Maternal Estriol Research Articles

CYP3A7 drug‐hormone Interactions in the Neonate: Adrenal Insufficiency and Low Birthweight in the HIV infected Neonate caused by Inhibition of CYP3A7 DHEA‐S Oxidation by Ritonavir

In the neonate and developing infant, CYP3A7 is the predominant CYP3A isoform and is responsible for the majority of metabolism of CYP3A substrates. However, its primary function is the 16α-hydroxylation of the endogenous hormone DHEA-S, which is important for maintenance of hormone homeostasis in the adrenal gland and production of estriol during the third trimester of pregnancy. Low maternal estriol levels have been reported to lead to low birth weight and premature birth. It has been previously reported that cohorts of HIV infected mothers and their newborns on a combined therapeutic regimen of Lopinavir and Ritonavir have increased adrenal insufficiency and low birth weight, as well as substantially elevated levels of DHEA-S, leading to adverse outcomes in this fragile patient group. Since Ritonavir is a known potent inhibitor of CYP3A4, we hypothesized that it might also be an inhibitor of CYP3A7-mediated DHEA-S oxidation and that this inhibition might be responsible for the adrenal insufficiency and low birth weight associated with Lopinavir-Ritonavir treatment. In order to test this hypothesis, we employed both recombinant CYP enzyme and neonatal human liver microsomes (nHLMs). We observed significant inhibition of CYP3A7 DHEA-S hydroxylation activity in the presence of Ritonavir with an IC50 of 0.05 µM. Furthermore, Ritonavir displayed time-dependent inhibition of DHEA-S oxidation, with a Ki of 0.336 µM and a Kinact of 0.1077 min-1, suggesting that it may be a mechanism based inactivator of CYP3A7. Lopinavir was also capable of inhibiting CYP3A7, albeit to a much lesser extent than Ritonavir with an IC50 of 5.88 µM for DHEA-S 16α-hydroxylation, and without the associated time-dependency. Interestingly, we observed that Lopinavir alone had a lower intrinsic clearance (Clint) rate in nHLMs compared to adult HLMs, suggesting that a pharmacokinetic enhancer adjuvant may not be necessary in this patient population in order to slow drug clearance and maintain efficacy. At a minimum, our results suggest that closer monitoring of the effective dose of the pharmacokinetic enhancer in neonatal HIV therapy may be required in order to prevent significant inhibition of CYP3A7 DHEA-S oxidation and the associated adverse effects.

Cortisol and estriol responses to awakening in the first pregnancy trimester: Associations with maternal stress and resilience factors

BackgroundLittle is known about the maternal cortisol awakening response (CAR) in the first pregnancy trimester. Similarly unknown is how the CAR in early gestation relates to other steroid hormones, such as estriol. Maternal estriol in blood and urine is used to monitor fetal well-being since it is produced by the fetoplacental unit from fetal precursors. Low levels have been associated with maternal-fetal complications. We were recently able to show that estriol is measurable in maternal saliva from 6 weeks’ gestation onwards. However, its pattern following morning awakening and potential links with salivary cortisol in early gestation is relatively unknown. In this prospective study, we explored the cortisol and estriol responses to morning awakening in first-trimester pregnant women, the potential association of these endocrine variables with maternal stress and resilience factors, and their predictive value for the further pregnancy course. MethodsFifty-one women with an uncomplicated, singleton pregnancy responded to questionnaires measuring chronic and pregnancy-specific stress, emotional support, and daily uplifts at 6 weeks’ gestation. At 8 and 10 weeks, the women collected saliva samples immediately, 30, and 60 min after morning awakening. After 12 weeks, 40 women reported on the further pregnancy course, of whom 6 had developed complications. ResultsIn response to morning awakening, cortisol levels increased significantly at 10 weeks (p = .04), while estriol levels decreased significantly at both 8 and 10 weeks (p < .001). A stronger cortisol increase was linked to a stronger estriol decrease at 8 (p = .03), but not at 10 weeks. Then, perceived emotional support at 6 weeks was negatively associated with cortisol baseline at 8 (p = .01) and positively with estriol baseline at 10 weeks (p = .03). Moreover, higher pregnancy-specific stress was related to a lower estriol baseline at 8 weeks (p = .047). Furthermore, compared to healthy women, those with complications at follow-up had already reported less emotional support (p = .03) and fewer daily uplifts (p = .03) at 6 weeks. These women also seemed to lack a significant estriol response to morning awakening at 8 weeks (p > .10). DiscussionThese findings advance our knowledge of cortisol and estriol secretion following morning awakening and encourage the investigation of E3 in addition to cortisol when researching prenatal stress and its consequences for maternal and fetal health.

Relations between second-trimester aneuploidy screening results and prediction of labour induction success in term pregnancies

We aimed to assess whether the second-trimester maternal serum markers could be used for the prediction of labour induction success. This prospective study enrolled women planned labour induction at term. Women were assigned to one of two groups: vaginal prostaglandin or balloon dilatation. All patients were evaluated for Bishop score, maternal serum oestriol, human chorionic gonadotropin and progesterone at the time of second-aneuploidy screening. The total successful rate for induction of labour was 63.9% in both groups. Maternal serum oestriol multiple of median (MoM) values were significantly lower among the caesarean section group compared to the vaginal delivery group (p < .001). A MoM value of 0.74 for oestriol was associated with a sensitivity of 75.9%, specificity of 41.0%, a positive predictive value of 76.6% and a negative predictive value of 58.0% for a successful induction of labour. Oestriol had a good performance in the prediction of successful induction of labour at term. IMPACT STATEMENT What is already known on this subject? Induction of labour is a common procedure undertaken whenever the benefits of prompt delivery outweigh the risks of expectant management. Previous studies have reported that a decreased progesterone/oestradiol ratio and increased maternal plasma oestriol levels are associated with successful labour. What the results of this study add? The results of this study showed that second-trimester oestriol multiple of median (MoM) value provide a significant contribution to the efforts of the prediction of successful induction of labour in term pregnancy, having a sensitivity of 69.8%, specificity of 92.4%, positive predictive value of 83.3% and negative predictive value of 82.5%. What the implications are of these findings for clinical practice and/or further research? This finding can be used as an additional method for prediction of labour induction as well as multiparity and Bishop score. This adds new valuable data to the literature which could be used for systematic reviews and for implementing guidelines and protocols on labour induction.

MON-062 46 XX DSD Due to POR Deficiency

BackgroundPORD (P450 oxidoreductase deficiency) is a rare form of CAH with marked phenotypic variations due to differences in the degree of steroid hormone excess/deficiency. PORD results in17αhydroxylase/17,20lyase- CYP17, 21αhydroxylase- CYP21, and aromatase- CYP19A1 inhibition. In the absence of characteristic skeletal features of Antley Bixler phenotype, differentiating PORD from other types of CAH is challenging.Case details04 day child, second of the non-identical twins, product of 2nd degree consanguinity, third in birth order was brought with abnormal genitalia. The other male twin had no genital ambiguity but had pigmented scrotum. There was no adrenal crisis in index case or maternal virilization. First child is normal female. Child was hemodynamically stable weighed 02 kgs and measured 51 cms, had no hyperpigmentation, skeletal deformities or dysmorphic features. Phallus was 10mm, clitoral index 40mm2 with single urogenital opening and posteriorly fused labia (anogenital ratio 0.6).Gonads were not palpable. Karyotype was 46XX with normal Mullerian structures and non-visualized gonads on ultrasonography. Biochemical workup showed random plasma glucose level of 99mg/dl and normal electrolytes. Baseline serum 8am Cortisol was 1.15 mcg/dl (normal 5-18 mcg/dl) and 17OHP was 20 ng/ml (normal < 02 ng/ml). Serum Androstenedione level was 0.39 nmol/L (normal 0.5-3.4 nmol/L).In view of clinical, laboratory and imaging findings, presumptive diagnosis of 46 XX DSD due to 21 alpha hydroxylase deficiency CAH was made. Oral Hydrocortisone 15mg/m2 and Fludrocortisone 0.05 mg were initiated. Therapy was monitored with serum 17(OH)P levels and Androstenedione. Genetic testing for 21 alpha hydroxylase gene however came negative.This led to further genetic mutational analysis, and there was a homozygous R457H POR gene mutation at exon 12 leading to protein change p.Arg457His (nucleotide change c.1370G>A), confirming PORD. Retrospectively, maternal triple test done during the candidate pregnancy showed low serum estriol, suggestive of placental aromatase deficiency. Mineralocorticoid supplements were stopped thereafter. Conclusions PORD needs to be considered and differentiated from garden variety of CAH in 46 XX DSD when elevation of 17(OH)P is modest with isolated cortisol deficiency and aromatase deficiency (evidenced by low maternal estriol levels and/or virilization), as its course and follow up are different.

CYP3A7 drug‐hormone Interactions in the Neonate: Adrenal Insufficiency and Low Birthweight in the HIV infected Neonate caused by Inhibition of CYP3A7 DHEA‐S Oxidation by Ritonavir

In the neonate and developing infant, CYP3A7 is the predominant CYP3A isoform and is responsible for the majority of metabolism of CYP3A substrates. However, its primary function is the 16α‐hydroxylation of the endogenous hormone DHEA‐S, which is important for maintenance of hormone homeostasis in the adrenal gland and production of estriol during the third trimester of pregnancy. Low maternal estriol levels have been reported to lead to low birth weight and premature birth. It has been previously reported that cohorts of HIV infected mothers and their newborns on a combined therapeutic regimen of Lopinavir and Ritonavir have increased adrenal insufficiency and low birth weight, as well as substantially elevated levels of DHEA‐S, leading to adverse outcomes in this fragile patient group. Since Ritonavir is a known potent inhibitor of CYP3A4, we hypothesized that it might also be an inhibitor of CYP3A7‐mediated DHEA‐S oxidation and that this inhibition might be responsible for the adrenal insufficiency and low birth weight associated with Lopinavir‐Ritonavir treatment. In order to test this hypothesis, we employed both recombinant CYP enzyme and neonatal human liver microsomes (nHLMs). We observed significant inhibition of CYP3A7 DHEA‐S hydroxylation activity in the presence of Ritonavir with an IC50 of 0.05 μM. Furthermore, Ritonavir displayed time‐dependent inhibition of DHEA‐S oxidation, with a Ki of 0.336 μM and a Kinact of 0.1077 min−1, suggesting that it may be a mechanism based inactivator of CYP3A7. Lopinavir was also capable of inhibiting CYP3A7, albeit to a much lesser extent than Ritonavir with an IC50 of 5.88 μM for DHEA‐S 16α‐hydroxylation, and without the associated time‐dependency. Interestingly, we observed that Lopinavir alone had a lower intrinsic clearance (Clint) rate in nHLMs compared to adult HLMs, suggesting that a pharmacokinetic enhancer adjuvant may not be necessary in this patient population in order to slow drug clearance and maintain efficacy. At a minimum, our results suggest that closer monitoring of the effective dose of the pharmacokinetic enhancer in neonatal HIV therapy may be required in order to prevent significant inhibition of CYP3A7 DHEA‐S oxidation and the associated adverse effects.Support or Funding InformationThis work was supported by the National Institutes of Health, Institute of General Medical Sciences [Grant R01 GM128508‐03] to JNL.

In utero and postnatal programing of dehydroepiandrosterone sulfate (DHEAS) in young adult women

Fetal adrenal-derived OH-DHEAS is the primary precursor for maternal estriol, an abundant, human, placental estrogen. We measured maternal pregnancy estriol as a marker of fetal adrenal function + placenta capacity to synthesize estriol. We hypothesized that maternal estriol is directly correlated with the adrenal hormone, DHEAS, in young adult women. We tested this hypothesis in a subset of women in the Child Health and Development Studies (351 of 470 eligible). 176 of these had serum samples collected at ages 27–30 for DHEAS assays, archived maternal pregnancy serum for estriol assays, and childhood growth data. In regression analyses, both maternal estriol and accelerated growth in middle childhood were independently, directly associated with DHEAS (+19% for quartile 4 versus quartile 1 of estriol, 95%CI=+ 2%, +36% and +12% for quartile 4 versus quartile 1 for middle childhood growth, 95%CI= +3%, +21%). Adrenal function may be programmed in utero and middle childhood with long-term consequences.

Maternal estriol concentrations in early gestation predict infant telomere length.

Telomere biology plays a fundamental role in genomic integrity, cellular regeneration, physiology, aging, disease risk, and mortality. The initial setting of telomere length (TL) in early life has important implications for telomere maintenance and related disorders throughout the life span. However, little is known about the predictors of this initial setting. Given the established role of estrogen on adult TL and the role of estriol (E3) in the context of fetal development, the goal of this study was to test the hypothesis that higher maternal E3 concentration during early pregnancy is associated with longer infant telomere length. Study participants comprised a cohort of N = 100 infants followed prospectively from intrauterine life and birth through early childhood from a population-based, representative sample of pregnant mothers recruited in early pregnancy at university-based obstetric clinics in Southern California. Maternal unconjugated E3 concentrations were assessed in plasma in early gestation (around wk 15). Infant TL was assessed in buccal cells at approximately 15 months of age. After accounting for the effects of potential confounding maternal and infant variables, there was a significant, independent effect of maternal E3 concentration on infant TL (unstandardized β = 0.297; P = .001; 95% Cl, 0.121-0.473). Specifically, a one-multiple-of-the-median (MoM) increase in maternal E3 concentration during early pregnancy was associated with a 14.42% increase in infant TL. This study supports the concept of developmental plasticity of the telomere biology system and highlights specifically the role of a potentially modifiable intrauterine factor for additional mechanistic and clinical investigation.

Maternal and cord blood hormones in relation to birth size.

Birth size has been associated with adult life diseases, but the endocrine factors that are likely involved are not established. We evaluated the associations of maternal and cord blood hormones with birth size in normal pregnancies, and examined possible effect modification by maternal height, on the basis of prior suggestive evidence. In a prospective study of normal singleton pregnancies in Boston, USA and Shanghai, China, maternal hormone levels at the 27th gestational week were available for 225 pregnancies in Boston and 281 in Shanghai and cord blood measurements for 92 pregnancies in Boston and 110 in Shanghai. Pearson partial correlation coefficients of log-transformed hormone levels with birth weight and length were calculated. Overall, positive correlations with birth weight were found for maternal estriol (r = 0.19; p < 0.001) and progesterone (r = 0.15; p < 0.001) and these associations were more evident among taller mothers. There was an inverse association of cord blood progesterone (r = -0.16; p < 0.03) with birth weight. In Boston, cord blood IGF-1 was positively associated with birth weight (r = 0.22; p < 0.04) and length (r = 0.25; p < 0.02), particularly among taller mothers (r = 0.43 and 0.38, respectively; p < 0.02), whereas among taller mothers in Shanghai the associations of IGF-2 with birth size appeared to be at least as strong as those of IGF-1. In conclusion, maternal estriol and progesterone, and cord blood IGF-1 were positively correlated with birth size. All correlations tended to be more pronounced among offspring of taller mothers. Among taller mothers in Shanghai, IGF-2 appeared to be at least as strongly associated with birth size as IGF-1.

Low estriol levels in the maternal marker screen as a predictor of X-linked adrenal hypoplasia congenita: case report.

X-linked adrenal hypoplasia congenita (AHC) is a rare cause of adrenocortical insufficiency. Early postnatal diagnosis may prevent severe hypoglycemia, Addisonian crises and death. Low maternal estriol (E3) levels in the second trimester of pregnancy could indicate the possibility that the fetus suffers from a disorder that causes adrenal insufficiency. Suspicion is based on the fact that E3 originates from dehydroepiandrosterone (DHEA) synthesized in the fetal adrenals. In case of adrenal insufficiency, the impaired production of fetal DHEA leads to a subsequent reduction of E3 concentrations in maternal serum. There are only a few reports of AHC suspected prenatally due to low maternal E3 levels. We describe two brothers with adrenal insufficiency due to AHC. The older brother was admitted to the hospital at the age of 33 days due to failure to thrive, vomiting, and dehydration. Genetic analysis revealed a hemizygous mutation in DAX-1 gene, thus confirming the diagnosis of ACH. The same mutation was detected in his mother. In the second pregnancy, E3 concentrations were determined from maternal serum. Estriol levels during the second trimester were extremely low suggesting the diagnosis of AHC. The diagnosis was confirmed during the neonatal period by genetic testing, and replacement therapy was started at the age of 10 days. This boy never experienced an adverse episode such as hypoglycemia or adrenal crises. Since determination of E3 is a simple, sensitive, noninvasive and cheap method, its use as an obligatory prenatal screening test should be accepted as a standard practice in Serbia.

Are low maternal estriol levels a predictor for pro‐opiomelanocortin (POMC) deficiency caused by POMC mutation during pregnancy?

Isolated adrenocorticotropic hormone deficiency is a rare cause of adrenocortical insufficiency, especially in children, and may be an underestimated cause of neonatal death. Low estriol levels are usually correlated with compromised uteroplacental perfusion and associated with fetal death. A 30-years old woman applied for pregnancy follow-up. Ultrasonographic evaluation and karyotype of the fetus are normal. Low estriol level 0.34 MoM (% 0.24) was detected in maternal triple screening test. Amniocentesis was performed, and chromosomal disorders, steroid sulfatase deficiency, and Smith-Lemli-Opitz syndrome (SLOS) were excluded with karyotype, fluorescence in situ hybridization (FISH), and molecular analysis of SLOS, respectively. As their first child had pro-opiomelanocortin (POMC) deficiency, POMC gene analysis was performed from both amniotic fluid and ethylene diamine tetra aceticacid (EDTA) blood sample of affected previous child, and homozygote mutation was detected. Fetus is diagnosed as POMC deficiency. We are presenting this case to discuss possible relationship of low maternal E3 levels and fetal POMC deficiency.

Correlation between spontaneous preterm birth and mid-trimester maternal serum estriol

Objective: Elevated third trimester salivary estriol levels have been associated with preterm birth. We evaluated whether maternal estriol concentrations from second trimester serum correlated with preterm delivery.Methods: A retrospective cohort study of 7767 patients evaluated with second trimester aneuploidy screening. Unconjugated serum estriol was measured by immunoassay, expressed as multiples of the median (MoM) for gestational age and evaluated for association with preterm (<37 week) birth.Results: Elevated maternal serum estriol was significantly associated with preterm birth (1.15 MoM versus 1.03 MoM for delivery at term, OR 1.69 CI 1.41 to 2.02). 9.95% of spontaneously laboring patients <34 weeks had estriol MoM > 2, as opposed to 6.23% of >34 week deliveries (p = 0.031). There was a direct correlation between level of estriol concentrations and gestational age at time of delivery.Conclusions: Elevated second trimester maternal serum unconjugated estriol is independently associated with a higher rate of spontaneous preterm birth.

Gebelik Komplikasyonlarının Öngörüsünde Maternal İkinci Trimester AFP, HCG, ESTRİOL Değerleri ve Uterin Arter Doppler Bulguları Arasındaki İlişkinin Değerlendirilmesi

Gebelik Komplikasyonlarının Öngörüsünde Maternal İkinci Trimester AFP, HCG, ESTRİOL Değerleri ve Uterin Arter Doppler Bulguları Arasındaki İlişkinin Değerlendirilmesi

17. Pregnancy-related stress influences maternal corticotropin-releasing factor and estriol concentrations affecting birth outcome

17. Pregnancy-related stress influences maternal corticotropin-releasing factor and estriol concentrations affecting birth outcome

Co-occurrence of X-Linked Congenital Adrenal Hypoplasia and Autistic Disorder

Back to table of contents Previous article Next article LETTERFull AccessCo-occurrence of X-Linked Congenital Adrenal Hypoplasia and Autistic DisorderKarl G. Sieg M.D.,Karl G. Sieg M.D.Search for more papers by this author,Published Online:1 Apr 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: One form of congenital adrenal hypoplasia is associated with the Xp21 chromosomal region. These patients have clinical abnormalities including mental retardation, hearing loss, hypogonadism, glycerol kinase deficiency, ornithine transcarbamoylase deficiency, and Duchenne muscular dystrophy. This letter presents a case of a patient with X-linked congenital adrenal hypoplasia whose mental status as a preadolescent male was also consistent with the diagnosis of autistic disorder. Case ReportA 12-year-old Caucasian boy presented with features of autistic disorder including marked lack of awareness of the feelings of others; no seeking of comfort in times of distress; gross impairment in ability to make peer friendships; abnormal nonverbal communication; abnormalities in speech production including perseveration and echolalia; stereotyped body movements including flapping, clapping, and rocking; and persistent preoccupation with parts of objects reflecting a restricted range of interests. His Autism Behavior Checklist total score was 126 with the following subscale profile results: sensory 15, relating 33, body and object use 31, language 25, social and self-help 22. Speech and language testing indicated an age equivalency of 2.8 to 3.0 years old with severe delays of receptive and expressive language as well as speech articulation. MRI brain scan was unremarkable. Chromosomal analysis had confirmed a deletion at the Xp21 region. His family pedigree noted several female congenital adrenal hypoplasia carriers including his mother as well as male infants who had died from congenital adrenal hypoplasia with no family history of autism, nor other developmental, neurologic, or psychiatric conditions. The patient had been prenatally diagnosed with congenital adrenal hypoplasia and survived with in utero replacement therapy initiated at 40 weeks gestation with 100 mg of dehydroepiandrosterone sulfate infused into the amniotic space. Subsequent assessments revealed normalizing maternal estriol excretion. After birth at 43.5 weeks gestation, mineralocorticoid replacement therapy was administered during infancy. Later evaluations revealed steroid deficiencies as well as chronic failure to thrive. Progressive motor, language, and socialization delays followed as described.Comment Despite receiving replacement treatment, it is conceivable that congenital adrenal hypoplasia-related neurophysiologic abnormalities may have already been staged. Adrenal hormone imbalances have been linked to disturbances of development, language, memory, and mood. 1 Congenital adrenal hypoplasia can impact the function of the mineralocorticoid and glucocorticoid receptor systems for cortisol binding in the limbic system. The mineralocorticoid receptors, located in the lateral septum and hippocampus, affect tonic influences on brain function. 2 They demonstrate a 10-fold higher binding affinity for cortisol over glucocorticoid receptors. 1 Glucocorticoid receptors are more widely distributed in the lateral septum, central amygdala, locus coeruleus, and dentate nucleus having involvement with feedback action on stress-activated brain mechanisms. 2 Other studies demonstrated the selective loss of hippocampal granule cells after adrenalectomy suggesting adrenal hormones are a requirement for limbic structural integrity. 3 Adrenal deficiency causes hippocampal serotonin receptor density to selectively increase along with development of subsensitivity at presynaptic receptors. 4 Such impacts on serotonin receptors are particularly significant as alterations of serotonergic neurotransmission have been implicated in both autistic disorder and mental retardation. 5La Amistad Behavioral Health Services, Maitland, Florida

Linking Antley–Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency

The Antley-Bixler syndrome (ABS) is a multiple congenital malformation syndrome with craniosynostosis, radiohumeral synostosis, femoral bowing, choanal atresia or stenosis, joint contractures, urogenital abnormalities and, often, early death. Autosomal recessive and dominant inheritance have been postulated, as has fluconazole teratogenesis. Mutations in POR (P450 (cytochrome) oxidoreductase, an essential electron donor to enzymes participating in cholesterol biosynthesis), have been identified in some patients with the ABS phenotype. Recent evidence suggests that these mutations cause attenuated steroid hydroxylation, which in turn, causes congenital adrenal hyperplasia (CAH) with ambiguous genitalia in both sexes and glucocorticoid deficiency. Here, we report on a new patient with findings of both ABS and CAH that further illustrates how low maternal estriol at prenatal screening can serve as a marker steroid facilitating early diagnosis.

High maternal estriol level in pregnancy as a predictor of surgical intervention for undescended testis

To assess whether elevated levels of estriol (E3) in pregnancy are a factor in the fetal environment associated with undescended testes, we carried out a two-part study: case-control followed by a retrospective cohort study on cryptorchid boys born in the Sapir Medical Center (Kfar Saba, Israel). We found significantly lower pregnancy urinary E3 levels in cryptorchid newborns as compared to controls; however, subgroup comparison yielded significantly higher pregnancy unconjugated E3 levels in the infants who underwent orchiopexy as compared to those who did not.

Associations of maternal and umbilical cord hormone concentrations with maternal, gestational and neonatal factors (United States).

Risks of some cancers in adults have been associated with several pregnancy factors, including greater maternal age and birth weight. For hormone-related cancers, these effects are hypothesized to be mediated through higher in utero estrogen concentrations. In addition, racial differences in pregnancy hormone levels have been suggested as being responsible for differences in testicular and prostate cancer risk by race. However, data on hormonal levels related to these characteristics of pregnancy are sparse, particularly those from studies of the fetal circulation. Estrogen and androgen concentrations were measured in maternal and umbilical cord sera from 86 normal, singleton pregnancies. Birth size measures (weight, length and head circumference) were positively correlated with maternal estriol (r = 0.25-0.36) and with cord DHEAS concentrations (r = 0.24-0.41), but not with estrogens in cord sera. Maternal age was inversely correlated with maternal DHEAS, androstenedione and testosterone concentrations (r = -0.30, -0.25 and -0.30, respectively), but uncorrelated with estrogens in either the maternal or cord circulation. Black mothers had higher androstenedione and testosterone concentrations than white mothers, however, there were no racial differences in any of the androgens in cord sera. Cord testosterone concentrations were higher in mothers of male fetuses, while both maternal and cord concentrations of estriol were lower in these pregnancies. These data demonstrate associations between hormone concentrations and pregnancy factors associated with offspring's cancer risk, however, the hormones involved and their patterns of association differ by whether the maternal or fetal circulation was sampled. Hormone concentrations in the fetal circulation in this study are not consistent with the hypothesis that greater estrogen concentrations in high birth weight babies mediate the positive association with breast cancer risk observed in epidemiologic studies, or with the hypothesis that higher testosterone exposure in the in utero environment of black males explains their higher subsequent prostate cancer risk.

#19 Associations of maternal and umbilical cord hormone concentrations with maternal, gestational and neonatal factors

PURPOSE: High birth weight has been associated with adult breast and prostate cancer risk in epidemiologic studies and is hypothesized to be mediated through higher in utero estrogen concentrations. This hypothesis is based on maternal estrogen concen- trations, while limited data exist on the fetal circulation. METHODS: Concentrations of androstenedione, testosterone, estradiol, estriol, estrone, dehydroepiandrosterone (DHEA) and DHEA-Sulfate (DHEAS) were measured in maternal and mixed umbilical cord sera from 86 normal, singleton pregnancies. Maternal samples were collected at admission for labor and delivery. RESULTS: In the maternal sera, only estriol was positively correlated with gestational age (Spearman r = 0.35 ) and birth size including, birth weight (r = 0.36), length (r = 0.30) and head circumference (r = 0.25). Cord DHEAS concentrations, but none of the other hormones, were positively correlated with gestational age (r = 0.32), birth weight (r = 0.34), birth length (r = 0.41) and head circumference (r = 0.24). In linear regression analyses, maternal estriol and cord DHEAS predicted birth weight after adjustment for gestational age. No other hormones were independently associated with birth weight. Inspection of mean hormone levels by strata of birth weight (<2500, 2500–3499, 3500+), however, revealed nonlinear relations with the lowest birth weight babies having the lowest maternal estriol and cord DHEAS and no consistent pattern in the upper two categories. CONCLUSION: These data show an association between hormone concentrations and birth weight, however, the hormones involved and their patterns of association differ between the fetal and maternal results. In addition, these data are not consistent with the hypothesis that higher estrogen concentrations in high birth weight babies mediate the positive association with breast cancer risk observed in epidemiologic studies.

Accuracy of Expected Risk of Down Syndrome Using the Second-Trimester Triple Test

Second-trimester maternal serum screening (MSS) for Down syndrome has been widely used in routine prenatal care in developed countries. The screening combines maternal age-specific risk of Down syndrome with risk estimation obtained by measuring maternal serum markers to assign women an expected risk of having a term Down syndrome pregnancy. Diagnostic tests were offered to women whose risk exceeded the risk cutoff determined by the screening program. The commonly used triple test, which involves the use of maternal age, serum α-fetoprotein, unconjugated estriol, and human chorionic gonadotropin, was expected to have a Down syndrome detection rate of 60–65% and false-positive rate of 5% (1). Although the expected screening performance has been achieved in many screening programs, the accuracy of individual risk calculated by a relatively complex computation based on a statistical model was not immediately obvious. Good agreement between the expected risk of Down syndrome and observed prevalence has been reported previously in several screening programs (2)(3)(4)(5). We evaluated the accuracy of expected risk of Down syndrome in a large provincial, multiple test center, MSS program in Ontario, Canada. MSS has been coordinated at the provincial level in Ontario since 1993. Triple maker screening (α-fetoprotein, unconjugated estriol, and β-human chorionic gonadotropin) was carried out in seven regional laboratory centers. Information including screen utilization, results, follow-up data, and the pregnancy outcomes of all women screened in the seven centers was collected …

516 Timing of spontaneous abortion after amniocentesis

TIMING OF SPONTANEOUS ABORTION AFTER AMNIOCENTESIS DENA TOWNER ], LINDA GREVE t, BOB CURRIER 2, FRED LOREy2; lUniversity of California, Davis, Obstetrics & Gynecology, Sacramento, G&; 2Genetic Disease Branch, DHS, Berkeley, CA OBJECTIVE: To compare, in a prenatal diagnosis population, when spontaneous abortions (SAB) occur in women accepting and declining an amniocen tesis. STUDY DESIGN: From the Calitornia State Expanded AFP program, 44,525 women with outcomes ascertained were identified where the fetal ultrasound was normal and if an aumiocentesis was pertc)rlned it was uornlal. There were 156 spontaneous abortions at < 24 weeks gestation. An amniocentesis was performed in 69. The remaining 87 had declined anmiocentesis. The two groups were compared tot maternal age, gestational age (GA) at prenatal diagnosis (PDC) visit, number of days to loss after PDC visit, GA at loss, maternal sermn AFP (MSAFP), maternal serum hCG (MShCG), and maternal seruna estriol (MSuE3). Student t test and Logrank test were used to compare the groups. RESULTS: The overall rate of SAB was 0.36%. There was no statistical difference between the two groups in the factors assessed: GA at loss was 21 weeks 2 days ~br both groups (P = .93), days until loss was 23 days with amnio and 20.4 days w, ithout (P = .29), maternal age was 30.5 years with amnio and 30.1 years in those declining (P = .72), MSAFP was 3.18 MoM in those with amnio and 2.83 MoM in those declining (P = .36), MShCG was 2.10 MoM in those having an anmio and 1.80 MoM in those declining (P = .24). The Logrank test revealed no significant difference between the groups for either GA at loss (P= .61) or days until loss (P= .40). The Figure shows the cumulative losses by GA at loss. CONCLUSION: There is no clustering of losses innnediately following anmiocentesis with the average time to loss about 3 weeks. The same pattern is present in the women declining amniocentesis, suggesting there is minimal impact of amniocentesis in this population of women.