 807 placentas from unselected, consecutive deliveries at a single hospital over approximately 6 months with specific recording of the presence of chorionic microcysts or linear membrane necrosis. Clinical factors that might indicate uteroplacental ischemia were abstracted from the pathology report, including small for gestational age, pregnancy-induced hypertension, meconium macrophages in the membranes, infarctions, and small placenta. We found that both chorionic microcysts and linear membrane necrosis are very common lesions in unselected placentas, involving 28% and 18% of all placentas, respectively. There was no correlation between the presence of chorionic membrane microcysts and any marker of uteroplacental ischemia. Linear necrosis correlated only with the presence of meconium macrophages. We conclude that these membrane changes are not a useful marker of ischemia in an unselected population of placentas. We suggest caution in the interpretation of these findings, to avoid overdiagnosing ischemia or other pathologic processes.

Nosology: infarction hematoma, a placental infarction encasing a hematoma.

Six cases of mothers whose placentas demonstrate multiple infarctions with a central intraparenchymal hematoma are presented. The histology is distinct from intervillous thrombus and Kline hemorrhage. The mothers have a history of multiple fetal losses, eclampsia/preeclampsia, and at least 1 case of documented recurrence. A distinct name is proposed for this lesion, infarction hematoma, which would help clarify further studies.

Review of autopsies of stillborn infants with retroplacental hematoma or hemorrhage.

Intrathoracic petechiae are a potential marker of acute asphyxia in stillborn infants. Retroplacental hematoma (RPH) is a cause of acute asphyxia. The histological features of RPH can be timed using criteria for intrauterine duration of fetal death. Autopsies of stillborn infants of >26 weeks in gestation with RPH were evaluated for gross or microscopic evidence of petechiae. Placental gross and microscopic features were recorded. Eleven controls from other mechanisms of death were randomly selected. Intrathoracic petechiae were present in all 17 infants with RPH of >50% of the placental area, in 3 of 7 infants with <50% area RPH, and in 2 of 11 infants with other diagnoses. The placenta demonstrated basal plate neutrophils in all cases of RPH (N  =  21). Early coagulation necrosis in the villi overlying the RPH was present in 5 of 13 cases after 4 to 24 hours, and complete coagulation necrosis was present in 3 of 4 cases after 24 hours. Infants with RPH underlying >50% of the placenta demonstrate intrathoracic petechiae, but controls and infants with smaller RPH do so much less frequently. This is consistent with the hypothesis that intrathoracic petechiae are a marker for intrauterine asphyxia. Basal plate neutrophils are a useful early marker of retroplacental hemorrhage. Early coagulation necrosis of the placenta over RPH begins in 4 to 24 hours but is not complete after more than 24 hours.

Stillborn infant with calcified chorionic epithelium, corneal scarring, and pericarditis.

This autopsy of a stillborn term infant revealed a constellation of unusual features including calcification of the chorion membrane and portions of the umbilical vascular media, extensive white matter gliosis, arthrogryposis multiplex congenita, adhesions of one eyelid to the globe, pericarditis, a miniature left foot, and a cleft palate. We hypothesized that the membrane and umbilical cord lesions resulted from an episode of resolved chorioamnionitis earlier in the pregnancy. Mare reproductive loss syndrome (MRLS) demonstrates a bacteremic infection of the amniotic cavity, pericarditis, and uniocular endophthalmitis in the mare. On the basis of analogy, we speculated that this infant suffered an intrauterine bacteremia with tissue predilection similar to that of MRLS.

Stillbirth due to placental hypoperfusion after salpingo-oophorectomy for an ovarian cyst.

BACKGROUND: Gravid oophorectomy past mid-pregnancy may be necessary, but the alterations of blood flow to supply the placenta may present risks to the mother and fetus. CASE: A salpingo-oophorectomy for a mucinous cystadenoma resulted in a postoperative hemorrhage of 2 L and fetal death. The placenta demonstrated a unique lesion that was consistent with global hypoperfusion of the placenta. CONCLUSION: The postoperative hemorrhage occurred despite good immediate operative hemostasis. Blood flow was shunted from the uteroplacental circulation due to the large utero-ovarian collateral circulation.

Complement component 9 activation, consumption, and neuronal deposition in the post-hypoxic-ischemic central nervous system of human newborn infants.

The role of complement in neonatal hypoxic-ischemic brain injury is not known. Therefore, cerebral spinal fluid (CSF) and post-mortem cerebral tissue were analyzed to determine whether complement is activated and complement component 9 (C9) is deposited on neurons in the central nervous systems (CNS) of newborn infants who developed moderate to severe hypoxic-ischemic encephalopathy (HIE). Control CSF samples were obtained during routine evaluation for possible sepsis from infants who were not depressed at birth. In ELISA assays of CSF obtained from 16 infants with HIE, compared to CSF from 7 control infants, the mean concentration of terminal complement complexes was elevated and the mean C9 concentration was diminished. Immunofluorescence microscopy of post-mortem frozen brain tissue obtained from two infants who expired at 4-5 days of life after severe HIE revealed that activated C9 was deposited on cells in all lobes. Double label immunofluorescence microscopy demonstrated that nearly all of the C9-positive cells were neurons and essentially all of the neurons were C9-positive. Immunoperoxidase immunohistochemistry of formalin-fixed tissue also confirmed the presence of many C9-positive cells, particularly in the hippocampus. The C9-positive cells usually manifested morphology consistent with neurons, most of which contained fragmented nuclei. In summary, complement was activated in the CNS of newborn infants who developed moderate to severe HIE. C9 was deposited on neurons, including morphologically apoptotic neurons. Further investigations into a possible role of complement in the pathogenesis of neonatal hypoxic-ischemic cerebral injury are warranted.

Non-iatrogenic pathology of the preterm infant.

Non-iatrogenic anatomical findings at autopsy provide insight into preterm infant physiology. The different patterns of lipid accumulation in the adrenal may correspond to long-term differences in stress response. Cardiac papillary muscle infarction occurs with asphyxia or shock and can explain myocardial dysfunction. Underdevelopment of preterm kidneys may correlate with susceptibility to renal disease and hypertension in adult life. Immaturity of the lung or immature responses to inflammation, rather than high oxygen concentrations or high ventilation pressures, may underlie chronic lung disease in premature infants. Hepatic extramedullary haematopoiesis is normal but, if excessive or abnormally persistent, can be an indicator of fetal disease. Hypertrophic somatostatin islet cells found with intra-uterine growth retardation may correlate with low serum insulin. Thymic involution may mark the degree of stress. Small thyroglobulin stores may limit the premature neonate's initiation of thermogenesis.

What we have learned regarding antibiotic therapy for the reduction of infant morbidity after preterm premature rupture of the membranes.

Preterm premature rupture of the membranes (pPROM) is responsible for approximately one third of the over 450,000 preterm births occurring in the United States annually. In this manuscript, we summarize the outcomes and analyses related to the National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network (NICHD-MFMU) network multicenter trial of antibiotics to reduce infant morbidity after pPROM. Based on evident reduction in gestational age dependent and infectious infant morbidity, we provide the rationale for aggressive intravenous and oral, broad spectrum Ampicillin/Amoxicillin, and Erythromycin therapy during conservative management of pPROM before 32 weeks' gestation. We further review the histopathologic correlates to pPROM, to antibiotic treatment, and to perinatal outcome, and discuss the relationships between maternal and neonatal cytokine levels intercellular adhesion molecule, and other clinical and plasma markers regarding perinatal morbidity. The use and limitations of ultrasound and vaginally collected amniotic fluid pulmonary maturity assessment are discussed.

Developmental field defects: coming together of associations and sequences during blastogenesis.

We report on two patients with an unusual combination of multiple congenital anomalies including holoprosencephaly, encephalocele, and additional defects commonly observed in the VACTERL and schisis "associations." One of the infants had a chromosome abnormality characterized by partial duplication and deletion of chromosome 18. VACTERL association was characterized recently as a primary developmental field defect (DFD) [Martínez-Frías et al., 1998: Am J Med Genet 76:291-296]. In some cases, sequences may also represent uncomplicated DFDs. We suggest that findings in both of these cases represent abnormalities of blastogenesis involving the primary field resulting in holoprosencephaly and VACTERL and schisis anomalies, and show that similar primary DFDs are causally heterogeneous.