Holger Maul

Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle

OBJECTIVEnThe purpose of this study was to evaluate cervical changes and delivery at term during pregnancy in rats after various progestin treatments.nnnSTUDY DESIGNnPregnant rats were treated by various routes and vehicles with progesterone, 17-alpha-hydroxyprogesterone caproate (17P), R5020, and RU-486. Delivery time was determined and cervical ripening was assessed in vivo by collagen light-induced fluorescence.nnnRESULTSnThe cervix is rigid in the progesterone injection, 17P, and vaginal R5020 groups vs controls. Vaginal progesterone had no effect. RU-486 treatment softened the cervix during preterm delivery. Only subcutaneous injected progesterone, R5020 (subcutaneous and vaginal), and topical progesterone in sesame and fish oil inhibits delivery. Delivery is not changed by subcutaneous injection of 17P, vaginal progesterone, oral progesterone, and topical progesterone in Replens (Crinone; Columbia Labs, Livingston, NJ).nnnCONCLUSIONnInhibition of cervical ripening and delivery by progestins depends on many factors that include their properties, the route of administration, and the vehicle. This study suggests reasons that the present treatments for preterm labor are not efficacious.

Cervical ripening and insufficiency: from biochemical and molecular studies to in vivo clinical examination.

To understand cervical ripening and especially the pathophysiology of cervical insufficiency, it is important to know the cervical composition: the cervix is dominated by fibrous connective tissue, consisting predominantly of Type I collagen (70%). Despite many studies of the cervix, we still rely upon relatively crude methods for clinical evaluation of the cervix. If the amount of cervical collagen plays a role in cervical insufficiency and in success of or length of induction of labor, then measurements of cervical collagen may provide an objective means of establishing the diagnosis or prognosis. We have established and reported a non-invasive means, called Collascope, to measure collagen cross-linking using light-induced fluorescence (LIF), and which is specifically designed to assess cervical ripening, and functions by measuring the natural fluorescence of non-soluble collagen in the cervix. Studies conducted in animals and humans in a variety of settings indicate that cervical function can be successfully monitored using the Collascope during pregnancy: LIF correlates negatively with gestational age and positively with time-to-delivery interval, and is predictive of delivery within 24h. Additionally LIF is significantly lower in women with cervical insufficiency. We suggest that the Collascope might be useful to better define management in cases of spontaneous preterm or induced term cervical ripening. From our studies and others, it is clear that in forecasting (pre-)term cervical ripening, the capability of the technologies and bioassays that have been generally accepted into clinical practice are limited. Any devices shown to be superior to the clinically accepted tests currently used should be quite useful for clinicians. The Collascope offers an objective measurement of both the function and state of the cervix, by directly measuring collagen cross-linking using LIF.

mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour

BackgroundPreterm birth is the primary cause of the neonatal mortality and morbidity. There will be no preterm birth without a cervical softening. Nitric oxide (NO) is shown to be a mediator of term cervical ripening. The aim of this study was to investigate mRNA expression of the three isomers of NO synthases (NOS) and to identify them by immunohistochemistry in the human cervix at preterm birth compared to term.MethodsThe three isomers of NOS- inducible (iNOS), endothelial (eNOS) and neuronal (bNOS) – were investigated in the human cervix. The expression of mRNA was determined using Real-Time Multiplex RT-PCR. The localisation of synthases in the cervical tissue was analysed using immunohistochemistry. Cervical biopsies were obtained from 4 groups of women without clinical signs of infection: preterm (PTL), term labour (TL), preterm not in labour (PTnotL) and term not in labour (TnotL) patients. One-Way ANOVA, Kruskal-Wallis, Student t-test or Mann-Whitney test were applied as appropriate to determine statistically significant differences among the groups.ResultsPatients in preterm labour had significantly (p < 0.01) higher mRNA levels of all the three NOS isomers compared to those in term labour. Women not in labour, irrespective of gestational age, thus with unripe cervices, had significantly lower eNOS mRNA levels compared to those in labour (p < 0.01). Immunoreactivity for all three NO synthases was observed in each examined sample in all groups. The bNOS staining was the most prominent.ConclusionThe mRNA levels were higher in the preterm labour group compared to the women at term labour. The significant increase of the eNOS mRNA expression, from the unripe to the favourable cervical state during labour, may indicate a role of eNOS and supports the role of NO in the cervical ripening process. All the three synthases were identified by immunohistochemistry in all the groups of study.

Monitoring the progress of pregnancy and labor using electromyography.

At present, there is no effective treatment for preterm labor. The most obvious reason for this anomaly is that there is no objective manner in which to evaluate the progression of pregnancy through steps leading to labor, either at term or preterm. Understanding the physiology of the uterus during term and preterm parturition is important for developing methods to control uterine function and is essential to solving clinical problems related to labor. Several techniques have been adopted to monitor and/or to diagnose labor. Unfortunately they are either subjective or indirect and do not provide an accurate prediction especially for preterm labor. Uterine electromyography (EMG) may provide more objective, highly accurate, and clinically useful information. This may be especially important in clinical scenarios such as prediction of preterm labor, differentiation between true and false labor, and management of labor augmentation, labor induction or tocolysis. Thereby EMG would enable clinicians to apply much better treatment for pregnant patients.

Tissue concentrations of cytokines in the lower uterine segment during preterm parturition

Abstract Aims: To determine the concentrations of tumor necrosis factor α, interleukin-1β, interleukin-6, and interleukinin the lower uterine segment during preterm parturition. Methods: In 71 patients who delivered prematurely nonelective cesarean tissue specimens were obtained from the lower uterine segment. The patients were grouped in relation to the stage of cervical dilatation (< 2 cm, 2–< 4 cm, ≥ 4 cm), duration of labor (≤ 6h, > 6–12 h; > 12 h), and parity (1 versus > 1). Cytokine concentrations in protein extracts of the tissue samples were measured using enzyme-linked immunosorbent assays. Results: Median concentration of tumor necrosis factor α did not change, but that of interleukin-1β, interleukin-6, and interleukin-8 were significantly higher at 2–< 4 cm than at < 2 cm cervical dilatation (6.6, 67.7, and 125.8 versus 1.1, 17.6, and 22.2 pg/mg protein, respectively). The concentrations of interleukin-6 and interleukin-8 showed a further increase at ≥ 4 cm (297.2 and 468.6 pg/mg, respectively), but for interleukin 1β a decrease was observed (0.6 pg/mg). Cytokine concentrations were not related to duration of labor or parity. Conclusions: Local inflammationassociated changes that are mainly related to the stage of cervical dilatation and to only a minor degree to uterine activity may play a crucial role in preterm parturition.

Prediction of term and preterm parturition and treatment monitoring by measurement of cervical cross-linked collagen using light-induced fluorescence.

One of the keys to treating preterm labor is the early detection of changes indicating the onset of parturition. Recently, we have developed a non-invasive method for the objective evaluation of the status of the cervix, where changes in collagen content of the cervix can be detected using an optical system and light-induced autofluorescence (LIF). This system measures the collagen fluorescence in the cervix as an indirect estimate of collagen concentration. Studies of pregnant women during the past few years support the use of this technique.

Advanced first trimester screening (AFS): an improved test strategy for the individual risk assessment of fetal aneuploidies and malformations

ObjectiveFirst trimester risk assessment for fetal aneuploidies is computed on the base of a general background risk, which is depending on the maternal age. Thereby, the adjusted risk tends to rise with increasing age. Obversely, more unsuspicious fetal parameters [measurement of the nuchal translucency (NT) and biochemical parameters, free beta human chorionic gonadotropine (fß-Hcg) and pregnancy associated plasma protein A (Papp-A)] have to be observed to result in an unsuspicious test at higher age. It was the aim of this study to investigate the potential value of a novel risk assessment algorithm explicitly disregarding the maternal age.MethodsThis was an ultrasound cohort study of 1,463 singleton pregnancies at 11–14xa0weeks of gestation undergoing a first trimester screening for fetal aneuploidies by measuring the (NT), Papp-A and fß-hCG. In each case, the pregnancy outcome was obtained. Regarding either the detection of genetic affections or the combined detection of genetic or somatic anomalies, the test performance parameters (sensitivity, specificity, positive and negative predictive values) were calculated and compared with each other. For risk calculation the standard Fetal Medicine Foundation (FMF)-Software and an alternative software with a similar algorithm (JOY-Software) were utilized. Compared to this, the risk assessment had been modified by implementing a novel calculation algorithm (advanced first trimester screening algorithm, AFS) purposely disregarding the maternal age and again, the test performance parameters had been computed and were compared with the first ones.ResultsAt the mere genetic analysis, all four test-strategies revealed to have identical sensitivity and negative predictive values. Compared to the standard FMF-Software, the JOY-Software showed a reduced false positive rate. In addition, in both softwares, the false positive rate is highly significant-reduced by implementing the AFS-algorithm. At combined genetic and somatic analysis, analogous results on different counts could be found.ConclusionIn the effort to create an algorithm characterising somatic and fetal conditions of the fetus most properly, the inclusion of maternal age is not a helpful value and excluding the age from risk calculation leads to a high significant reduction of the false positive rate. Further, a comparable marked increase of both, specificity and positive predictive values, can be achieved for the FMF- and JOY-Software on the background of the generally more favourable JOY test performance.

A novel optical method to assess cervical changes during pregnancy and use to evaluate the effects of progestins on term and preterm labor

OBJECTIVEnThe purpose of this study was to determine whether optical methods can estimate cervix function during pregnancy and whether progestins modify this process.nnnSTUDY DESIGNnPhotos of the external cervix of timed-pregnant rats were taken every other day from day 13 until postpartum day 5 after daily treatments with vehicle (controls) or progestin treatments (progesterone, subcutaneously or vaginally; 17-alpha-hydroxyprogesterone caproate [17P] and RU-486 subcutaneously, once on day 16). The surface area of the cervix was estimated from photos.nnnRESULTSnThe surface area of cervix increases throughout pregnancy and reverses after delivery in controls. In the progesterone subcutaneously or 17P subcutaneously groups, increases in surface area are lower (17P group until day 19 only; P < .05). Vaginal progesterone does not prevent surface area increases. Only the progesterone subcutaneously blocked delivery. RU-486 increases the surface area of the cervix (P < .05) during preterm delivery.nnnCONCLUSIONnAn optical method is useful for quantitative assessment of the cervix and evaluation of agents that modify cervical function.

Prediction of axillary lymph node status of breast cancer patients by tumorbiological factors of the primary tumor.

Background and Purpose:The increasing use of systemic adjuvant therapy even in lymph node-negative breast cancer patients and breast cancer screening programs detecting smaller tumors with less probability of metastatic lymph nodes questions the need for routine axillary lymph node dissection. Since morbidity of breast cancer surgery is predominantly related to axillary lymph node dissection, predictive models for lymph node involvement may provide a way to avoid lymph node surgery and its side effects in subgroups of patients.Patients and Methods:Using a multivariate logistic regression model, tumorbiological parameters such as expression of estrogen and progesterone receptors, Ki-67, p53, cathepsin D, HER2, S-phase fraction, and ploidy were analyzed regarding their ability to predict axillary lymph node involvement in 655 breast cancer patients.Results:The model correctly predicted axillary lymph node metastases in 58% of the patients by including expression of progesterone receptor, HER2, and Ki-67. In a subgroup of 200 patients predicted to be at extremely high or extremely low risk for axillary lymph node metastases, the accuracy of the prediction was 70%.Conclusion:With a model just based on tumorbiological parameters obtained in the primary tumor it is possible to predict axillary lymph node status. By including additional parameters it appears to be feasible to further improve the model in order to avoid axillary lymph node surgery in low-risk women.Hintergrund und Ziel:Die zunehmende Anwendung adjuvanter Therapien auch bei nodal negativen Mammakarzinompatientinnen sowie die im Rahmen von Screeningprogrammen immer frühzeitigere Entdeckung kleiner Mammakarzinome mit geringer Wahrscheinlichkeit einer axillären Lymphknotenmetastasierung stellen den Nutzen der axillären Lymphonodektomie zunehmend in Frage. Da die axilläre Lymphonodektomie maßgeblich für die Morbidität der Mammakarzinomoperation verantwortlich ist, stellt sich die Frage, ob das Risiko eines axillären Lymphknotenbefalls für Subgruppen von Mammakarzinompatientinnen präoperativ vorhergesagt werden kann.Patienten und Methodik:Mit Hilfe einer multivariaten logistischen Regression wurden tumorbiologische Parameter (Expression von Östrogen- und Progesteronrezeptoren, Ki-67, p53, Cathepsin D, HER2, S-Phasen-Anteil, Ploidie) in Bezug auf ihre Vorhersagekraft für den axillären Lymphknotenstatus bei 655 Patientinnen mit primärer Mammakarzinomerkrankung untersucht.Ergebnisse:Das Modell konnte in 58% der Fälle bei Einschluss von Progesteronrezeptorexpression, HER2 und Ki-67 den Nodalstatus korrekt vorhersagen. Für die 200 Patientinnen, deren Risiko als besonders hoch vorhergesagt wurde, lag die Rate von richtig positiven Befunden bei 70%.Schlussfolgerung:Modelle, die sich lediglich auf tumorbiologische Faktoren des Primärtumors stützen, können unabhängig von klinischen Stagingparametern den axillären Lymphknotenstatus vorhersagen. Durch Erweiterung auf zusätzliche Faktoren ließe sich so ein Modell entwickeln, auf dessen Grundlage bei Frauen mit geringem Risiko für eine axilläre Metastasierung auf die axilläre Lymphonodektomie verzichtet werden könnte.

Prevalence of hepatitis B virus infection among women at reproductive age at a German university hospital

BACKGROUNDnMother to infant transmission of hepatitis B virus (HBV) represents a major factor in maintaining chronic infection and depends on the degree of maternal infectivity status.nnnOBJECTIVESnTo examine the seroprevalence of hepatitis B virus surface antigen (HBsAg) in women at reproductive age admitted to the Department of Gynaecology at a German university hospital.nnnSTUDY DESIGNnThe seroprevalence of hepatitis B surface antigen (HBsAg) in 5518 women at reproductive age was examined, HBsAg-positive samples were tested for additional HBV markers to verify the infection status.nnnRESULTSnOut of 5518 samples from women at reproductive age, 88 women (1.59%) were positive for HBsAg and 7 of these HBV-positive women (7.95%) were additionally positive for HBeAg. The majority of the study population were German citizens, however most HBV infected persons originated from countries with a high HBV prevalence. The HBV seroprevalence in our study group is about two times higher compared to the average seroprevalence in the German citizen adult population, thus probably resulting in an underestimation of the infection rate in a multinational setting.nnnCONCLUSIONSnScreening for HBsAg during pregnancy is still necessary and important for reduction of perinatal HBV transmission even in countries with low HBV prevalence.