Eva Karpf

Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction

OBJECTIVE The objective of the study was to evaluate perinatal and long-term complications of fetuses with intrauterine growth restriction (IUGR) compared with constitutionally small for gestational age (SGA) ones. STUDY DESIGN The outcome of infants with IUGR and SGA born at the Medical University Graz (Austria) between 2003 and 2009 was retrospectively analyzed. Group assignment was based on birthweight, Doppler ultrasound, and placental morphology. The primary outcome was neurodevelopmental delay at 2 years corrected age. The secondary outcomes were perinatal complications. RESULTS We included 219 IUGR and 299 SGA infants for perinatal and 146 and 215 for long-term analysis. Fetuses with IUGR were delivered earlier (35 vs 38 weeks) and had higher rates of mortality (8% vs 1%; odds ratio [OR], 8.3) as well as perinatal complications (24.4% vs 1.0%; OR, 31.6). The long-term outcome was affected by increased risk for neurodevelopmental impairment (24.7% vs 5.6%; OR, 5.5) and growth delay (21.2% vs 7.4%; OR, 3.4). CONCLUSION IUGR infants are subject to an increased risk for adverse short- and long-term outcome compared with SGA children.

Age Dependency of Selenium and Cadmium Content in Human Liver, Kidney, and Thyroid

Selenium and cadmium concentrations were investigated in 60 autopsy tissue samples obtained from fetal life up to adulthood (defined in this study as 25-87 y of age) in Styria, a moderately industrialized region in Austria that has a low selenium supply. During the first 2 y after birth, median liver selenium concentrations were slightly lower (i.e., 1.5 nmol/g wet weight) than concentrations found in fetal life (i.e., 2.9 nmol/g) and adulthood (2.1 nmol/g). Whereas in the fetal period median selenium content in the kidney cortex (2.1 nmol/g) and the thyroid gland (1.6 nmol/g) was lower than that found in the liver, the reverse was true for adults (i.e., kidney, 5.5 nmol/g; thyroid, 4.3 nmol/g). Tissue cadmium concentrations approached 0 during gestation. Accumulation in the kidney and liver commenced immediately after birth. In the thyroid gland of adults, significantly higher concentrations of cadmium were found. Median concentrations in adults showed no statistical significant age dependency (i.e., liver, 7.6 nmol/g; kidney, 59.8 nmol/g; thyroid, 11.2 nmol/g). In summary, the data revealed very low tissue selenium concentrations and low cadmium burdens for the Styrian population that was not exposed occupationally.

Vascular Endothelial Expression of Indoleamine 2,3-Dioxygenase 1 Forms a Positive Gradient towards the Feto-Maternal Interface

We describe the distribution of indoleamine 2,3-dioxygenase 1 (IDO1) in vascular endothelium of human first-trimester and term placenta. Expression of IDO1 protein on the fetal side of the interface extended from almost exclusively sub-trophoblastic capillaries in first-trimester placenta to a nearly general presence on villous vascular endothelia at term, including also most bigger vessels such as villous arteries and veins of stem villi and vessels of the chorionic plate. Umbilical cord vessels were generally negative for IDO1 protein. In the fetal part of the placenta positivity for IDO1 was restricted to vascular endothelium, which did not co-express HLA-DR. This finding paralleled detectability of IDO1 mRNA in first trimester and term tissue and a high increase in the kynurenine to tryptophan ratio in chorionic villous tissue from first trimester to term placenta. Endothelial cells isolated from the chorionic plate of term placenta expressed IDO1 mRNA in contrast to endothelial cells originating from human umbilical vein, iliac vein or aorta. In first trimester decidua we found endothelium of arteries rather than veins expressing IDO1, which was complementory to expression of HLA-DR. An estimation of IDO activity on the basis of the ratio of kynurenine and tryptophan in blood taken from vessels of the chorionic plate of term placenta indicated far higher values than those found in the peripheral blood of adults. Thus, a gradient of vascular endothelial IDO1 expression is present at both sides of the feto-maternal interface.

Spontaneous Intrauterine Umbilical Artery Thrombosis Leading to Severe Fetal Growth Restriction

Intrauterine thrombosis of umbilical cord vessels is a rare event (2.5-4.5/10,000) and usually followed by poor fetal outcome. We present the rare case of spontaneous intrauterine thrombosis of an umbilical artery leading to severe intrauterine growth restriction (IUGR) and provide clinical and pathological findings. A 28-year-old nulliparous third gravida was referred to our institution because of IUGR at 32+4 weeks of gestation. Fetal growth had been appropriate until the 31st week of gestation and had stopped thereafter. There were no signs of abruption of the placenta and no structural abnormalities except an absent paravesical colour Doppler flow in the region of the right umbilical artery. Other Doppler measurements, karyotype and TORCH serology were normal. Intermittent non-reassuring fetal heart rate led to cesarean section at 34+3 weeks of gestation. A healthy girl with measurements on the 3rd centile was born (weight of 1,590 g, length of 41 cm and head circumference of 29 cm). Gross examination displayed an elongated, highly twisted umbilical cord with a length of 70 cm, central insertion and three umbilical vessels. Microscopic examination confirmed the diagnosis of umbilical artery thrombosis along the entire length of the umbilical cord. Calcification within the thrombus and microcalcification in occluded chorionic vessels were observed as well as hemorrhagic endovasculitis and endangiopathia obliterans in the stem villi arteries. This fetal thrombotic vasculopathy (FTV) comprised about 40% of the parenchyma. The coagulation parameters and blood counts of the mother and the infant were normal apart from transient neonatal thrombocytopenia. The reason for thrombosis remained unclear but could be attributed to the elongated and highly twisted umbilical cord. Intrauterine arterial thrombosis may cause severe IUGR. This condition might be detectable by ultrasound in the course of an IUGR workup, especially when no other reasons can be found.

Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro

Clinical symptoms of endometriosis, such as pain and infertility, can be described as persistent stressors. Such continuous exposure to stress may severely affect the equilibrium and bidirectional communication of the endocrine and immune system, hereby further aggravating the progression of endometriosis. In the present study, we aimed to tease apart mediators that are involved in the stress response as well as in the progression of endometriosis. Women undergoing diagnostic laparoscopy due to infertility were recruited (n = 69). Within this cohort, early stage of endometriosis were diagnosed in n = 30 and advanced stage of endometriosis in n = 8. Levels of progesterone in serum were determined. Frequency of progesterone receptor (PR) expression on CD56+ and CD8+ peritoneal lymphocytes was analysed by flow cytometry. The production of tumour necrosis factor (TNF) and interleukin (IL)-10 by peritoneal leukocytes upon stimulation with the potent stress mediator corticotropin-releasing hormone (CRH) and the progesterone derivative dydrogesterone, or both, were evaluated. Furthermore, the production of progesterone-induced blocking factor (PIBF) by peritoneal leukocytes and the expression of PR in endometriotic tissue were investigated. Levels of progesterone in serum were decreased in women with endometriosis and inversely correlated to pain scores. Furthermore, an increased frequency of CD56+PR+ and CD8+PR+ peritoneal lymphocytes was present in advanced endometriosis. The TNF/IL-10 ratio, reflecting cytokine secretion by peritoneal cells, was higher in cells derived from endometriosis patients and could be further heightened by CRH stimulation, whereas stimulation with dydrogesterone abrogated the CRH-mediated inflammation. Finally, the expression of PIBF by peritoneal leukocytes was increased in endometriosis. Low levels of progesterone in the follicular phase could be responsible for the progression of endometriosis and related pain. Peripheral CRH, increasing upon high psychological stress, might contribute to the peritoneal inflammation present in endometriosis. The therapeutic application of progesterone derivatives, CRH blocking agents as well as improvement of stress coping may disrupt the vicious circle between the chronic peritoneal inflammation and high perception of psychological stress in endometriosis.

Expression of Indoleamine 2,3-Dioxygenase In Carcinoma of Human Endometrium And Uterine Cervix

Expression of indoleamine 2,3-dioxygenase (IDO) in epithelium of the endometrium and the cervix is not restricted to normal but also present in carcinomatous tissue. The enzyme was found in the majority of cases studied, pioneer cells at the invasion front of the tumors being especially strongly reactive in immunohistology. In addition, also cells in the peritumoral infiltrate of the stroma expressed IDO. Taken together, these findings together with previous data on the immunosuppressive impact of tryptophan depletion suggest IDO-induced suppression of antitumoral immune response in both adenocarcinoma and squamous cell carcinoma of endometrium and cervix. On the other hand, IDO as also known to inhibit tumor cell proliferation by tryptophan depletion.

A case of a transient enlargement of the intracranial translucency

On the basis of the first description of the intracranial translucency (IT) as a marker for spina bifida, we started to measure the IT during the first trimester scan. In a fetus of a 28-year old healthy primigravida with no family history of neuroanatomical malformations, an abnormal IT was detected. She was referred to our unit at a gestational age of 12weeks and 3days for 11–13weeks scan. Transabdominal and transvaginal ultrasound examination revealed a fetus with a crown–rump length (CRL) of 61mm. The nuchal translucency was 1.6mm, and the combined screening revealed a calculated risk for Down syndrome of 1 : 27414. However, the IT measured was enlarged and the anterior posterior diameter was 4.7mm (Figure 1). The fetus showed no other structural abnormalities. A follow-up scan after 2weeks showed a fetus with a CRL of 91mm and a normal IT with an anteroposterior-diameter of 3.4mm (Figure 2). A repeat sonographic examination at 29weeks showed normal intracranial structures with a normal size and position of the vermis and a normal size of the cisterna magna. We concluded that this temporary enlargement of the fourth ventricle as a solitary finding might represent a normal variant. Knowledge of the embryological steps of cerebral development helps to understand the time of damage and consequences for further development. During embryologic development, the roof plate of the rhombencephalon (fourth ventricle) is divided by the plica choroidea; the superior part is called area membranacea superior, whereas the inferior part is called area membranacea inferior. The area membranacea inferior forms a small diverticulum called Blake’s pouch (BP), which fenestrates at 7 to 8weeks leaving a connection between the intraventricular space and the subarachnoid space. This median aperture is the foramen Magendie. A non-perforation of the area membranacea inferior results in the formation of a BP cyst. The extent of alteration depends on the degree of dilatation of the pouch, which in turn depends on the timing of Figure 1 Fetus at 12weeks and 3days, crown–rump length (CRL) 61mm, intracranial translucency (IT) 4.7mm (transvaginal approach) Figure 2 Fetus at 14weeks and 3days, crown–rump length (CRL) 91mm, intracranial translucency (IT) 3.4mm (transabdominal approach)

Endometrial stromal nodule embedded into term placenta

A 28‐year‐old patient presented with a 5 cm endometrial stromal tumor situated at the uteroplacental interface, which was diagnosed ultrasonographically at the 28th week of pregnancy. The tumor was asymptomatic and closely attached to the decidua; after a normal term delivery, it was revealed to be embedded within the placenta. Microscopically, the neoplasm had a high mitotic rate and characteristic features of endometrial stromal tumor, such as CD10, progesterone receptor positivity, and an expansile linear, non‐infiltrative pushing border. There were also pregnancy‐related changes such as decidualization and myxoid change. In conclusion, the lesion was considered a benign endometrial stromal nodule with an unusual morphology and increased proliferation rate due to the hormonal stimuli of pregnancy.

Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age–matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.

P34.10: Umbilical artery thrombosis leading to fetal growth restriction

rate has been reported. Therefore, it is important that obstetricians recognize risk factors for vasa previa and diagnosis of this condition should be made before rupture of the membrane. The risk factors include velamentous insertion of the cord, a bilobed, succenturiate, or low-lying placenta, multifetal pregnancy, or pregnancy resulting from in vitro fertilization. Evaluation of high-risk patients with transvaginal color flow Doppler ultrasound has been recommended. We experienced 9 cases of vasa previa without placenta previa out of 5,000 women over a 5-year period. Prenatal detection was made in 8 patients because low-lying placenta and velamentous insertion of the umbilical cord were identified during the 2nd trimester screening. Vasa previa was confirmed by 3D color flow ultrasound in these cases and Cesarean section was performed after pulmonary maturation was confirmed, or in some cases after betamethasone administration. In one case, however, vasa previa could not be identified because the cord insertion was not velamentous. Although the placenta was low-lying, vaginal color flow Doppler ultrasound was not performed. This case resulted in a rupture of vasa previa at 40 weeks’ gestation and required emergency Cesarean section. Apgar scores of the neonate at 1 and 5 minutes were 2 and 5. The neonate required blood transfusion. Advances in ultrasound have led to improved ability to diagnose this condition. Transvaginal color flow Doppler ultrasound in high-risk groups is mandatory even if a velamentous insertion of the cord is not identified.