Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics

OBJECTIVES: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. METHODS: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). RESULTS: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90. CONCLUSIONS: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.     

Experience of nevirapine use in a London cohort of HIV-infected pregnant women

¹ King's College Hospital, ² St Thomas' Hospital, ³ St George's Hospital and ⁴ St Mary's Hospital, London, UK Objective To describe the experience of four London HIV centres prescribing nevirapine (NVP) to HIV‐1 infected pregnant women with respect to immunological and virological response, tolerability and pregnancy outcome. Methods We identified all HIV‐1‐infected women who received NVP as part of a triple antiretroviral regimen during pregnancy between January 1997 and September 1999. Laboratory results, clinical events, side‐effects and pregnancy outcome were abstracted using a standardized proforma from the medical records. Results Forty‐six women were identified, 85% of whom were black African. At initiation of NVP, the median age was 29 years and the median baseline CD4 cell count and viral load were 242 cells/μL and 4.15 log₁₀ copies/mL, respectively. Thirty‐two out of 36 women who had a plasma sample obtained at, or just prior to, delivery had an undetectable viral load (< 50 to < 400 copies/mL). Adverse events that were definitely attributed to NVP included a generalized rash (n = 2) and hepatitis (n = 2). Obstetric complications occurred in nine women (19.5%), which was not statistically different (P = 0.36) from that found in a historical (1990–96) control group 7/51 (14%). The rate of preterm delivery (13%) was similar to that previously reported in HIV‐1 infected pregnant women (18%). Conclusions NVP (as part of highly active antiretroviral therapy) reduced plasma viraemia to below the limit of detection in 89% of women. It was generally well tolerated and clinical and laboratory adverse events were infrequent. There was no evidence of an increase in obstetric complications including preterm delivery during the second and third trimesters of pregnancy.     

Free-to-total leptin ratio in maternal plasma is constant throughout human pregnancy

To clarify the mechanism of leptin resistance during pregnancy, we measured plasma leptin concentrations, free to total leptin ratio (percent free leptin) and soluble leptin receptor concentrations in pregnant women, and compared the results with those in non-pregnant women. We collected plasma samples from 23 non-pregnant and 31 pregnant women in the third trimester. Plasma samples from 5 pregnant women were collected longitudinally in each trimester. Plasma leptin concentrations in pregnant women in the second trimester (17.4 +/- 3.2 ng/ml) were higher than those in the first trimester of pregnancy (11.0 +/- 2.8 ng/ml, n = 5), as previously reported. However, percent free leptin did not change significantly throughout pregnancy. Percent free leptin correlated with total leptin concentrations (ng/ml) in non-pregnant women (r = 0.727, P < 0.0001), but not in women in the third trimester of pregnancy (r = 0.006). Constant percent free leptin during pregnancy despite increased leptin concentrations indicates increased leptin binding capacity in pregnant women, that might partly contribute to the establishment of leptin resistance. On the other hand, soluble leptin receptor concentrations showed significant negative correlation with BMI and plasma leptin concentrations in pregnant women (r = -0.470, P < 0.01 and r = -0.493, P < 0.01, respectively) but not in non-pregnant women. These data suggest the possibility that soluble leptin receptor is a minor component of leptin binding capacity in the plasma of pregnant women.     

Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery

BACKGROUND: Antiretroviral combination therapies, including nevirapine (NVP) and protease inhibitors (PI), are increasingly used in the treatment and for the prophylaxis of vertical HIV-1 transmission in HIV-1 infected pregnant women. OBJECTIVE: To determine pharmacokinetics and placental transfer of NVP and different PI in pregnancy we measured drug levels in maternal and foetal compartments at the day of delivery. DESIGN AND METHODS: We conducted a prospective study in 40 eligible HIV-1 infected pregnant women who gave birth in our hospital. A pre-dose to 6 h post-dose steady-state pharmacokinetic analysis (n = 35) of the drugs on the day of the scheduled Caesarean section was performed. In addition cord blood and amniotic fluid drug levels were measured (n = 40). RESULTS: In all women NVP plasma concentrations (n = 20) were below the recommended level. PI plasma concentrations (nelfinavir, n = 5; saquinavir, n = 3; lopinavir, n = 10; ritonavir, n = 13) were extremely variable. Cord blood and amniotic fluid drug levels suggested that NVP passes the placenta unrestricted whereas PI were detected in smaller concentrations in the foetal compartment. CONCLUSIONS: Because of the changed pharmacokinetics of antiretroviral drugs in pregnancy therapeutic drug monitoring could be important and dose adjustment should be considered. The minimal placental transfer of PI is desirable from the perspective that the foetus is protected from potentially teratogenic agents. However, it is not known if antiretroviral compounds in the foetal compartment contribute to the risk reduction of vertical HIV-1 transmission, and whether the property of missing placental transfer is in fact beneficial for the newborn.     

孕期家庭暴力与新生儿血浆氨基酸及皮质醇的关系

目的 探讨母孕期家庭暴力(DV)与新生儿谷氨酸、γ-氨基丁酸及血浆皮质醇的关系.方法 采用横断面调查,运用孕产妇受虐评估问卷(AAS)完成住院待产妇DV筛查,分DV组和非DV组,新生儿归为以上两组.检测血浆谷氨酸和γ-氨基丁酸含量,血浆皮质醇含量采用放免法测定.结果 孕期遭受精神暴力者49例(87.5%),躯体暴力者2例(3.6%),近1年遭受性暴力者29例(51.8%).DV组新生儿血浆谷氨酸、γ-氨基丁酸及血浆皮质醇含量高于非DV组[(1509±339)pmol/L比(811±270)pmol/L,(1460±369)pmol/L比(707±296)pmol/L,(491±87)μg/L比(392±108)μg/L],差异均有统计学意义(t=14.326、14.138和5.916,P＜0.001).谷氨酸、γ-氨基丁酸及皮质醇含量与精神暴力严重程度呈显著正相关(r=0.705、0.696和0.425,P＜0.01),与性暴力严重程度呈显著正相关(r=0.471、0.424和0.274,P＜0.01).结论 母孕期DV可能会导致新生儿部分兴奋性和抑制性氨基酸及内分泌的改变.     

Timing of the maternal drug dose and risk of perinatal HIV transmission in the setting of intrapartum and neonatal single-dose nevirapine

CONTEXT: Single-dose intrapartum and neonatal nevirapine (NVP) reduces perinatal HIV transmission and is in increasingly common use throughout the developing world. OBJECTIVE: We studied risk factors for perinatal transmission in the setting of NVP. DESIGN AND SETTING: A prospective cohort study at two public obstetrical clinics in Lusaka, Zambia. PATIENTS AND METHODS: In a volunteer sample of HIV-infected pregnant women and their newborns, the women received a 200 mg oral dose of NVP at the onset of labor; their infants received 2 mg/kg of NVP syrup within 24 h of birth. The main outcome measure was the infant HIV infection status at 6 weeks of life, determined by DNA polymerase chain reaction. RESULTS: Only 31 of 278 (11.2%) infants were infected at 6 weeks. In logistic regression, viral load exceeding the median [adjusted odds ratio (AOR), 3.1; 95% confidence interval (CI), 1.1-8.7] and 1 h or less elapsing between NVP ingestion and delivery (AOR, 5.0; 95% CI, 1.8-14) were associated with transmission. Women delivering within 1 h of NVP ingestion had a lower mean drug concentration (351 versus 942 ng/ml; P<0.001) and were more likely to have a 'sub-therapeutic' NVP level of less than 100 ng/ml (56 versus 20%; P<0.001) than those who delivered more than 1 h post-ingestion. However, concentrations <100 ng/ml were not more likely to be associated with transmission than concentrations > or = 100 ng/ml (12.9 versus 11.7%; P=0.8). We did not identify a threshold concentration below which risk of transmission increased. CONCLUSIONS: We confirmed low perinatal transmission rates with single-dose NVP. At least 1 h of pre-delivery NVP prophylaxis was a critical threshold for efficacy.     

Impact of vitamin A supplementation on anaemia and plasma erythropoietin concentrations in pregnant women: a controlled clinical trial

INTRODUCTION: Although studies suggest that vitamin A or its metabolites influence the synthesis of erythropoietin in vitro and in animal models, it is unclear whether vitamin A supplementation increases plasma erythropoietin concentrations in humans. OBJECTIVE: To determine whether daily vitamin A supplementation increases plasma erythropoietin concentrations in pregnant women with a high prevalence of anaemia. METHODS: A randomized, double-blind, controlled clinical trial was conducted to examine the effect of daily vitamin A (3000 microg retinol equivalent), iron (30 mg), and folate (400 microg) versus iron (30 mg) and folate (400 microg) (control) on haemoglobin and plasma erythropoietin concentrations in 203 pregnant women in Malawi, Africa. RESULTS: Mean gestational age at enrollment was 23 wk, at which time 50% of the women were anaemic (haemoglobin <110 g/L). Mean (+/-SEM) change in haemoglobin from enrollment to 38 wk was 4.7+/-1.6 g/L (p=0.003) and 7.3+/-2.3 g/L (p=0.003) in the vitamin A and control groups, respectively. Mean change in plasma erythropoietin concentrations from enrollment to 38 wk was 2.39+/-5.00 (p=0.63) and -2.87+/-3.92 IU/L (p=0.46) in the vitamin A and controls groups, respectively. There were no significant differences between vitamin A and control groups in the slope of the regression line between log10 erythropoietin and haemoglobin at enrollment or 38 wk, and between enrollment and follow-up within either group. CONCLUSIONS: Vitamin A supplementation does not appear to increase haemoglobin and plasma erythropoietin concentrations among pregnant women with a high prevalence of anaemia in Malawi.     

Endocrine determinants of fertility: serum androgen concentrations during follow-up of adolescents into the third decade of life

We have completed a 13-yr longitudinal study of endocrine features in females originally aged 7-17 yr and report now factors related to fertility in these women, mainly serum testosterone (T) and androstenedione (A) concentrations in relation to becoming pregnant. Longitudinal regression analysis, corrected for the effect of age, showed that current serum T and A concentrations are correlated with those measured 12 yr earlier (T: r = 0.47, P less than 0.01; A: r = 0.57, P less than 0.001). Age-adjusted serum T and A concentrations before any pregnancies were higher in women who subsequently had no pregnancies than in those who had been pregnant (T: never pregnant, mean +/- SEM, 1.10 +/- 0.06 nmol/L, pregnant 0.81 +/- 0.07 nmol/L, P = 0.004; A: never pregnant 4.00 +/- 0.28 nmol/L, pregnant 2.98 +/- 0.33 nmol/L, P = 0.03). Serum androgen concentrations were not related to variables reflecting sexual behavior and the use of oral contraception. The data therefore show that adolescent serum androgen concentrations are preserved into adulthood and are reflected in fertility patterns during the third decade of life. Higher serum androgen concentrations are associated with lower fertility. Together with our previous findings, these data demonstrate that endocrine characteristics formed during puberty seem to persist at least until 30 yr of age.     

The effect of heartburn and acid reflux on the severity of nausea and vomiting of pregnancy

BACKGROUND:

Heartburn (HB) and acid reflux (RF) in the non-pregnant population can cause nausea and vomiting; therefore, it is plausible that in women with nausea and vomiting of pregnancy (NVP), HB/RF may increase the severity of symptoms.

OBJECTIVE:

To determine whether HB/RF during pregnancy contribute to increased severity of NVP.

METHODS:

A prospectively collected cohort of women who were experiencing NVP and HB, RF or both (n=194) was studied. The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale and its Well-being scale was used to compare the severity of the study cohort’s symptoms. This cohort was compared with a group of women experiencing NVP but no HB/RF (n=188). Multiple linear regression was used to control for the effects of confounding factors.

RESULTS:

Women with HB/RF reported higher PUQE scores (9.6±2.6) compared with controls (8.9±2.6) (P=0.02). Similarly, Well-being scores for women experiencing HB/RF were lower (4.3±2.1) compared with controls (4.9±2.0) (P=0.01). Multiple linear regression analysis demonstrated that increased PUQE scores (P=0.003) and decreased Well-being scores (P=0.005) were due to the presence of HB/RF as opposed to confounding factors such as pre-existing gastrointestinal conditions/symptoms, hyperemesis gravidarum in previous pregnancies and comorbidities.

CONCLUSION:

The present cohort study is the first to demonstrate that HB/RF are associated with increased severity of NVP. Managing HB/RF may improve the severity of NVP.     

Impact of pregnancy on abacavir pharmacokinetics

OBJECTIVE: To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition. DESIGN: The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily. METHODS: Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30-36 weeks of gestation) and again postpartum (6-12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography. RESULTS: Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration-time curve (AUC) of 5.9 mg.h/l [90% confidence interval (CI), 5.2-6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6-2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91-1.18) and 0.79 (90% CI, 0.65-0.98), respectively. CONCLUSIONS: Abacavir AUC during pregnancy was similar to that at 6-12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg.h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.     

Glycogen phosphorylase isoenzyme BB plasma concentration is elevated in pregnancy and preterm preeclampsia

Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. However, plasma GPBB concentration during pregnancy is unknown. This study was conducted to determine maternal plasma GPBB concentration in normal pregnancy and in preeclampsia. Plasma samples from 6 groups (n=396) were studied: nonpregnant and pregnant women with normal term delivery, term and preterm preeclampsia, and term and preterm small-for-gestational-age neonates. GPBB concentration was measured with a specific immunoassay. Placental tissues (n=45) obtained from pregnant women with preterm and term preeclampsia, spontaneous preterm delivery, and normal term delivery were analyzed for potential GPBB expression by immunoblotting. Median plasma GPBB concentration was higher in pregnant women than in nonpregnant women (38.7 versus 9.2 ng/mL; P<0.001), which remained significant after adjusting for age, race, and parity. Maternal plasma GPBB concentrations did not change throughout gestation. Cases of preterm (but not term) preeclampsia had higher median plasma GPBB concentrations than gestational age-matched normal pregnancy cases (72.6 versus 26.0 ng/mL; P=0.001). Small-for-gestational-age neonates did not affect plasma GPBB concentration. GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P<0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin.     

Dietary fiber intake in early pregnancy and risk of subsequent preeclampsia

BackgroundSubstantial epidemiological evidence documents diverse health benefits, including reduced risks of hypertension, associated with diets high in fiber. Few studies, however, have investigated the extent to which dietary fiber intake in early pregnancy is associated with reductions in preeclampsia risk. We assessed the relationship between maternal dietary fiber intake in early pregnancy and risk of preeclampsia. We also evaluated cross-sectional associations of maternal early pregnancy plasma lipid and lipoprotein concentrations with fiber intake.MethodsThe study population comprised 1,538 pregnant Washington State residents. A 121-item food frequency questionnaire (FFQ) was used to assess maternal dietary intake, 3 months before and during early pregnancy; and generalized linear regression procedures were used to derive relative risk (RR) and 95% confidence intervals (CIs).ResultsDietary total fiber intake was associated with reduced preeclampsia risk. After adjusting for confounders, the RR of preeclampsia for women in the highest (>/=21.2 g/day) vs. the lowest quartile (<11.9 g/day) was 0.28 (95% CI = 0.11-0.75). We observed associations of similar magnitude when the highest vs. the lowest quartiles of water-soluble fiber (RR = 0.30; 95% CI = 0.11-0.86) and insoluble fiber (RR = 0.35; 95% CI = 0.14-0.87) were evaluated. Mean triglyceride concentrations were lower (-11.9 mg/dl, P = 0.02) and high-density lipoprotein cholesterol concentrations were higher (+2.63 mg/dl, P = 0.09) for women in the highest quartile vs. those in the lowest quartile.ConclusionsThese findings of reduced preeclampsia risk with higher total fiber intake corroborate an earlier report; and expand the literature by providing evidence, which suggests that dietary fiber may attenuate pregnancy-associated dyslipidemia, an important clinical characteristic of preeclampsia.American Journal of Hypertension (2008). doi:10.1038/ajh.2008.209American Journal of Hypertension (2008); 21, 8, 903-909. doi:10.1038/ajh.2008.209.     

Cobalamin status during normal pregnancy and postpartum: a longitudinal study comprising 406 Danish women

OBJECTIVES: To assess cobalamin (vitamin B(12)) status during normal pregnancy and postpartum in a longitudinal setting. METHODS: This study was performed in 1995-1996. It comprised 406 healthy, pregnant Danish Caucasian women, living in Copenhagen County. Cobalamin status, i.e. plasma (P-) cobalamin, P-methylmalonic acid and P-homocysteine was measured at 18, 32 and 39 wk gestation and 8 wk postpartum during lactation. RESULTS: P-cobalamin showed a gradual, significant decline during pregnancy (P < 0.0001) followed by a significant increase postpartum (P < 0.0001); at 18, 32, 39 wk gestation and 8 wk postpartum median values were 225, 172, 161 and 319 pmol/L, respectively. P-methylmalonic displayed a gradual, significant increase during pregnancy as well as postpartum (P < 0.001) with median values of 0.11, 0.13, 0.14, and 0.16 micromol/L, respectively. P-homocysteine demonstrated a significant increase during pregnancy and postpartum (P < 0.001). The frequency of P-cobalamin values <150 pmol/L increased during pregnancy from 15% at 18 wk to 43% at 39 wk gestation and subsequently declined to 3% postpartum. CONCLUSION: Low cobalamin status may occur among pregnant women, especially in late pregnancy. The recommendations for periconceptional vitamin B(12) supplementation should be reconsidered.     

高水碘地区甲状腺抗体阴性妊娠期妇女甲状腺功能分析

目的 探讨高水碘地区甲状腺抗体阴性妇女妊娠各期甲状腺功能的变化特征.方法 在高水碘地区选天津市静海县妇幼保健院(饮水水碘>200μg/L)和在适碘地区选天津市和平区妇幼保健院(饮水水碘<10μg/L,碘盐普及率>90%,居民尿碘中位数>100μg/L)作为调查地点.在妇幼保健院门诊,选取妊娠资料完整的妊娠早、中、晚期孕妇各50名,采集血样,用化学发光法检测甲状腺功能.同时收集日间随意一次尿样、家中饮用水样和食用盐样,尿碘测定采用砷铈催化分光光度法,水碘测定采用快速定量检测试剂盒,盐碘测定采用硫代硫酸钠滴定法.结果 ①甲状腺抗体阴性孕妇中,高水碘地区孕早期妇女血清TT_4、TT_3、FT_4明显低于适碘地区(111.97 nmol/L vs 140.46 nmol/L,Z=3.56,P<0.01;1.86 nmol/L vs 2.26 nmol/L,Z=2.35,P<0.05;14.13 pmol/L vs 16.32 pmol/L,Z=5.14,P<0.01);孕中期妇女血清FT_4、FT_3明显低于适碘地区(11.98 pmol/L vs 14.30 pmol/L,Z=5.75,P<0.01;4.04 pmol/L vs 4.32 pmol/L,Z=2.76,P<0.01);孕晚期妇女血清,TT_3、TSH明显高于适碘地区(2.88 nmol/L vs 2.70 nmol/L,Z=-2.27,P<0.05;2.37 mU/L vs 1.75mU/L,Z=-2.70,P<0.01).②高水碘地区孕妇家中饮水碘和孕妇尿碘明显高于适碘地区(205.57μg/L vs8.22μg/L,Z=-14.71,P<0.01;305.91μg/L vs 191.86μg/L,Z=-4.01,P<0.01),家中盐碘明显低于适碘地区(26.5 mg/kg vs 31.7 mg/kg,Z=5.68,P<0.01).③健康且没有甲状腺病史的被调查孕妇中,妊娠各期甲状腺抗体阳性率在高水碘和适碘地区之间比较差异无统计学意义(孕早期:10.20%vs 10.64%;孕中期:14.00%vs9.52%;孕晚期:4.00%vs 7.69%,P均>0.05).结论 高水碘地区甲状腺抗体阴性孕妇妊娠各期甲状腺功能不同于适碘地区,对高水碘地区孕妇应加强孕期(特别是孕早、中期)甲状腺功能监测.     

Plasma and urinary aluminum concentrations in severely anemic geophagous pregnant women in the Bas Maroni region of French Guiana: a case-control study

The clays consumed by geophagous individuals contain large quantities of aluminum, a known neurological and hematological toxin. This is the first study to evaluate the risk of aluminum poisoning in geophagous individuals. Blind determinations of plasma and urinary aluminum concentrations were carried out in 98 anemic geophagous pregnant women and 85 non-anemic non-geophagous pregnant women. Aluminum concentrations were significantly higher (P < 0.0001) in the geophagous anemic women than in the controls, with odds ratios of 6.83 (95% confidence interval [CI] = 2.72-19.31) for plasma concentrations (13.92 ± 14.09 μg/L versus 4.95 ± 7.11 μg/L) and 5.44 (95% CI = 2.17-14.8) for urinary concentrations (92.83 ± 251.21 μg/L versus 12.11 ± 23 μg/L). The ingested clay is the most likely source of this overexposure to aluminum. If confirmed, the clinical consequences of this absorption for pregnant women and their offspring should be explored.     

Atrial natriuretic peptide and plasma volume in pregnancy-induced hypertension.

Pregnancy-induced hypertension (PIH) is characterized by a relative decrease in plasma volume and renin and aldosterone concentrations as well as increased capillary permeability compared with normal pregnancy. As many of these features could be explained by the actions of atrial natriuretic peptide (ANP), we examined the relationship between plasma volume and plasma ANP in women with PIH and in normal third trimester pregnant women, and whether ANP responses to alterations in posture were intact in women with PIH. Basal plasma ANP measured after 20 min lateral recumbency in women with PIH was 24.0 (13.9, 33.1) pmol/L (median [25th, 75th percentile]), which was significantly greater than in normal pregnant women (9.9 [6.3, 16.0]), (P less than .05). Plasma ANP did not differ between those with and without proteinuria in the PIH group. Plasma volume was decreased in women with PIH (20.1 [19.0, 23.2] mL/cm) v 23.5 [21.4, 25.3], P less than .05). Plasma renin concentration but not plasma aldosterone concentration was also decreased significantly in women with PIH compared with normal pregnant women (P less than .001) and both were correlated negatively with plasma ANP. Following prolonged lateral recumbency, plasma ANP rose to 26.9 [19.1, 44.1] pmol/L in women with PIH (P less than .05), which was still significantly greater than in normal pregnant women (15.5 [6.7, 21.9] pmol/L) (P less than .05). In a subgroup of these subjects, 30 min head-up tilt decreased plasma ANP by 5.2 [0.9, 22.3] pmol/L in women with PIH and by 6.1 [2.2, 10.3] pmol/L in normal pregnant women, a nonsignificant difference.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changing osteocalcin concentrations during pregnancy and lactation: implications for maternal mineral metabolism

We measured serum osteocalcin concentrations in 82 pregnant and 21 nonpregnant women. Osteocalcin values declined in the second trimester, but returned to nonpregnant levels late in the third trimester. The mean serum osteocalcin concentration in 36 women during pregnancy (mean gestation, 26 weeks) of 2.8 ng/mL was significantly lower than that in nonpregnant women (6.4 ng/mL; P less than 0.001) or term pregnant women at delivery (6.1 ng/mL; n = 46). Serum immunoreactive PTH (iPTH) levels were significantly higher during pregnancy than in nonpregnant women [97 +/- 5 vs. 56 +/- 4 ng/L (mean +/- SE); P less than 0.001]. No significant correlations were found between maternal osteocalcin concentrations and serum phosphorus, alkaline phosphatase, or iPTH, but significant negative correlations were found between osteocalcin and total calcium or total protein. Osteocalcin concentrations in midtrimester amniotic fluid were very low (mean, 0.3 +/- 0.1 ng/mL; n = 11). In 29 lactating mothers, the mean serum osteocalcin level was 9.5 +/- 1.5 ng/mL, significantly higher than in any of the other groups (P less than 0.05), but their serum calcium and iPTH levels were normal. There was no correlation between serum osteocalcin and calcium or iPTH concentrations in lactating women. These changes are compatible with a sequence in which bone turnover is reduced during early pregnancy, rebounds in the third trimester, and increases in postpartum lactating women.     

Reference intervals for haematological variables during normal pregnancy and postpartum in 434 healthy Danish women

AIM: To report reference intervals for haematological variables during normal pregnancy and postpartum. MATERIAL AND METHODS: The series comprised 434 healthy ethnic Danish women with a normal pregnancy > or =37 wk duration and a normal delivery with newborns weight >2500 g. Blood samples were obtained at 18, 32 and 39 wk gestation and at 8 wk postpartum. The following variables were analysed: Haemoglobin (Hb), haematocrit (Hct), blood erythrocyte count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white cell count, platelet count, erythrocyte folate, plasma folate, plasma cobalamin, plasma methylmalonic acid, plasma total homocysteine, serum ferritin, serum soluble transferrin receptor and plasma creatinine. Reference intervals were calculated using log(10)-transformed values (which showed normal distributions) as mean +/- 1.96 x SD. RESULTS: The lower reference value for Hb during pregnancy was 6.45 mmol/L (105 g/L) and 7.3 mmol/L (118 g/L) postpartum. The lower reference value for Hct was 0.31 in pregnancy and 0.35 postpartum. There was a gradual decline in the lower reference value for erythrocyte folate during pregnancy and postpartum from 0.46 to 0.29 micromol/L and in plasma folate from 6 to 4 nmol/L. Lower reference value for plasma cobalamin declined during pregnancy from 96 to 71 pmol/L, but increased postpartum to 148 pmol/L. Upper reference value for plasma homocysteine increased gradually during pregnancy and postpartum from 11.0 to 20.6 micromol/L. Geometric mean serum ferritin at 18 wk gestation was 32 microg/L. Plasma creatinine values were low during pregnancy and displayed a significant increase postpartum. CONCLUSION: The characteristic changes occurring in haematological indices during pregnancy and postpartum are described in this study. The results may be used as reference values in the assessment of health status of pregnant women with a similar socio-economic and racial background.     

HEPTEST: a suitable method for monitoring heparin during pregnancy.

Methods of monitoring heparin in pregnancy are problematic. The aim of this study was to assess the plasma HEPTEST as a rapid and reliable test for heparin monitoring in pregnancy. HEPTEST, activated partial thromboplastin time (APTT) and chromogenic anti-Xa assays were performed on individual heparin-spiked plasma samples from two groups: normal non-pregnant women (n = 6) and normal pregnant women during the third trimester (n = 6). Heparin activity curves were established in plasma from both groups for low (< 0.3 IU/ml), intermediate (0.3-0.7 IU/ml) and high (> 0.7 IU/ml) heparin concentrations and validated by comparison with the anti-Xa chromogenic assay. Both the APTT and HEPTEST demonstrated good correlation with anti-Xa levels across all heparin concentrations in both plasma groups (r range = 0.879-0.945). In comparison with the APTT, the HEPTEST showed better correlation with anti-Xa levels at low concentrations of heparin (r values 0.933 vs. 0.772, respectively). For both the APTT and HEPTEST there were significant differences between the clotting times in pregnant and non-pregnant plasma at a number of heparin concentrations. This data supports the plasma HEPTEST as an acceptable alternative to the chromogenic anti-Xa assay for monitoring heparin thromboprophylaxis in pregnancy.     

Erythrocyte folate, plasma folate and plasma homocysteine during normal pregnancy and postpartum: a longitudinal study comprising 404 Danish women

OBJECTIVE: To assess folate and homocysteine status during normal pregnancy and postpartum in a longitudinal setting. METHODS: This study, performed in 1995-1996, comprised 404 healthy pregnant Danish Caucasian women residential in Copenhagen County. Women taking folic acid tablets or vitamin B12 injections were not included. Dietary multivitamin supplements containing folic acid 100 microg or vitamin B12 1 microg, taken by 34%, were discontinued at inclusion. Participants had normal renal function. Folate status [erythrocyte (Ery-) folate, plasma (P-) folate, P-homocysteine] was measured at 18, 32 and 39 wk of gestation and 8 wk postpartum when the women were lactating. RESULTS: Through 18, 32 and 39 wk of gestation and postpartum, P-folate demonstrated a significant fall: median values were 14.4, 10.2, 9.3 and 8.9 nmol/L, respectively (P < 0.0001). The prevalence of low P-folate <6 nmol/L increased during pregnancy from 0.7% to 19.0% postpartum (P < 0.0001). Ery-folate displayed a similar, significant fall: median value was 0.84, 0.75, 0.65 and 0.55 micromol/L, respectively (P < 0.0001). The prevalence of low Ery-folate <0.40 micromol/L increased during pregnancy from 0.5% to 17.2% postpartum (P < 0.0001). P-homocysteine demonstrated a significant increase: median value was 6.4, 7.0, 7.7 and 10.8 micromol/L, respectively (P < 0.0001). The prevalence of P-homocysteine >13 micromol/L increased during pregnancy from 0.7% to 20.8% postpartum (P < 0.0001). The prevalence of low folate status (defined as P-folate <6 nmol/L and P-homocysteine >13 micromol/L) was 0%, 0%, 1.2%, and 8.4% at 18, 32 and 39 wk of gestation and 8 wk postpartum, respectively. CONCLUSION: Low folate status occurs among Danish pregnant women, especially in late pregnancy and postpartum during lactation. Despite new guidelines for folic acid supplement since 1997, only 13% of pregnant women followed the guidelines in 2003. The official recommendations for periconceptional folic acid supplement should be reconsidered and reinforced.