Serum biomarkers and Doppler pulsatile index increases likelihood ratio for prediction of preeclampsia in the second trimester of pregnancy.

This study aims to compare the accuracy of risk prediction for preeclampsia (PE) of three calculators during the second trimester of gestation: American College of Obstetricians and Gynaecologists (ACOG), National Institute for Health and Care Excellence (NICE), and Foetal Medicine Foundation (FMF). Complete medical history, mean uterine artery Doppler pulsatile index were performed (PI) and venous blood samples for placental growth factor (PIGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and Endoglin measurements were obtained from 214 women between 20-24 weeks gestation. PE frequency was 8.4% (18/214). Sensitivity and specificity were 94.4% and 37.2% and 44.4% and 74.5% for ACOG and NICE respectively. Sensitivity for FMF was 66.7% and 44.4% at <32 weeks and <36 weeks respectively and specificity was 97.2% and 98.1%. The highest positive likelihood ratio, 22, was obtained for FMF as compared to 1.49 and 1.76 for ACOG and NICE. These findings suggest that the addition of US and serum biomarkers in the FMF calculator increases accuracy for prediction of PE.Impact StatementWhat is already known on this subject? Several strategies have been implemented to evaluate risk for PE. The ACOG and NICE calculators, based on medical and anthropomorphic data, and the FMF calculator, which includes ultrasound and serum biomarkers, have been used for the prediction of PE risk in the first trimester of gestation.What do the results of this study add? Although the identification of markers for the prediction of PE during the first trimester of pregnancy has been of major clinical interest, in many countries women attend their first prenatal visit up until the second trimester of pregnancy. This is the first multicentre study in Latin American population to compare the three risk prediction systems including serum biomarkers during the second trimester of pregnancy.What are the implications of these findings for clinical practice and/or further research? We propose the FMF calculator (including PI and serum biomarkers) as a useful tool for PE risk detection during the second trimester of pregnancy. However, as this study is limited by its small sample size, larger multicenter studies are needed to confirm our findings and assert the usefulness of the FMF calculator.

Synthesis of -fetoprotein by liver, yolk sac, and gastrointestinal tract of the human conceptus.

PIP: Synthesis of serum alpha fetoprotein (AFP) was studied in 16 human embryos and fetuses from 4.2-18 weeks of gestation by incubation of selected tissues in radiolabeled amino acids followed by immunoelectrophoresis of the culture fluids and radioautography. Relatively large amounts of radioactive AFP, judged by relative intensity of AFP precipitation line on radioautography, were found in each of the liver cultures of the developing yolk sac. AFP was observed in smaller amounts in almost all gastrointestinal tract cultures studied. Labeled AFP formed in kidney cultures from 1 of 9 conceptuses and in only 1 of 14 placentas cultured. None of the cultures containing lung, thymus, pancreas, skeletal muscle, amnion, chorion, or blood produced detectable amounts of AFP.^ieng

Alpha-fetoprotein in ontogenesis and its association with malignant tumors.

PIP: The major steps in development of ontogenesis and the role of alpha fetoprotein (AFP) synthesis are outlined. AFP is defined and its physiocochemical characteristics are described including methods of detection and identification. The liver and yolk sac of fetuses are shown as the principle sites of AFP synthesis in ontogenesis, and the dynamics of AFP in ontogenesis from the early embryonic period through midpregnancy to pregnancy termination to AFP shut-down in early postnatal period are displayed. AFP synthesis during regeneration of the liver provides the model for studying the nature of AFP production. The role of AFP in hepatocellular cancer receives a great deal of attention, focusing on the site of AFP synthesis in cancer of the liver; demonstration of AFP in blood of cases of hepatic cancer (and other diseases) by agar-gel precipitation; quantitative aspects of AFP production by liver tumors; and etiologic and pathogenic influences on AFP production by hepatomas. Clinical aspects of the diagnosis of liver cancer are reviewed. The occurrence of AFP with teratocarcinomas is remarked upon. The article's central objective was to emphasize the importance of basic research on AFP, especially the development of an accessible high-sensitivity test for use in broad epidemiological surveys. Experimental approaches to some immediate problems were formulated: 1) Is there any external factor controlling AFP synthesis and determining its intensity? 2) Is synthesis performed only by certain cell types or is AFP production inherent in any hepatocyte? 3) Is control of AFP synthesis accomplished by regulating the intensity of the process in individual cells or by involvement of a varying number of cells? And 4) is AFP synthesis in a tumor due to maintained ability of the stem tumor cell to differentiate or is it the result of dedifferentiation of the mature hepatocyte??^ieng

Plasma immunoreactive relaxin levels in pregnant and nonpregnant women.

Immunoreactive relaxin was measured in plasma samples obtained from human volunteers utilizing the RIA procedure of Sherwood et al., as modified by O'Byrne and Steinetz for heterologous plasma samples. Immunoreactive hormone was not detected in samples obtained from men, and only rarely in plasma of nonpregnant women. Immunoreactive relaxin was present as early as the fourth week of pregnancy and was detectable throughout the course of gestation. Immunoreactive relaxin tended to be higher early in pregnancy, and there was no peak just before parturition as occurs in many other species. Our results are at variance with those of Bryant and coworkers, who reported high levels of immunoreactive relaxin in men and nonpregnant as well as pregnant women. The possible reasons for this discrepancy are presented.

Vitamin B6 nutriture during pregnancy and lactation. II. The effect of long-term use of oral contraceptives.

Vitamin B6 nutriture was assessed during pregnancy and lactation to determine whether previous use of oral contraceptive agents (OCA) resulted in reduced reserves of the vitamin. Vitamin B6 levels were measured in maternal serum and urine at 5 and 7 months gestation and at delivery, in cord serum and in milk at 3 and 14 days postpartum. Long-term use of OCA (greater than 30 months) resulted in low levels of vitamin B6 in maternal serum at 5 months gestation and at delivery and in milk compared with values for short-term (1 to 30 months) and nonusers of OCA. Levels of vitamin B6 were also lower in the cord serum of long-term users of OCA as compared to nonusers.

PIP: A study involving 106 women was conducted to determine whether pregnant and lactating women experienced vitamin B6 deficiency after using oral contraceptives. Maternal serum and urine were measured at 5 and 7 months gestation and at delivery, in cord serum, and in milk at 3 and 14 days postpartum to measure vitamin B6 levels. Among 13 long-term pill users (greater than 30 months), the mean vitamin B6 level in maternal serum at 5 months gestation was 8.1 ng/ml; for 44 short-term pill users (1-30 months), 13.7 ng/ml; and for 49 nonusers, 16.6 ng/ml. Long-term pill users also had significantly lower vitamin B6 levels at delivery, in cord serum, and in milk at 14 days postpartum than nonusers, and lower B6 levels at delivery and in milk at 14 days than short-term pill users.

Effect of food supplementation (WIC) during pregnancy on birth weight.

Of 824 women screened, 410 were enrolled at midpregnancy in a prospective, randomized, controlled nutrition intervention study. Of these, 226 were predicted as likely to have small or large babies, 184 to have average-sized babies. Two hundred thirty eight mothers received USDA Women, Infants and Children (WIC) Food Supplementation vouchers from midpregnancy, 172 did not. Leukocyte protein synthesis (as a cell model) was significantly higher (p = 0.009) by 36 weeks gestation in supplemented mothers. Mean birth weight of their babies was greater, 3254 vs 3163 g, (+91 g) p = 0.039, adjusted for sex, gestational age, prenatal visits, pregnancy interval, smoking, and previous low birth weight infants. Controlling for entry weight obviated the significance of the difference, except for WIC supplemented smokers (greater than 10 cigarettes/day) whose babies were significantly heavier by +168 g (p = 0.017) than those of unsupplemented smokers. WIC partially protects fetal growth in smokers.

PIP: Low birth weight and small for gestational age (SGA) babies demonstrate a greater incidence of cogenital malformation, perinatal death or morbidity, imparied postnatal growth, and neurologic disabilities. Consequently, studies have been designed to increase birth weight. These studies indicate that supplementation during both the 2nd period of most rapid fetal growth and 3rd trimesters have the greatest effect in increasing birth weight. Subjects were 824 women attending the prenatal clinics at the Oklahoma Memorial Hospital (OMH). Of the 824 women screened, 410 were enrolled at midpregnancy in a prosepctive, randomized, controlled nutrition intervention study. Of these, 226 were predicted as likely to have small or large babies, 184 to have average-sized babies. 238 mothers received USDA Women, Infants and Children (WIC) Food Supplementation vouchers from midpregnancy; 172 did not. WIC vouchers were for supplements of milk, eggs, and cheese and were intended to provide 40-50 g of protein and 900-1000 kcal daily. These were intended to augment the NRC Recommended Dietary Allowances for pregnancy and add to the regular diet of 1.1 g protein/kg/d and 28 kcal/kg/d. Leukocyte protein synthesis (as a cell model) was significantly higher (p=0.009) by 36 weeks gestation in supplemented mothers. By this time, a reduction in plasma alanine and B-globulin levels became evident. Mean birth weight of their babies was greater, 3254 vs 3163 g, (+91g) p=0.039, adjusted for sex, gestational age, prenatal visits, pregnancy interval, smoking, and previous low birth weight infants. Controlling for entry weight obviated the significance of the difference, except for WIC supplemented smokers (10 cigarettes/day) whose babies were significantly heavier by +168 g (p=0.017) than those of unsupplemented smokers. WIC partially protects fetal growth in smokers.

Plasma concentrations of oestrone, oestradiol, oestriol and progesterone during mechanical stretch-induced abortion at mid-trimester.

Plasma levels of unconjugated oestrone, oestradiol, oestriol and progesterone were serially studied in six uncomplicated patients in the mid-trimester of pregnancy before and during abortion induced by purely mechanical stretching of the uterus by laminaria and rubber balloon. Variability of these hormonal levels among patients was significant before the treatment. In four cases where the fetus was aborted alive, the plasma value of these hormones remained at a high level during the treatment with the exception of oestriol level in one case. In two early mid-trimester cases the fetus died during the treatment and plasma oestriol dropped significantly, while the level of the other hormones remained raised until fetal delivery. In these two cases the apparent onset of labour was noted before fetal death. It was concluded that the onset and progress of labour by mechanical stretching of the uterus is probably unrelated to the steroid hormones estimated in the present study.

Prostaglandins. Has the initial promise been realised?

PIP: This review of prostaglandins (PGs) covers the following: PGs in obstetrics and gynecology (induction of labor, cervical priming, termination of pregnancies complicated by fetal death, use in 1st and 2nd trimester abortions, and potential contraceptive use); and PGs in other areas of medicine. The original work on the use of PGs in the induction of labor indicated that of the naturally occurring PGs only PGE2 and PGF2alpha are clinically important in reproduction. Ensuing clinical trials confirmed this observation but lead to the conclusion that intravenous PGs for routine labor induction provided no real benefit over intravenous oxytocin, and, in contrast to oxytocin, were associated with frequent gastrointestinal side effects and a pyrexia which could lead to confusion. A recent modification using a cross linked polymer pessary has been designed in an effort to provide a constant sustained release of the incorporated PGE2 for absorption by the vaginal surface. Further studies to assess this innovation are necessary. There was renewed interest in PGs in the mid 1970s when it was observed that they possibly enhanced the outcome of induced labor in patients with an unfavorable cervix. Recent research has established PGE2 as possibly the most efficient cervical priming agent available at this time. A cervical effect may be the reason why PGs are successful in evacuating pregnancies complicated by fetal death. The vaginal route has gained preference as a simple, nontraumatic means of stimulating uterine activity without increasing the chances of intrauterine infection. It seems unlikely that PGs will ever supersede routine aspiration termination of 1st trimester pregnancy. Longterm studies have not been reported yet to indicate that occult cervical damage will be avoided with preoperative PG treatment. Considerable research has been conducted into the safety of PGs for late abortion. Initial concerns of possible coagulopathy, encephalopathy and cardiopulmonary system disturbances have now been largely dismissed; the drugs have been confirmed as safe. The possibility of PGs becoming fertility controlling agents was initially explored in the early 1970s. Although abortion has been successfully induced in 80-90% of treated cases, in many reported series the observed side effects, particularly severe uterine effects, have thus far made the method untenable for routine management. Other uses of PGs include the treatment of spasmodic dysmenorrhea and dysfunctional uterine bleeding and the treatment of gastric ulcers.^ieng

Prostaglandins: current therapeutic status in obstetrics.

PIP: Recent research suggests that the action of prostaglandins on the pregnant uterus is more complex than that of oxytocin. Despite the fact that prostaglandins, like oxytocin, may fall short of the ideal, preliminary work makes it apparent that prostaglandins have attributes for induction of labor that will ultimately rank them as far superior to oxytocin. A 1st sign that prostaglandins might be more than just oxytocic agents came from the discovery of the effectiveness of prostaglandin F2alpha (PGF2alpha) and prostaglandin E2 (PGE2) in inducing mid-trimester abortion. For a long time it has been known that oxytocin seldom causes abortion of a normal pregnancy. Prostaglandins cause rapid dilatation of the cervix and expulsion of the conceptus despite a lesser degree of measurable uterine activity than that induced by oxytocin. Prostaglandins do something more, either to the quality of uterine contractions or to the cervix. A major problem associated with the pharmacological use of prostaglandins has been a high incidence of unpleasant side-effects when given by routes that are associated with substantial systemic uptake. In general, doses of prostaglandins that are oxytocic result in nausea, vomiting and diarrhea when administered by the intravenous, oral or intravaginal routes. The intra-amniotic and extra-ovular routes of administration for induction of mid-trimester abortion, as described by Doctors Karim and Hillier, are examples of the successful application of the principle that prostaglandins can be effective without side-effects when they are delivered close to the site of action. Prostaglandins appear particularly well suited to induction of labor in women with prolonged fetal death, anencephaly or hydatidiform mole.^ieng

Spontaneous foetal losses in women using different contraceptives around the time of conception.

Spontaneous losses between the 5th and 27th weeks of pregnancy were measured in a prospective study of 32 123 women whose contraceptive history around the time of conception was known. Diaphragm use prior to conception was associated with a significant reduction in second-trimester losses, after taking into account the effects of age, parity, race, marital status, alcohol use, and previous spontaneous or induced abortions. Women who used oral contraceptives and stopped them more than one month prior to their LMP experienced a deficit of first-trimester losses but conceptions occurring immediately after stopping the pill were followed by a small but nonsignificant increase in spontaneous abortions. After oral contraceptive failures there was an increase in first-trimester losses, but no change in the incidence of second-trimester ones. IUD failures were followed by a significant two-fold increase in the risk of both first and second-trimester losses: no differences were detected between the different brands.

PIP: Spontaneous losses between the 5th and 27th weeks of pregnancy were measured in a prospective study of 32,123 women whose contraceptive history around the time of conception was known. Diaphragm use prior to conception was associated with a significant reduction in second trimester losses, after taking into consideration the effects of parity, race, marital status, alcohol use, and previous spontaneous or induced abortions. Women who used (OC) oral contraceptives and then stopped them more than 1 month prior to their last menstrual period experienced a deficit of first trimester losses but conceptions occurring immediately after stopping the pill were followed by a small but nonsignificant increase in spontaneous abortion. After OC failures, there was an increase in first trimester losses, but no change in the incidence of second trimester ones. IUD failures were followed by a significant 2-fold increase in the risk of losses during the first and second trimesters with no differences detected between the different brands.