Plasma copeptin in preterm infants: a highly sensitive marker of fetal and neonatal stress.

CONTEXT: Copeptin is a stable by-product of arginine-vasopressin synthesis and reflects its secretion by the pituitary. OBJECTIVE: The objective of the study was to investigate perinatal factors affecting copeptin concentrations in preterm infants at birth and at 3 d of life. DESIGN AND SETTING: This was a prospective cross-sectional study at two Swiss university hospitals. PATIENTS: One hundred sixty-seven preterm infants were enrolled, 59 infants born between 24 and 31 wk gestational age, 50 infants between 32 and 34 wk, and 58 between 35 and 36 wk. MAIN OUTCOME MEASURE: Plasma copeptin concentrations, determined by a CT-proAVP-luminescence-immunoassay, were measured. RESULTS: Copeptin at birth was significantly higher in preterm infants born vaginally [median (range) 366 (1-2900) pmol/liter, n = 43] than those born by cesarean section [6.9 (2-1580), n = 124]. In infants born after cesarean without prior labor (n = 66), estimated fetal weight less than the fifth percentile, suspect fetal heart rate, compromised placental perfusion, and chorioamnionitis were each associated with significantly elevated cord copeptin. Copeptin at 3 d of life was not associated with cord blood copeptin but inversely related to gestational age (Rs = -0.6, P < 0.001) and birth weight (Rs -0.612, P < 0.001). Day 3 copeptin increased alongside the level of mechanical respiratory support. CONCLUSION: Copeptin is a highly sensitive marker of perinatal stress.

NEK1 mutations cause short-rib polydactyly syndrome type majewski.

Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype.

"Broken heart" after cesarean delivery. Case report and review of literature.

OBJECTIVE: To present a rare case of a multiparous woman undergoing elective cesarean section with apparent symptoms of acute coronary syndrome and who was later diagnosed with Takotsubo cardiomyopathy (TCM; "broken heart syndrome"). To review similar case reports already reported in literature. METHODS: Literature search on the occurrence of TCM in pregnancy using MEDLINE and Cochrane databases. RESULTS: TCM might occur in women with no known pre-existing cardiomyopathy and uncomplicated pregnancies undergoing cesarean section, especially in combination with the administration of catecholamines/vasoconstrictive substances and possibly also oxytocin and prostaglandins. CONCLUSIONS: Since TCM is related to emotional and physical stress, the surroundings during cesarean section should be kept quiet and smooth. Adrenergic stimulants (adrenaline, phenylephrine, ergonovine, ephedrine) and anticholinergics (atropine) should be used with caution and adequate volume substitution prior to the onset of spinal analgesia for the prevention of hypotension should be provided. If signs of an acute coronary syndrome during cesarean section do occur, echocardiography is obligatory for diagnosis of TCM.

High copeptin concentrations in umbilical cord blood after vaginal delivery and birth acidosis.

CONTEXT: The pituitary-secreted nonapeptide arginine-vasopressin (AVP) is unstable and therefore unsuited for diagnostic use, but its secretion can be estimated by measuring copeptin, the C-terminal portion of the AVP precursor (pro-AVP). OBJECTIVE: Our objective was to investigate perinatal factors affecting copeptin concentrations in infants at birth and at 3 d of life. DESIGN AND SETTING: We conducted a prospective cross-sectional study at a tertiary university hospital. PATIENTS: Copeptin plasma concentrations were evaluated in 177 infants at birth, including 117 paired arterial/venous umbilical cord and 102 venous blood samples obtained at 3 d of life. MAIN OUTCOME MEASURE: Copeptin concentrations were determined by a C-terminal pro-AVP luminescence immunoassay. RESULTS: Arterial umbilical cord copeptin concentrations were consistently higher than matched venous ones (median 18 vs. 10 pmol/liter, P < 0.001), but both values were closely related (R(s) = 0.825; P < 0.001), and both were negatively related to arterial umbilical cord pH (R(s) arterial/venous = -0.578/-0.639; P < 0.001). Although exceedingly high copeptin concentrations were observed after vaginal birth in umbilical cord arterial [median (5-95% range) = 1610 (85-5000) pmol/liter] and venous [793 (6-4836) pmol/liter] plasma, copeptin concentrations were low after primary cesarean section [arterial/venous = 8 (3-907)/5 (5-504) pmol/liter]. Postnatal body weight loss was associated with increased copeptin concentrations at d 3 (R(s) = 0.438; P < 0.001) and was inversely related to copeptin concentrations at birth (R(s) = -0.289 and -0.309; both P = 0.001). CONCLUSION: Vaginal birth is associated with a large release of copeptin that exceeds all values published so far, including those in critically ill adult patients with shock or brain injury. Thus, vaginal birth is arguably the most intense stressor in life.

Impact of the estrus cycle and reduction in estrogen levels with aromatase inhibition, on renal function and nitric oxide activity in female rats.

Estradiol increases mRNA and/or protein expression of the nitric oxide synthase (NOS) isoforms in a variety of tissues including kidney. In this study we determined the relationship between cyclical variations in estradiol levels and renal function and total NO production in the virgin female rat. In addition, we used an aromatase inhibitor (Anastrozole), to inhibit synthesis of estradiol from testosterone. Estradiol levels were higher in proestrus vs. diestrus, and were markedly suppressed by 7 days treatment with aromatase inhibitor. There was no difference in total NO production (from urinary and plasma nitrate+nitrite=NO(X)) between proestrus and diestrus but aromatase inhibition resulted in increases in total NO production. The renal cortical NOS activity and protein abundance also increased in aromatase-inhibited female rats. There were no differences in blood pressure (BP) in any group but the renal vascular resistance (RVR) was low in proestrus, increased in diestrus and did not change further after aromatase inhibition. In summary, the cyclical changes in renal function correlate with estradiol but not NO levels. Pharmacologic castration with aromatase inhibition leads to a marked increase in total and renal NOS. This contrasts to earlier work where surgical castration causes decreased NOS.

Effect of antenatal betamethasone administration on neonatal cardiac autonomic balance.

Beneficial effects of antenatal glucocorticoid treatment in pregnancies at risk for preterm delivery may entail long-term consequences for the establishment of sympathoadrenergic system balance. We analyzed the cardiac autonomic system activity in neonates with a single course of antenatal betamethasone (2 × 12 mg) treatment by calculating heart rate variability (HRV) time-domain parameters from 24 h ECG recordings and short-term frequency-domain parameters during infant active and resting states. In addition, resting and challenged salivary α-amylase levels were measured in 23 betamethasone-exposed neonates and compared with controls. Indicators for overall HRV (SDNN: p = 0.258; triangular index: p = 0.179) and sympathovagal balance [low- to high-frequency power (LF/HF): p = 0.82 (resting state)] were not significantly different in neonates of the betamethasone treatment group. Parameters mostly influenced by sympathetic activity [SD of the average of valid NN intervals (SDANN): p = 0.184 and SDs of all NN intervals (SDNNi): p = 0.784] and vagal tone [RMSSD: p = 1.0; NN50: p = 0.852; HF: p = 0.785 (resting state)] were unaltered. Resting α-amylase levels were not significantly different in the betamethasone treatment group (p = 0.304); however, α-amylase release after a neonatal challenge was slightly reduced (p = 0.045). Thus, cardiac autonomic balance seems to be preserved in neonates exposed to a single course of antenatal betamethasone treatment.

Fetal MRI of conjoined twins who switched their relative positions.

Conjoined twinning is a very rare occurrence with no genetic predisposition. Twisting of conjoined twins around the axis of their connecting tissue bridge, close to the third trimester, has not been previously reported. We describe a unique case of in utero twisting of conjoined omphalopagus twins who survived without any adverse effects. Fetal US and fetal MRI played a vital role in the diagnosis and perinatal management of these twins.

Antenatal betamethasone administration alters stress physiology in healthy neonates.

OBJECTIVE: To analyze hypothalamic-pituitary-adrenal axis balance in healthy newborns after antenatal betamethasone treatment for lung maturation where delivery could be prolonged until or near term. METHODS: In a prospective observational study, salivary cortisol and cortisone levels were measured at the fourth day of life during resting conditions and in response to a pain-induced stress event in 23 neonates with antenatal exposure to a single course of betamethasone (2x12 mg) and compared with 40 controls. The mean interval between betamethasone treatment and delivery was 60+/-23 days. RESULTS: On day 4 of life, neonates in the control group exhibited a significant increase in cortisol and cortisone from baseline levels after the stress induction (1.175-2.4 ng/mL for cortisol and 11.35-18.15 ng/mL for cortisone [both P<.05]), whereas, in betamethasone-exposed neonates, cortisol and cortisone stress response was not significantly different from baseline levels (1.39-1.6 ng/mL for cortisone [P=.76] and 14.8-17.1 ng/mL for cortisol [P=.69]). No influence of gestational age at betamethasone administration (P=.76) or gestational age at delivery (P=.71) on stress response patterns was observed in a multiple stepwise regression. CONCLUSION: A single course of antenatal betamethasone treatment induces a suppression of stress reactivity in healthy newborns.

Blunted stress response in small for gestational age neonates.

There is evidence that adverse conditions during intrauterine development affect future health of the offspring. Hypothalamus-pituitary-adrenal (HPA) axis dysregulation is assumed to play an important role in the association of small for gestational age (SGA) and the pathogenesis of hypertension and the metabolic syndrome. Stress response patterns in SGA neonates may identify a link with intrauterine-induced permanent maladaptation of the HPA axis. Salivary cortisol and cortisone levels were therefore analyzed during resting conditions and in response to a pain-induced stress event in SGA (<5th percentile) and appropriate for gestational age (AGA) neonates born > or =34 wk of gestation. In AGA neonates, salivary cortisol and cortisone levels significantly increased after the stress event (p < 0.05). In contrast, SGA infants exhibited a blunted steroid release after stress induction (p = 0.76, p = 0.65, respectively). No influence of mode of delivery (p = 0.93), gender (p = 0.21), and gestational age (p = 0.57) on stress response patterns was observed in a multiple stepwise regression. SGA neonates show a blunted physiologic activation of the HPA axis in response to a stress stimulus. Thus, intrauterine-induced alteration of HPA axis regulation seems to persist into the postnatal period and represents a prerequisite for the hypothesis of HPA axis involvement in the fetal origin of adult diseases.

[Fetal growth retardation and diseases in adult life]. / Fetale Wachstumsrestriktion und Erkrankungen im Erwachsenenalter.

Numerous epidemiologic studies in different populations reveal an association between intrauterine growth restriction and the occurrence of arterial hypertension, arteriosclerosis, hyperlipidemia, type 2 diabetes mellitus and mental diseases later in life. Animal studies confirm these associations to be independent from genetic conformation and postpartum influences. However, both the mechanisms of intrauterine programming and the critical time of an insult to result in fetal problems are unclear. Therefore, the results of large-scale, prospective studies are needed before therapeutic interventions during pregnancy or post partum to prevent adverse effects of fetal programming are scientifically justified.

Post-delivery oxidative stress in women with preeclampsia or IUGR.

AIM: To compare oxidative stress in patients with preeclampsia (PE) or intrauterine growth restriction (IUGR) vs. normal pregnancy (controls) during 48 h after delivery. STUDY DESIGN: Women with singleton pregnancies were recruited immediately after delivery (gestational age >26.0 weeks). Women with PE or IUGR were matched with healthy controls by age, BMI, gestational age and delivery mode. Venous blood samples and urine samples were tested for oxidative stress products 24 h and 48 h after delivery. RESULTS: Plasma malondialdehyde (MDA) concentration 24 h after delivery was significantly higher in subjects with PE or IUGR (3.41+/-1.14 micromol/L, n=20) than in controls (2.91+/-0.82 micromol/L, n=38) (P=0.04). Urine iPF(2alpha)-VI declined from 24 to 48 h after delivery significantly in controls (P=0.006) and not in subjects with PE or IUGR (P=0.71). CONCLUSION: Of the markers tested only MDA is indicating higher oxidative stress in women with PE/IUGR than in normal pregnancy and only at 24 h after delivery. No consistent pattern of change in the oxidative stress markers exists between 24-48 h after delivery.

17-Hydroxyprogesterone in premature infants as a marker of intrauterine stress.

AIMS: Amniotic infection (AI) and preeclampsia (PE), which are commonly the reason for prematurity, inflict stress of different duration on immature fetuses. Whether chronic stress, as reflected by intrauterine growth retardation, influences the level of 17-OH progesterone (17-OHP), was not previously examined. METHODS: We analyzed 17-OHP and TSH levels during neonatal screenings in the first hours of life of 90 premature infants born between 25 and 33 weeks of gestation in infants with AI (n=37) or with PE (n=53). Control of acute stress parameters was derived from umbilical arterial cord blood pH and base excess (BE). RESULTS: Mean 17-OHP levels of infants born to mothers with PE were 85.7 nmol/L compared to 54.6 nmol/L (P<0.001) in AI infants. 17-OHP was even higher when intrauterine growth restriction was present (99.8 nmol/L). Antenatal steroids and mode of delivery did not significantly affect 17-OHP levels. CONCLUSIONS: Stress of relatively long duration, as in cases of PE, leads to a significant increase of 17-OHP level in preterm infants. The postnatal 17-OHP level may be considered as a measure for severity of intrauterine stress and might be used as an individualized indicator for earlier intensive care.

Scar appearance of different skin and subcutaneous tissue closure techniques in caesarean section: a randomized study.

OBJECTIVES: To determine the role of skin and subcutaneous space closure in caesarean section on the cosmetic appearance of the scar and the patients' satisfaction. STUDY DESIGN: 153 patients undergoing caesarean section without prior abdominal delivery were included and randomly assigned in a non-blinded study to four different combinations of skin and subcutaneous tissue closure. The scar was assessed after a period of at least 4 months by a self-developed protocol and the patient was asked to complete a survey regarding her satisfaction with the scar. RESULTS: One hundred patients were eligible for long-term evaluation of the scar. Skin closure by either staples or intracutaneous suture in combination with closure or non-closure of the subcutaneous space has a comparable outcome in view of cosmetic outcome and patient satisfaction. CONCLUSIONS: All four methods of skin closure seem to be a reasonable choice in caesarean section because they have comparable cosmetic outcome, do not differ with respect to the patients' satisfaction and bear comparable costs.

Cardiac autonomic balance in small-for-gestational-age neonates.

The cardiac sympathetic nervous system is one putative key factor involved in the intrauterine programming of adult cardiovascular disease. We therefore analyzed cardiac autonomic system activity in small for gestational age (SGA) neonates. Heart rate variability (HRV) from 24-h ECG recordings were analyzed for time-domain and frequency-domain parameters in 27 SGA neonates [median 261 (240-283) days of gestation] compared with 27 appropriate for gestational age (AGA) neonates [median 270 (239-293) days of gestation]. In addition, salivary alpha-amylase levels were analyzed during resting conditions and in response to a pain-induced stress event in 18 SGA [median 266 (240-292) days of gestation] and 34 AGA [median 271 (240-294) days of gestation] neonates. Overall HRV was not significantly different in SGA neonates compared with AGA neonates (SD of all valid NN intervals: P = 0.14; triangular index: P = 0.29), and the sympathovagal balance [low frequency (LF)/high frequency (HF)] was similar (P = 0.62). Parameters mostly influenced by sympathetic activity did not reveal significant differences: (SD of the average of valid NN intervals: P = 0.27; average of the hourly means of SDs of all NN intervals: P = 0.66, LF: P = 0.83) as well as vagal tone-influenced parameters were unaltered (average of the hourly square root of the mean of the sum of the squares of differences between adjacent NN intervals: P = 0.59; proportion of pairs of adjacent NN intervals differing by >50 ms: P = 0.93; HF: P = 0.82). Median resting levels for alpha-amylase were not significantly different in SGA neonates (P = 0.13), and a neonatal stress stimulus revealed similar stress response patterns (P = 0.29). HRV and salivary alpha-amylase levels as indicators of cardiac autonomic activity were not altered in SGA neonates compared with AGA neonates. Thus, it appears that the intrauterine activation of the sympathetic system in SGA fetuses does not directly persist into postnatal life, and neonatal sympathovagal balance appears to be preserved.

Abnormal placental invasion experience at 1 center.

OBJECTIVE: To identify the incidence, risk factors, and maternal and neonatal outcome of pregnancies with abnormal placentation at a single center. STUDY DESIGN: A retrospective review of the medical records of the deliveries in 1999-2003 at the Department of Obstetrics, University Hospital Zurich, was conducted with respect to abnormal placentation, and the incidence, risk factors and outcomes were observed. RESULTS: Thirty-one women with abnormal placentation were identified. They represented 0.31% of deliveries during the 5-year period. The significant factors associated with abnormal placentation were previous uterine curettage (OR = 19.3, 95% CI 11.6-32.3), previous uterine surgery other than cesarean sections (OR = 49.6, 95% CI 24.3-102.3) and coexistent placenta previa (OR = 16.1, 95% CI 4.7-43.7). No case of maternal death occurred, and 1 neonatal death due to uterine rupture occurred in the study group. CONCLUSION: The most important risk factor in abnormal placentation was a previous uterine intervention.

Metabolic changes, hypothalamo-pituitary-adrenal axis and oxidative stress after short-term starvation in healthy pregnant women.

AIM: To compare metabolic effects and oxidative stress in pregnant and non-pregnant women after 12 h of fasting. METHODS: Twenty-six healthy women with uncomplicated singleton pregnancies between the 24(th) and 28(th) gestational week were recruited. After an overnight fast, venous blood samples and urine samples were tested for metabolic parameters characteristic for starvation, cortisol and oxidative stress products. Healthy non-pregnant women matched by age, body mass index and length of fasting comprised the control group. RESULTS: The metabolic parameters beta-hydroxybutyrate and free fatty acids in blood and ketones in urine showed no differences in pregnant and non-pregnant women. However, the oxidative stress parameters, 8,12-iso-iPF(2alpha)-VI, isoprostanes and malondialdehyde were significantly higher in pregnant subjects, as was cortisol. CONCLUSION: Healthy pregnant women are exposed to oxidative stress and activation of the hypothalamo-pituitary-adrenal axis, but not to metabolic changes resembling starvation during short fasting periods in comparison to non-pregnant healthy women.

Temporary resolution of preeclamptic symptoms after intrauterine death of one twin.

In a 34 year old woman with dichorionic twin pregnancy preeclampsia resolved after the intrauterine death of one of the HLA-identical twins and recurred with the growth of the placenta of the surviving twin later in pregnancy. This case gives indirect evidence that the clinical course of preeclampsia is a dose-dependent phenomenon in conjunction with vital placental tissue.

Axillary cavernous lymphangioma in pregnancy and puerperium.

BACKGROUND: Cavernous lymphangioma is a form of benign congenital abnormality grouped under lymphatic malformations, which can clinically manifest as a cystic tumor. Common areas are the neck and axillary region. Most cases are diagnosed in children under the age of 2, and occasionally the diagnosis is made in utero. CASE: We present the case of a 29-year-old primigravid woman with an axillary cavernous lymphangioma which rapidly increased in size during pregnancy, and describe the treatment plan in this unusual situation. CONCLUSION: The treatment of a large lymphangioma during pregnancy has to be well planned, considering the welfare of the mother and baby. Most of the current therapies have never been tested in pregnant or lactating women. We discuss the possible pathomechanisms for the growth of lymphangioma during pregnancy with the overproduction of cytokines such as vascular endothelial growth factor.

Evidence for compromised aldosterone synthase enzyme activity in preeclampsia.

BACKGROUND: In normal pregnancy, an increased aldosterone (Aldo) concentration coincides with volume expansion. In preeclampsia, Aldo levels are low despite intravascular volume depletion. The present investigation aimed to characterize the compromised Aldo synthesis in preeclampsia, and to identify the molecular basis hereof. METHODS: We recruited 66 pregnant women (24 uneventful, 42 preeclamptic). Genomic DNA was isolated from peripheral blood leukocytes. Urine samples were obtained for gas chromatography-mass spectroscopic measurements of steroid hormones reflecting apparent Aldo synthase (CYP11B2) and 11-hydroxylase (CYP11B1) activities. Polymerase chain reaction (PCR)-based screening for CYP11B2 mutations was performed by SSCP, restriction analysis, and sequencing. RESULTS: CYP11B1 activity was unaltered, but reduction of mean tetrahydro (TH)-Aldo excretion by a factor of 3.9 indicated a diminished CYP11B2 activity in preeclampsia. Accordingly, the ratios of (TH-11-dehydrocorticosterone [A]+TH-corticosterone [B]+5alpha-THB) to (TH-cortisone +TH-cortisol [F]+5alpha-THF) and of 18-OH-THA to THAldo were increased in preeclampsia 2.6- and 15.2-fold, respectively, indicating reduced Aldo synthesis due to diminished methyl oxidase (MO) activity. A lower percentage of women with normal pregnancies had CYP11B2 mutations when compared to preeclamptic women (P < 0.05). Eight polymorphisms were detected, two of which were non-amino acid conserving. Of those, the mutation V386A, earlier found to jeopardize MO activity, was exclusively observed in preeclampsia (0% vs. 17%; P < 0.05). CONCLUSION: Aldo deficiency due to a compromised MO step of Aldo synthesis favors extracellular volume depletion, and may account for an increased risk of placental hypoperfusion and consecutive development of preeclampsia. The sole presence of mutation V386A in preeclamptic mothers may identify a subgroup with an increased risk to develop preeclampsia during pregnancy.