Ernst Beinder

Nitric Oxide Synthase Activity and Doppler Parameters in the Fetoplacental and Uteroplacental Circulation in Preeclampsia

OBJECTIVE We investigated the hypothesis that changes in blood flow in the uteroplacental and fetoplacental circulation in preeclampsia are associated with an abnormality of placental or uterine placental bed nitric oxide (NO) synthesis. METHODS We measured pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries in 20 patients with preeclampsia and 14 healthy pregnant controls before elective cesarean section. During cesarean section, biopsies from the uterine placental bed and the placenta were taken and the nitric oxide synthase (NOS) activity was measured by the [3H] L-arginine-[3H] L-citrulline conversion assay in these samples. RESULTS The NOS activity was significantly lower in the uterine placental bed in comparison to the placental tissue (p < 0.01). Placental NOS activity was similar between patients with preeclampsia and healthy controls and in the groups with either a pathological or a normal Doppler flow in the umbilical artery. In the uterine placental bed however, NOS activity from patients with preeclampsia was significantly lower (p < 0.01), whereas the blood flow resistance in the uterine arteries was elevated (p < 0.01) in comparison to healthy controls. CONCLUSIONS Our data show that pathological Doppler waveforms in the uterine arteries of patients with preeclampsia are paralleled by diminished NOS activity in the uterine placental bed. Therefore, the compromised NO production in the uterine placental bed may play an important role in the impaired uteroplacental blood flow and potentially in some pathological features of preeclampsia such as intervillous thrombosis formation and fetal growth retardation.

Intrauterine Treatment of Fetal Goitrous Hypothyroidism Controlled by Determination of Thyroid-Stimulating Hormone in Fetal Serum

We report a rare case of fetal goitrous hypothyroidism complicated by polyhydramnios and preterm labor in a mother without thyroid gland pathology. The diagnosis was made in the 26th week by ultrasound and cordocentesis [TSH 170 µU/ml, free T4 0.2 ng/dl]. The therapeutic regime required repeated fetal blood sampling for determination of thyroid hormones. Five intra-amniotic administrations of 250 µg levothyroxine (LT4) weekyl were initiated. Because of the persisting goiter and the elevated level of TSH (128 µU/ml in 32 weeks) in the fetal serum the dosage had to be adjusted to 500 µg LT4 in the next five injections. TSH in fetal serum declined to 49.2 µU/ml in 36 weeks. Normal fetal growth and an uncomplicated course of pregnancy between the 27th and 37th week of gestation were observed. Monitoring of intrauterine therapy by determination of TSH in fetal serum may provide more reliable data than measuring TSH in amniotic fluid. A review of 15 cases of fetal goitrous hypothyroidism in the English literature is presented.

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 (2×12 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. LEVEL OF EVIDENCE: II

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.

Prognosis of children born to mothers with HELLP-syndrome

In literature there have been differences in the assessment of the outcome of children born to mothers with HELLP syndrome. In a retrospective study we investigated six annual groups (1989-1994) at the Perinatal Center in Erlangen (11,235 births, 68 children of mothers with HELLP syndrome), 53 children were treated in our neonatal intensive care unit (NICU). The control group (n = 219) consisted of a complete age group in our NICU. The gestational age (mean 33 weeks, p < 0.003) and the birth weight (mean 1671 g, p < 0.001) were significantly lower in the HELLP group. No significant differences were detected with respect to the frequency of leucocytopenia (p = 0.518) and thrombocytopenia (p = 0.215). Despite a relatively high rate (37.7%) of RDS there was only a significant tendency to the disadvantage of HELLP children (p = 0.075). There was no difference in frequency of intracranial hemorrhage (ICH) (p = 0.566). Infections were diagnosed less frequently in HELLP children (p = 0.042). Mortality in the control group was higher only as a tendency (p = 0.07). The follow-up examinations of the neurological development covered 31 of the 53 treated children. After 6-72 months (median 24 months), 90.3% of these children showed normal development or only minor disabilities. The prognosis of children of mothers with HELLP syndrome is not as bad as has been assumed so far.

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.

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

Abstract 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.

Skin flux during reactive hyperemia and local hyperthermia in patients with preeclampsia

OBJECTIVE To test the contribution of the endothelium to the maximum vasodilatation in patients with preeclampsia and healthy pregnant controls. METHODS Laser‐Doppler flowmetry, which is a noninvasive method for the continuous measurement of skin blood flow, was used to test the response of skin microcirculation to the above‐mentioned stimuli in 14 patients with preeclampsia and 20 normotensive pregnant controls. RESULTS In normotensive pregnant controls, the reactive hyperemic response after a 3‐minute ischemia in the forearm reaches values of 77 ± 16% of the maximum vasodilatation, which was induced by local hyperthermia of 42C. In patients with preeclampsia, this response was significantly (P < .05) reduced (43 ± 9%). CONCLUSION Vascular reactivity is altered in skin vessels of patients with preeclampsia in vivo. This alteration seems to be attributable mainly to the endothelium.

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.

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

Abstract 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 μmol/L, n=20) than in controls (2.91±0.82 μmol/L, n=38) (P=0.04). Urine iPF2α-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.