The number of multinucleated trophoblastic giant cells in the basal decidua is decreased in retained placenta.

AIMS: Retained placenta (RP) is a major cause of obstetric haemorrhage. The aim of the study was to obtain a better understanding of the mechanisms that cause some placentas to become retained, while most are not. METHODS: 23 RPs clinically diagnosed as placenta adhesiva and 10 control placentas (CPs) were examined for differences in trophoblast fusion into multinucleated trophoblastic giant cells (MTGCs), defects in the basal decidua, and decidual attachment of myometrial fibres. RESULTS: The number of MTGCs in the basal decidua was significantly smaller in RPs (0.23 MTGC/standard length) than in CPs (1.11 MTGC/standard length) (p<0.001). Defects in the decidua were observed in 4% of the RPs and in 0% of the CPs. Myometrial fibres were attached to the decidua in 78% of the RPs and in 0% of the CPs (p<0.001). CONCLUSIONS: In placenta adhesiva compared with CPs, significantly less MTGCs were present in the basal decidua, the basal decidua was intact, and myometrial fibres were more frequently attached to the basal decidua. It is speculated that these findings may indicate that defective fusion of trophoblastic cells into MTGCs plays a causative role in placenta adhesiva.

[Hydrops fetalis as an indication for a systematic investigation into the presence of lysosomal storage diseases]. / Hydrops foetalis als indicatie voor systematisch onderzoek naar lysosomale stapelingsziekten.

As a result of the decreased incidence of immunological hydrops fetalis and increased insight, the role of inborn errors of metabolism (IEM) as a cause of hydrops fetalis has acquired increased significance. This growing awareness of the manifestation of IEM in pregnancy has revealed that some 20 of these disorders may cause hydrops fetalis, accounting for a few percent of all cases. These IEM are, for the most part, lysosomal storage diseases. We recommend that standard metabolites and enzymes reflecting lysosomal storage diseases be measured in the amniotic fluid and the amniocytes already withdrawn for karyotyping. The value of the diagnosis of lysosomal storage diseases lies in the opportunity for risk evaluation, genetic counselling and targeted prenatal diagnostics in case of subsequent pregnancies. Obtaining insight into the possible therapestic interventions during the pregnancy in which the hydrops is observed is not a goal of this protocol since the necessary investigations are too time-consuming.

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of carbetocin (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: Carbetocin was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg carbetocin were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg carbetocin.

The role of oral (methyl)ergometrine in the prevention of postpartum haemorrhage.

Postpartum haemorrhage (PPH) is one of the most important causes of maternal mortality in developing countries. A consensus was reached on active management of the third stage of labour for all parturients especially for those for whom the access to hospital services is difficult or time-consuming. Oral (methyl)ergometrine was considered to be a possible alternative prophylactic oxytocic, that was easy to administer and suitable to be used in developing countries. A research project was set up to investigate its suitability to be used for active management of the third stage of labour. It was examined on its stability under tropical conditions; on its pharmacokinetic and pharmacodynamic properties and on its clinical effect on the amount of bloodloss after childbirth. Oral (methyl)ergometrine is unstable even when stored after refrigerated conditions. Its pharmacokinetic and dynamic properties are unpredictable and no clinical effect on reduction of bloodloss after childbirth has been shown. To ameliorate a product's stability seems unlogical, if the same product shows unfavourable pharmacokinetics. All the more so, since the tablets do not show the wanted clinical effects. Oral (methyl)ergometrine is not an alternative to parenteral prophylactic oxytocic drugs in the active management of the third stage of labour.

Survey of the management of third stage of labour in The Netherlands.

UNLABELLED: The standard practice during the third stage of labour of Dutch midwives and obstetricians was elucidated by a questionnaire mailed to all Dutch midwives and obstetricians. Prophylactic oxytocics in the third stage are used as a routine by 55% of the obstetricians and only 10% of the midwives. Oxytocin is the drug of first choice. CONCLUSION: Routine use of prophylactic oxytocics in the third stage is not the standard practice in the Netherlands. Obstetricians are much more likely to use prophylaxis than midwives.

A placebo-controlled trial of oral ergometrine to reduce postpartum hemorrhage.

BACKGROUND: Active management with oral ergometrine 0.4 mg was compared with expectant management for the control of blood loss in the third stage of labor in women at low risk of postpartum hemorrhage (PPH). METHODS: A three-arms randomized trial in which 0.4 mg ergometrine (2 tablets of 0.2 mg) was set off against placebo, both groups allowing comparison with a standard oxytocin regimen of 5 IU. Women at low risk for PPH. Of 367 parturients, 146 were randomised to ergometrine 0.4 mg, 143 to placebo and 78 to intramuscular oxytocin in a 2:2:1 design. RESULTS: Compared with placebo, ergometrine reduced blood loss with 5% (-5%; Confidence interval: -20% to +13%). Oxytocin reduced blood loss with 9% (-9%; Confidence interval: -26% to +12%) versus placebo. CONCLUSION: Oral ergometrine has too little effect on blood loss after childbirth in order to be a good alternative to parenteral prophylactic management.

Prevention of postpartum haemorrhage.

Primary prevention of PPH is advocated at all levels of obstetric care. This implies active management of the third stage of labour also at the first and most peripheral levels of obstetric care. Active management includes the use of an oxytocic, early cord clamping and active delivery of the placenta. The oxytocic drug of choice at this moment is oxytocin 5 IU given intramuscularly. Women with high-risk factors for PPH (polyhydramnios, previous complications in third stage, APH or multiple pregnancies) should be delivered in hospital. Timely antepartum referral is necessary. In these women, prevention and anticipatory management includes the availability of intravenous treatment, as well as active management with an oxytocic. Evidence for the effectiveness of active management of the third stage of labour in women at low risk of PPH is not yet available. Whether women delivering at home with easy accessibility to hospital, or those at low risk delivering in hospital, should be actively managed remains controversial, and such an approach is not supported by us until a clinical trial in this particular group of women has shown the effectiveness of the active management.

Bioavailability and pharmacokinetics of sublingual oxytocin in male volunteers.

The aim of this investigation was to assess the bioavailability and pharmacokinetics of oxytocin in six male subjects after a sublingual dose of 400 int. units (684 micrograms) and after an intravenous dose of 1 int. unit (1.71 micrograms). After intravenous administration, the pharmacokinetic profile could be described with a two-compartment model. The distribution half-life was 0.049 +/- 0.106 h, the elimination half-life was 0.33 +/- 0.23 h, the total body clearance was 67.1 +/- 13.4 L h-1 and the volume of distribution was 33.2 +/- 28.1 L. After sublingual administration, a poor bioavailability with a 10-fold variation between 0.007 and 0.07% was observed. The pharmacokinetic profile could be described with a one-compartment model. The lag time was subject-dependent and ranged between 0.12 and 0.30 h (40% CV). The absorption half-life was 0.45 +/- 0.29 h, and the apparent elimination half-life 0.69 +/ - 0.26 h. This study showed a very poor and interindividual variability in bioavailability. The sublingual route of administration with its 'long' lag time and 'long' absorption half-life would not seem a reliable route for accurate high dosing for immediate prevention of post-partum haemorrhage.

Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women.

OBJECTIVE: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women. DESIGN: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender). RESULTS: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%. CONCLUSION: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Oral administration of methylergometrine shows a late and unpredictable effect on the non-pregnant human menstruating uterus.

OBJECTIVE: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation. STUDY-DESIGN: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design. RESULTS: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (Cmax), the time at which Cmax is reached (tmax) and the half-life of absorption (t1/2abs) also demonstrated large individual variations after oral administration. CONCLUSIONS: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.

History of ergot alkaloids from ergotism to ergometrine.

Epidemics of ergotism occurred frequently in the Middle Ages. They were a source of inspiration for artists and were popularly known as 'St. Anthony's Fire', resulting in gangrene, neurological diseases and death. It was caused by eating rye bread contaminated with the fungus claviceps purpurea. In 1582 it was described that a delivery could be hastened by administering a few spurs of the secale cornutum. The dosage was, however, very inaccurate resulting in frequent uterine ruptures. The nickname of the preparation of 'pulvis ad partum' was changed to 'pulvis ad mortem'. Therefore, after 1828 the ergot alkaloids were no longer used during delivery but only as a measure to prevent postpartum haemorrhage. From 1875 onwards many derivatives of ergot alkaloids were found. Dudley and Moir isolated ergometrine in 1932. It proved to have a very specific uterotonic action. However, because of severe and unpredictable side effects and the instability of the drug, ergometrine is not the drug of choice for either the prevention or the treatment of postpartum haemorrhage.

Ergometrine and methylergometrine tablets are not stable under simulated tropical conditions.

OBJECTIVES: This study is part of a programme on reduction of postpartum haemorrhage (PPH). Ergometrine and methylergometrine have a favourable effect on both blood loss and maternal morbidity and mortality and oral preparations were regarded as a possible treatment for use in tropical countries. The stability of oral preparations of the two ergometrine compounds under tropical conditions was unknown and was therefore examined in this study. STUDY METHODS: The 'experimental shelf lives' of ergometrine and methylergometrine tablets were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography at nine different sampling times over a period of 1 year to determine the content of ergometrine and methylergometrine. RESULTS: Under refrigeration (test I), less than 90% of the stated amount of active ingredient was found in the tablets after 14 weeks in the case of ergometrine and 21 weeks in the case of methylergometrine. When stored in the dark at 40 degrees C and 75% relative humidity (test VI), the tablets fall outside accepted specification (= 90-110% of state amount of active ingredient) within 3 weeks in the case of ergometrine and 21 weeks in the case of coated methylergometrine tablets. The stability of uncoated ergometrine tablets was far less than that of coated methylergometrine tablets. Instability worsened under extreme humid conditions (test IV and VI), and hot conditions (test V), for both ergometrine and methylergometrine. From week 31 onwards the coating did not seem to protect the compound anymore, irrespective of the condition of exposure. CONCLUSIONS: Tropical conditions make the tablets unstable with humidity as the main adverse factor. The sugar-coated methylergometrine tablets are more stable under humid/hot conditions than the non-coated ergometrine tablets. Under all simulated conditions both oral ergometrine and methylergometrine tablets are unstable.

Oxytocin and desamino-oxytocin tablets are not stable under simulated tropical conditions.

OBJECTIVES: This study is part of a programme on reduction of postpartum haemorrhage. Buccal oxytocin and desamino-oxytocin administration with a favourable effect on both blood loss and maternal morbidity and mortality were regarded as possible treatments for use in tropical countries. The stability of buccal oxytocin and desamino-oxytocin under tropical conditions was unknown and therefore tested in this study. STUDY METHODS: The 'experimental shelf lives' of buccal oxytocin and desamino-oxytocin were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography to determine the content of oxytocin and desamino-oxytocin at nine different times during the period of 1 year. RESULTS: Oxytocin and desamino-oxytocin are fairly stable under refrigeration. Instability for both drugs was detectable after 20 weeks' storage under humid conditions, independent of temperature. Desamino-oxytocin is more sensitive to light exposure; its concentration declines to 55.6% of the stated amount after 1 year of exposure to light compared to 85% in the case of oxytocin. Oxytocin packaged as supplied by the manufacturer were stable for 21 weeks when exposed to simulated humid (75% relative humidity) conditions. At 40 degrees C and 25% relative humidity there is no difference in stability between tablets in sealed aluminium packs as supplied by the manufacturer and unpackaged tablets. CONCLUSIONS: Tropical conditions make oxytocin and desamino-oxytocin tablets unstable, with humidity as the most adverse factor. The oxytocin tablets were partially protected from the harmful effect of humidity by sealed aluminium package.

Pharmacokinetics and bioavailability of oral ergometrine in male volunteers.

The aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0.200 mg and after an intravenous dose of 0.075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0.0073 h (0.4 min) and 0.47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a two-compartment model. The distribution half-life t1/2 alpha is 0.18 +/- 0.20 h, the elimination half-life t1/2 beta is 2.06 +/- 0.90 h, the total body clearance (CL) amounts to 35.9 +/- 13.4 l h-1 and the steady-state volume (Vss) of distribution is 73.4 +/- 22.01. After oral administration, the pharmacokinetic profile can be described by a one-compartment model. The absorption half-life t1/2 abs is 0.19 +/- 0.22 h, and the elimination half-life t1/2 beta 1.90 +/- 0.16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing in preventing post-partum haemorrhage.

Ergotamine-induced fetal stress: review of side effects of ergot alkaloids during pregnancy.

A case of sudden fetal stress after accidental administration of ergotamine tartrate (2 mg) suppository is reported. Caesarean section was performed because of unexplained fetal stress. In retrospect, we conclude that it is likely that sudden fetal stress was caused by the severe vasoconstrictive effect of ergotamine. The side effects of ergot derivatives during pregnancy are discussed.

High-performance liquid chromatography of ergometrine and preliminary pharmacokinetics in plasma of men.

An isocratic high-performance liquid chromatographic (HPLC) method with fluorescence detection has been developed for the measurement of ergometrine in human plasma. The quantitation limit in plasma was 75 pg/ml. An example of the plasma concentration-time curves obtained after both oral and intravenous administration of ergometrine in one volunteer is shown. This HPLC method makes it possible to describe the pharmacokinetic parameters of oral ergometrine.

Assessment of the risk approach to maternity care in a district hospital in rural Tanzania.

OBJECTIVE: The impact of the risk approach to maternity care in a district hospital in rural Tanzania has been investigated. METHOD: Data have been derived from a 1-month study. Of the women who lived within 5 km of a hospital (area I) 98% actually gave birth in hospital. The pattern of complications of this area is assumed to be representative for the pattern of the district as a whole. RESULT: Only 36/168 (21%) women with high risk pregnancies living further than 5 km from a hospital, came to hospital for delivery. Of the women with low risk pregnancies (in area I) 4/89 (5%) still had a complicated delivery. CONCLUSION: The risk approach, used to select women with high risk pregnancies should be used more extensively and as unexpected complications at the local center occur, basic facilities to deal with those problems should be made available at this level.

[Bladder schistosomiasis in school children; random study in the Ketu district, Ghana]. / Blaasschistosomiasis bij schoolkinderen; keuze-onderzoek in het Ketu-district, Ghana.

In 2 periods 1986/'87 and 1987/'88 1193 school children (5-19 years) from 13 randomly selected villages in the Ketu district, Ghana, were examined for Schistosoma haematobium (SH) in the urine. For the egg count the quantitative urine filtration technique was used and besides 3 indirect indicators of SH infection were evaluated. An arbitrary division was made into areas of high and low endemicity, showing SH prevalence rates of 54.3-23.0% and 2.3-16.0%, respectively. The condition of the "dams' in the different areas seemed to influence the infection rates. For all areas both prevalence and intensity of infection were both higher in boys than in girls. In the area of high endemicity it was possible to detect 99% of the heavily infected children (greater than or equal to 100 eggs/10 ml urine) by using the 3 indirect indicators combined.