Herbert Valensise

Early and Late Preeclampsia Two Different Maternal Hemodynamic States in the Latent Phase of the Disease

Because early and late preeclampsia (PE) are thought to be different disease entities, we compared maternal cardiac function at 24 weeks gestation in a group of normotensive asymptomatic patients with subsequent development of early (<34 weeks gestation) and late (≥34 weeks gestation) PE (blood pressure >140/90+proteinuria >300 mg/dL) to detect possible early differences in the hemodynamic state. A group of 1345 nulliparous normotensive asymptomatic women underwent at 24 weeks gestation uterine artery Doppler evaluation and maternal echocardiography calculating total vascular resistance. In the subsequent follow-up 107 patients showed PE: 32 patients had late and 75 had early PE. Five of 32 patients with late PE and 45 of 75 patients with early PE had bilateral notching of the uterine artery at 24 weeks (15.6% versus 60.0%; P<0.05). Total vascular resistance was 1605±248 versus 739±244 dyn · s · cm−5, and cardiac output was 4.49±1.09 versus 8.96±1.83 L in early versus late PE (P<0.001). Prepregnancy body mass index was higher in late versus early PE (28±6 versus 24±2 kg/m2; P<0.001). Early and late PE appear to develop from different hemodynamic states. Late PE appears to be more frequent in patients with high body mass index and low total vascular resistance; earlier forms of PE appear to be more frequent in patients with lower BMI and with bilateral notching of the uterine artery. These findings support the hypothesis of different hemodynamics and origins for early PE (placental mediated, linked to defective trophoblast invasion with high percentage of altered uterine artery Doppler) and late PE (linked to constitutional factors such as high body mass index).

Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage

BACKGROUND Endocannabinoids such as anandamide are thought to have adverse effects on pregnancy and embryonic development. The activity of the degradative enzyme anandamide hydrolase may therefore be crucial for prevention of excessive concentrations of anandamide in the uterus, and thus prevention of pregnancy failure or female infertility. We tested this hypothesis in a preliminary study, and then used the results to find out whether anandamide hydrolase activity could predict miscarriage in a group of pregnant women. METHODS We assessed anandamide hydrolase activity in peripheral lymphocytes from 50 healthy, pregnant women at weeks 6-11 of gestation by a specific radiochromatographic method. The expression of the enzyme at the protein level was measured by ELISA with specific polyclonal antibodies. In a further study, we measured anandamide hydrolase concentration in 120 women who were 7-8 weeks pregnant and compared these findings with subsequent pregnancy outcome. FINDINGS In the first study, seven of the 50 women had a miscarriage. Anandamide hydrolase activity was lower in the seven women who miscarried than in the 43 who did not (60.43 pmol/min per mg protein [SD 29.34] vs 169.60 pmol/min per mg protein [30.20]; difference 109.17 pmol/min per mg protein [95% CI 26.64-191.70]; p<0.0001 by the Mann-Whitney test). Enzyme activity correlated with enzyme concentration, and a threshold concentration represented by an optical density (after ELISA) of 0.15 absorbance units at 450 nm separated the women who had miscarriages from those who did not. In the second study, 15 women had anandamide hydrolase concentrations below the threshold, and 105 had concentrations at or above the threshold. All 15 women in the low anandamide hydrolase group had miscarriages, compared with one of the 105 women with high concentrations (p<0.0001 by Fishers exact test). INTERPRETATION Decreased anandamide hydrolase activity and expression in peripheral lymphocytes is an early (<8 weeks of gestation) marker of spontaneous abortion, and may prove useful as a diagnostic tool for large-scale, routine monitoring of gestation. Our results also suggest that endocannabinoids might be critical in regulating the lymphocyte-dependent cytokine network associated with human fertility and successful pregnancy.

Progesterone Up-Regulates Anandamide Hydrolase in Human Lymphocytes: Role of Cytokines and Implications for Fertility

Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human lymphocytes. At the same concentrations, the membrane-impermeant conjugate of progesterone with BSA was ineffective, suggesting that binding to an intracellular receptor was needed for progesterone activity. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level, and was partly mediated by the Th2 cytokines. In fact, lymphocyte treatment with IL-4 or with IL-10 had a stimulating effect on FAAH, whereas the Th1 cytokines IL-12 and IFN-γ reduced the activity and the protein expression of FAAH. Human chorionic gonadotropin or cortisol had no effect on FAAH activity. At variance with FAAH, the lymphocyte anandamide transporter and cannabinoid receptors were not affected by treatment with progesterone or cytokines. Good FAAH substrates such as anandamide and 2-arachidonoylglycerol inhibited the release of leukemia-inhibitory factor from human lymphocytes, but N-palmitoylethanolamine, a poor substrate, did not. A clinical study performed on 100 healthy women showed that a low FAAH activity in lymphocytes correlates with spontaneous abortion, whereas anandamide transporter and cannabinoid receptors in these cells remain unchanged. These results add the endocannabinoids to the hormone-cytokine array involved in the control of human pregnancy.

Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.

PROBLEM: The aim of this study is to evaluate the role of mild thyroid abnormalities in recurrent spontaneous abortion, and to assess the effects of two different therapeutical protocols.
 METHOD: A prospective study in the population of recurrent aborters with mild thyroid abnormalities, evaluating the obstetric outcome in 42 patients. Sixteen thyroid autoantibodies positive patients were treated with thyroid replacement therapy, while 11 patients received intravenous immunoglobulins (IVIG). Fifteen patients, characterized by negative antithyroid antibodies, and having underlying thyroid pathology, were treated with thyroid replacement therapy.
 RESULTS: Among patients with thyroid antibodies, 6 out of the 11 pregnancies (54.5%) treated with IVIG ended in live birth. In the thyroid supplementation group, 13 out of 16 pregnancies (81.2%) ended in live birth. Only one pregnancy loss occurred among patients with a mild underlying thyroid pathology treated with thyroid replacement therapy.
 CONCLUSIONS: Mild thyroid abnormalities are associated with an increased rate of miscarriage. This poor obstetrical prognosis seems to be related to an impaired thyroid adaptation to pregnancy. Thyroid replacement therapy appears to be more effective than IVIG in preventing a new miscarriage.

Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies : A comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin

PROBLEM: To compare the use of intravenous immunoglobulins (IVIG) with prednisone plus low‐dose aspirin (LDA) in treating pregnant women with a history of recurrent fetal loss having the antiphospholipid antibody (aPL), in terms of live‐birth rate and maternal and perinatal morbidity.
 METHOD: A prospective, two‐centers trial study included 82 recurrent aborters with aPL syndrome. Twenty‐nine were treated with prednisone and LDA in one center, 53 received IVIG in the other center. Maternal and fetal outcomes and pregnancy complications were compared between groups.
 RESULTS: Live‐birth rates were equivalent between groups (78 vs 76%). Mean birth weight was higher in the IVIG group than in the prednisone plus LDA group. In the prednisone‐ plus LDA‐treated patients, gestational hypertension and gestational diabetes were found significantly more often than in the IVIG‐treated group (14 vs 5% and 14 vs 5%, respectively).
 CONCLUSION: In patients with aPL syndrome, IVIG treatment improved pregnancy outcome, with significantly lower pregnancy complication rates, when compared with prednisone plus LDA therapy.

Intrauterine growth restriction and fetal body composition

To assess the differences in fetal body compartments between fetuses with normal growth and those with reduced intrauterine growth, during the third trimester, through ultrasonographic determination of subcutaneous tissue thickness (SCTT).

Fetal subcutaneous tissue thickness (SCTT) in healthy and gestational diabetic pregnancies

To determine reference values of fetal subcutaneous tissue thickness (SCTT) throughout gestation in a healthy population and to compare them with those from a population of pregnant women with gestational diabetes under standard therapy.

Total Vascular Resistance and Left Ventricular Morphology as Screening Tools for Complications in Pregnancy

We evaluated the predictive value of elevated total vascular resistance on the outcome of pregnancy in normotensive high-risk primigravidas with bilateral notching of the uterine artery Doppler. A total of 526 high-risk primigravidas referred to the obstetrics outpatient clinic of Tor Vergata University with bilateral notching of the uterine artery at 20 to 22 weeks’ gestation were submitted to a maternal echocardiographic examination and uterine artery Doppler evaluation at 24 weeks’ gestation. Blood pressure was recorded at the time of the examination, total vascular resistance was calculated, and the geometric pattern of the left ventricle was assessed. Patients were followed until the end of pregnancy to detect fetal/maternal adverse outcomes (gestational hypertension, preeclampsia, abruptio placentae, fetal growth restriction, perinatal death, etc). A total of 111 of the 526 pregnancies showed a bilateral notch at 24 weeks’ gestation, and 97 had an adverse outcome (18.44%). The best independent predictor for maternal and fetal complications was total vascular resistance (odds ratio: 91.25; 95% CI: 39.64 to 210.05; P<0.001). The cutoff value was 1400 dynes · s · cm−5, with a sensitivity and a specificity of 89% and 94%, respectively. A high relative wall thickness of the left ventricle (>0.37; odds ratio: 2.47; 95% CI: 1.12 to 5.44) and a hypertrophized ventricle (left ventricular mass >130 g; odds ratio: 2.52; 95% CI: 1.12 to 5.64) were also independent predictors (P<0.05). Echocardiography might identify at 24 weeks’ gestation patients who subsequently develop maternal and fetal complications through the assessment of maternal hemodynamics and left ventricular geometry.

Maternal Diastolic Dysfunction and Left Ventricular Geometry in Gestational Hypertension

Abstract—The objective of this study was to evaluate diastolic parameters and left ventricular geometry in gestational hypertension. Twenty-one consecutive pregnant women with gestational hypertension and 21 normotensive women matched for age and gestational age were enrolled in the third trimester of gestation. Echocardiographic and uterine color Doppler evaluations were performed. Systolic, diastolic, and mean blood pressure, total vascular resistance (TVR), and uterine resistance index were higher in hypertensive women than in control subjects (P <0.01). Left atrial function and cardiac output were significantly lower in gestational hypertension (P <0.01). Patients with gestational hypertension had longer left ventricular isovolumetric relaxation time (IVRT) (P <0.0001); lower velocity-time integral of the A wave (P <0.05) and of the diastolic pulmonary vein flow (P <0.05); and higher velocity-time integral of the reverse pulmonary vein flow (P <0.05). Systolic fraction of the pulmonary vein flow was higher in women with gestational hypertension than in control subjects (P <0.01); the difference in duration of pulmonary vein flow and A wave was closer to 0 in gestational hypertension (P <0.0001). Altered left ventricular geometry was found in 100% of hypertensive patients and in 19.05% of normotensive patients (P <0.001). IVRT, left ventricular end-systolic volume, atrial function, and uterine resistance index were directly related to TVR (P <0.01); deceleration time of the E wave showed a quadratic correlation with TVR (P <0.01). Gestational hypertension is characterized by an altered cardiac geometric pattern of concentric hypertrophy. The altered geometric pattern assessed during gestational hypertension is associated, in our study, with depressed systolic function, high TVR, altered diastolic function, and left atrial dysfunction. Deceleration time of the E wave, IVRT, and left atrial fractional area change, found in concomitance with the highest TVR, may be useful in the evaluation of cardiac function and hemodynamics present in pregnancy-induced hypertension.

Body composition during normal pregnancy: reference ranges

Abstract.Maternal body composition undergoes a deep adaptative change during the course of pregnancy. Fat mass, fat-free mass, and total body water (TBW) increase in different ways and their effects on pregnancy outcome represent a field of major interest in perinatal medicine. The aim of this study was to evaluate the changes in maternal body composition [maternal weight, TBW, intracellular water (ICW) and extracellular water (ECW)] during healthy pregnancy by using bioimpedance analysis (BIA). A total of 170 healthy pregnant women, aged 22–44 years, volunteered to participate in our study. The BIA measurements were carried out with a Tefal BIA scale determining resistance and reactance. Lukaski’s multiple-regression equation was used to estimate TBW and ICW and ECW were computed using the prediction formula of Segal. The evaluations were performed at 10–38 weeks’ gestation, every 3–4 weeks, and hematocrit was determined at every time interval. Analysis of variance and multiple comparisons of Bonferroni were performed to compare variables among the different study intervals. Second-order polynomial interpolation was used to obtain percentile values for each bioimpedance parameter. Percentile bioimpedance values of the healthy population are provided at each study time, by showing the mean value and the 5th, 25th, 75th, 95th percentiles. Moreover, normal reference ranges for TBW are provided for each gestational age, in relation to maternal weight gain. Reactance, TBW, and ICW enhance slightly during the course of gestation. Tetrapolar BIA could be an easy and practical tool for evaluating changes of maternal body components during pregnancy. It could also provide indirect proof of the normal hemodilution occurring in normal pregnancies. Moreover, fat mass deposition, and not only fluid retention, seems to be responsible for the mother’s gestational weight gain, since reactance is an indirect parameter in estimating fat mass amount.