The probability of multiple births when multiple gestational sacs or viable embryos are diagnosed at first trimester ultrasound

The live birth outcome when multiple gestational sacs were diagnosed at first trimester ultrasound was reviewed in 227 twin, 43 triplet and five quadruplet pregnancies. When two gestational sacs were present, the probability of delivering twins was 63% for maternal age less than 30 and 52% for maternal age greater than or equal to 30. With three gestational sacs, the probability of a triplet birth was 45% for maternal age less than 30 and 18% for maternal age greater than or equal to 30. When two viable embryos were present, the probability of a twin birth was 90% for maternal age less than 30 and 84% for maternal age greater than or equal to 30. With three viable embryos, the probability of a triplet birth was 90% for maternal age less than 30 and 44% for maternal age greater than or equal to 30. Two gestations resulting from ovulation induction with clomiphene citrate were more likely to result in twin delivery at term, compared to spontaneous twin gestations (P = 0.012). These findings may be useful in the treatment and management of patients when multiple gestations are diagnosed early in pregnancy.     

Maternal lead exposure and the secondary sex ratio

BACKGROUND: A reduction in the secondary sex ratio may be associated with exposure to environmental toxicants. Little data exists relating this outcome to lead exposure, a well-known reproductive toxicant. METHODS: We studied 1980 women having singleton births from 1994 to 1995 and from 1997 to 2001 who participated in a cohort study of lead exposure and infant outcomes in Mexico City. Levels of lead were measured in maternal and cord blood using graphite furnace atomic absorption spectroscopy, and levels of lead in maternal patella and tibia bone (a reflection of cumulative exposure) were measured using noninvasive K-X-ray fluorescence measurements. Using logistic regression models, we evaluated the relations of these measures to secondary sex ratio in the offspring, adjusting for maternal age, parity and year of infants' birth. RESULTS: We found no consistent association between any of the lead measures and secondary sex ratio. Results were unchanged when we adjusted for infants' year of birth, maternal age and parity. CONCLUSIONS: Despite a large sample size and the use of sensitive biomarkers, we did not find evidence that maternal and fetal lead exposure is associated with a lower secondary sex ratio among newborns.     

Circulating cell-free fetal DNA in maternal serum appears to originate from cyto- and syncytio-trophoblastic cells. Case report

Circulating cell-free fetal DNA in maternal serum offers an early and non-invasive method for prenatal diagnosis, but the origin of this DNA is still unknown. We report the absence of the SRY gene in maternal serum of a pregnant woman despite male genitalia at ultrasound. The karyotype was 45,X after direct trophoblast analysis and 45,X/46,Xidic(Yp) after culture and in all fetal tissues studied. Due to the absence of the SRY sequence in maternal blood and in the cytotrophoblast, we presume that free fetal DNA in this case originates from trophoblastic cells. As the case presented here is exceptional, it only has a minor impact on the accuracy of fetal sex determination by maternal serum analysis, but highlights the importance of and the necessity for the complementary ultrasonographic control.     

Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis

Strategies for genetic prenatal diagnosis on fetal cells in the maternal circulation have been limited by lack of a cell type present only in fetal blood. However, the recent identification of mesenchymal stem cells (MSC) in first trimester fetal blood offers the prospect of targeting MSC for non-invasive prenatal diagnosis. We developed protocols for fetal MSC enrichment from maternal blood and determined sensitivity and specificity in mixing experiments of male fetal MSC added to female blood, in dilutions from 1 in 10(5) to 10(8). We then used the optimal protocol to isolate fetal MSC from maternal blood in the first trimester, using blood taken after surgical termination of pregnancy as a model of increased feto-maternal haemorrhage. In model mixtures, we could amplify one male fetal MSC in 2.5 x 10(7) adult female nucleated cells, yielding a 100% pure population of fetal cells, but not one fetal MSC in 10(8) nucleated cells. Fetal MSC were identified in one of 20 post-termination maternal blood samples and confirmed as fetal MSC by XY fluorescence in-situ hybridization (FISH), immunophenotyping and osteogenic and adipogenic differentiation. We report the isolation of fetal MSC from maternal blood; however, their rarity in post-termination blood suggests they are unlikely to have a role in non-invasive prenatal diagnosis. Failure to locate these cells routinely may be attributed to their low frequency in maternal blood, to sensitivity limitations of enrichment technology, and/or to their engraftment in maternal tissues soon after transplacental passage. We speculate that gender microchimerism in post-reproductive maternal tissues might result from feto-maternal trafficking of MSC in early pregnancy.     

Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique

BACKGROUND: Fetal DNA circulating in maternal serum offers a possibility for non-invasive prenatal diagnosis but its kinetics during very early pregnancy is still unclear. In order to clarify this point, the studies on the kinetics of fetal DNA appearance in maternal serum were conducted on patients undergoing assisted reproduction. METHODS: Using a quantitative real time PCR assay, the presence of SRY gene sequences was evaluated in the serum of patients at the onset of pregnancy. RESULTS: Twenty-seven patients were originally studied but first trimester abortion occurred in five cases. Among the 22 ongoing pregnancies, ten were found to bear at least one male fetus and all sera from these women gave positive results for SRY gene detection. The SRY gene was found to be detectable as soon as day 18 after embryo transfer in one case and it had been found in the other nine patients by day 37. CONCLUSIONS: Fetal DNA is found in maternal serum even before the fetal circulation is established, which is highly suggestive that it is released, at least in part, from the trophoblast. Detection of fetal DNA in maternal serum very early in pregnancy may have clinical implications such as with the management of pregnant women carrying a fetus at risk for congenital adrenal hyperplasia.     

A study on placental transfer of diclofenac in first trimester of human pregnancy

Diclofenac is a commonly used non-steroidal anti-inflammatory drug in women of reproductive age. It has teratogenic effects in animals. The aim of this study was to investigate the placental transfer of diclofenac in the first trimester of human pregnancy. Thirty patients undergoing surgical termination of pregnancy between 8 and 12 weeks gestation were given two doses of diclofenac before the procedure. Corresponding samples of maternal serum, amniotic fluid, coelomic fluid and fetal tissue were analysed by high-performance liquid chromatography. Diclofenac was detectable in all fetal tissue samples, with a concentration similar to that found in maternal venous samples. However, diclofenac was detectable in only 56.7 and 23.3% of the coelomic and amniotic fluid samples respectively, and the highest concentration attained was 80 and 5% of the maternal concentration respectively. In summary, we confirmed that diclofenac crosses the human placenta readily during the first trimester. Further studies are required to investigate the potential teratogenic effect of diclofenac in human embryos.     

Relationships between the uterine environment and maternal plasma concentrations of insulin-like growth factor binding protein-1 and placental protein 14 inearly pregnancy

Blood was obtained from 218 women between 6 and 13 weeks ofgestation. Measurements of serum insulin-like growth factorbinding protein-1 (IGFBP-1) and placental protein 14 (PP14)concentrations were compared withmaternal weight and height,maternal smoking habit, indices of maternal haematological statusand two placental hormones [human chorionic gonadotrophin (HCG)and human placental lactogen (HPL)]. IGFBP-1 concentration wasnegatively correlated with maternal weight (P < 0.001) andbody mass index (P <0.001); PP14 concentration was not correlatedwith these measurements. PP14 concentration was negatively correlatedwith maternal haemoglobin concentration (P equals; 0.010), meancorpuscular volume (P equals; 0.003) and serum ferritin concentration(P equals; 0.016). The concentrations of PP14 were significantlyless among smokers (P < 0.001); IGFBP-1 concentrations wereuninfluenced by smoking. IGFBP-1 concentration was positivelycorrelated with maternal serum HCG (P equals; 0.003) and maternalserum HPL (P equals; 0.002). PP14 concentration was positivelycorrelated with maternal serum HCG (P < 0.0001) but not withHPL. These findings demonstrate that the maternal environmenthas an early influence on both endometrial and placental function.     

An in-vivo study on placental transfer of naproxen in early human pregnancy

BACKGROUND: Naproxen is one of the most common non-steroidal anti-inflammatory drugs used by women of reproductive age. Naproxen is known to be teratogenic in animals. The aim of this study was to investigate the placental transfer of naproxen in the first trimester of human pregnancy, and to determine the amount of the drug in different embryonic compartments. METHODS: Twenty-eight patients who requested surgical termination of pregnancy in the first trimester were given two oral 500 mg doses of naproxen before the surgical procedure. Four biological samples, maternal venous blood, coelomic fluid, amniotic fluid and fetal tissue, were collected from each patient for drug analyses by high performance liquid chromatography. RESULTS: Naproxen was detected in all samples. The mean (+/- SD) concentrations were 69.5 +/- 12.2 microg/ml, 6.4 +/- 2.4 microg/g, 1.85 +/- 1.03 microg/ml and 0.14 +/- 0.11 microg/ml in maternal serum, fetal tissue, coelomic fluid and amniotic fluid respectively. The mean amniotic fluid/maternal drug ratio and fetal/maternal drug ratio were 0.002 (range 0.0005-0.0064) and 0.092 (range 0.022-0.155) respectively. There was a positive correlation between the fetal drug concentration (r = 0.59, P = 0.001), amniotic fluid drug concentration (r = 0.47, P = 0.013), amniotic fluid/maternal ratio (r = 0.536, P = 0.003) and fetal/maternal ratio (r = 0.72, P < 0.001) with advancing gestational age. CONCLUSIONS: Although naproxen can cross the placenta readily in the first trimester of human pregnancy, only a small amount was present in fetal tissues. Since there is no information on whether this small amount of naproxen would be teratogenic or not, women of reproductive age who are taking naproxen regularly should be warned of the possible fetal side-effects.     

Maternal serum beta-HCG and alpha-fetoprotein concentrations in singleton pregnancies following assisted reproduction

BACKGROUND: The reason for the elevated levels of HCG in assisted reproduction pregnancies remains unknown. Our hypothesis was that this increase is caused by the ovarian superovulation therapy. METHODS: We compared the beta-HCG and alpha-fetoprotein (AFP) multiples of the median (MoM) in singleton pregnancies after IVF or ICSI with those achieved by frozen embryo transfer (FET) in spontaneous cycles. RESULTS: The HCG and AFP MoMs (plus minus SEMs) of 59 FET pregnancies were compared with 144 IVF (including 48 ICSI) pregnancies. The maternal HCG of pregnancies following ovarian stimulation was 1.31 plus minus 0.08 MoM compared with 1.35 plus minus 0.12 MoM in the unstimulated ones. The values for AFP were 1.06 plus minus 0.05 versus 1.11 plus minus 0.05 respectively. No significant differences could be observed between pregnancies following stimulated IVF/ICSI and unstimulated FET cycles. CONCLUSIONS: Our results show that second trimester maternal serum HCG is also elevated in singleton pregnancies following spontaneous FET cycles. The increased maternal serum HCG in IVF pregnancies is thus not related to superovulation therapy. Because of the elevated maternal serum HCG levels, serum screening cannot be performed reliably in pregnancies following assisted reproduction technology. Ultrasonographic detection of the nuchal translucency is unaffected and should be used for this group of women undergoing assisted reproduction.     

Prenatal diagnosis and normal outcome of a 46,XX/46,XY chimera: a case report

The phenotypic spectrum of 46,XX/46,XY chimeric patients is variable. It ranges from normal male or female genitalia to different degrees of ambiguous genitalia. Chimerism results from the amalgamation of two different zygotes in a single embryo, whereas mosaicism results from a mitotic error in a single zygote. Several other mechanisms resulting in a chimera have been discussed in the literature. Here, we report on a new case of chimerism (46,XX/46,XY) diagnosed at 17 weeks' gestation on amniocentesis performed because of advanced maternal age. Ultrasound examination revealed normal female external genitalia, and a healthy baby girl was delivered at term. We used polymorphic markers spanning the X chromosome and several autosomes in order to identify the genetic mechanism involved. Mosaicism was excluded because of the presence of 3 alleles at 11 autosomal and 4 X chromosome loci. On autosomes, the origin of this third allele was maternal for two pericentromeric markers (located on 2p11.2 band and 8p11.2 band), paternal for six markers and paternal or maternal for the other three markers. On the X chromosome, the origin of the third allele was maternal for all four markers. Thus, two different paternal and maternal haploid sets were observed. These results are compatible with a tetragametic chimera.     

Is maternal obesity related to semen quality in the male offspring? A pilot study

BACKGROUND: Obesity is a strong predictor of fecundity and maternal obesity may well program semen quality during pregnancy, but to our knowledge, no published studies have evaluated this hypothesis. METHODS: From a Danish pregnancy cohort established in 1984-87, 347 out of 5109 sons were selected for a follow-up study conducted from February 2005 to January 2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and related to information on maternal pre-pregnant body mass index (BMI) that was available for 328 men. Of these, 34 were sons of underweight, and 25 sons of overweight, mothers. RESULTS: Inhibin B decreased with increasing maternal BMI (P = 0.04) and the point estimates for sperm concentration, semen volume, percent motile sperm, testosterone and FSH suggested an impaired reproductive status among sons of overweight mothers, but none of the trends were statistically significant. CONCLUSIONS: The results suggest that there may be an effect of high maternal BMI on the sons' semen quality, but the study had only enough power to justify a critical evaluation of the hypothesis in a larger study.     

Fetal cell-free DNA circulates in the plasma of pregnant mice: relevance for animal models of fetomaternal trafficking

BACKGROUND: Cell-free fetal DNA (fDNA) can be detected in maternal plasma throughout human pregnancy and is rapidly cleared after delivery. fDNA measurement has clinical application in many complications of pregnancy. Our aim was to determine if fDNA could be detected in maternal plasma during pregnancy in a mouse model system. We then compared the levels of fDNA during pregnancies in which the mother and fetus were either congenic or allogenic. METHODS: C57BL/6J (H-2b) or DBA/2J (H-2d) wild-type female mice were mated to C57BL/6J mice transgenic for the enhanced green fluorescent protein (gfp) and sacrificed while pregnant. C57BL/6J female mice that had previously given birth to three to six litters after mating with transgenic males were sacrificed after delivery. We used real-time quantitative PCR amplification to detect and measure gfp sequences in maternal plasma. RESULTS: fDNA was consistently detected in maternal plasma during pregnancy and was always absent after delivery [median 211 genome equivalents (GE)/ml vs 0 GE/ml, respectively, P=0.0001]. The level of fDNA was higher in allogenic matings compared to congenic matings (median 167 GE/ml/GFP + fetus vs 81 GE/ml/GFP + fetus, respectively). CONCLUSIONS: fDNA sequences can be reliably detected in maternal plasma during murine pregnancy. Our data lends further support to the use of nonhuman species to investigate the mechanisms involved in fetomaternal trafficking.     

Third trimester iron status and pregnancy outcome in non-anaemic women; pregnancy unfavourably affected by maternal iron excess

A prospective observational study was performed on 488 women with haemoglobin >/=10 g/dl at booking to examine the relationship between serum ferritin concentration quartiles at 28-30 weeks gestation with maternal characteristics, pregnancy complications and infant outcome. While there was no difference in the maternal characteristics or gestational age, the infant size decreased significantly and progressively from the lowest to the highest quartile. Despite a significant difference in the incidence of multiparous women, there was no difference in the incidence of most complications except for prelabour rupture of the membranes and infant admission to the neonatal unit. Compared with the other three quartiles, the highest quartile was associated with increased risk for preterm delivery and neonatal asphyxia, while the lowest quartile was associated with decreased risk of pre-eclampsia, prelabour rupture of the membranes, and infant admission to the neonatal unit. Overall, ferritin quartiles were correlated with other parameters of iron status and red cell indices, and ferritin concentration was inversely correlated with infant birthweight. Our findings suggested that maternal ferritin concentration is primarily a reflection of maternal iron status, and a high level is associated with unfavourable outcome. The rationale of routine iron supplementation in non-anaemic women needs to be re-examined.     

Fetal cells participate over time in the response to specific types of murine maternal hepatic injury

BACKGROUND: In humans, fetal microchimeric cells transferred to maternal tissues during pregnancy can adopt a hepatocyte phenotype. Our objective was to determine whether fetal cells participate in the response to specific murine post-partum hepatic injuries. METHODS: Wild-type female mice were bred to males transgenic for the enhanced green fluorescent protein (GFP) (n = 42). Following delivery, we created models of chemical or surgical injury with carbon tetrachloride (CCl(4)) injection or by performing partial hepatectomy. Liver injury was assessed histologically. Fetal cells in maternal liver were detected and measured by real-time PCR amplification of the gfp transgene and by immunofluorescence using anti-GFP antibodies. RESULTS: PCR results showed that in chemical but not surgical injury, fetal GFP+ cells were detectable in maternal liver and spleen and that fetal cell presence was significantly increased over time following injury (4 versus 8 weeks, P = 0.006 for liver and P = 0.0006 for spleen). In some animals, following chemical injury, GFP+ cells were detected by immunofluorescence. CONCLUSIONS: The results of this preliminary study suggest that specific types of injury may elicit different fetal cell responses in maternal organs. There is a significant effect of time on fetal cell presence in liver and spleen. Furthermore, real-time PCR amplification is more sensitive than immunofluorescence for the detection of microchimeric fetal cells.     

Diagnosing and preventing inherited disease: Nucleated erythrocytes in maternal blood: quantity and quality of fetal cells in enriched populations

The discovery of nucleated erythrocytes in maternal circulationprovides a potential source for non-invasive prenatal diagnosis.We have evaluated the use of a three-stage procedure to determinethe number of cells that are of fetal rather than maternal origin.First, monoclonal antibodies specific for CD45 and CD14 wereused in conjunction with a magnetic (MACS) column to depleteunwanted leukocytes from maternal blood. This was followed bya positive MACS enrichment for nucleated erythrocytes, usingan anti-CD71 (transferrin receptor) monoclonal antibody. Todiscriminate between fetal nucleated erythrocytes and thoseof maternal origin, enriched fractions were simultaneously stainedwith an anti-fetal haemoglobin (HbF) antibody and hybridizedwith probes specific for X and Y chromosomes. Samples were thensubjected to blind analysis along with negative control samplesfrom non-pregnant volunteers. Using this dual analysis, we wereable to determine that less than one nucleated erythrocyte perml of maternal blood was of fetal origin. Small numbers of thesefetal cells were found in 87.5% of pregnancies, ranging from6 to 35 weeks gestational age. Comparison of HbF and X/Y probedata also suggests that the fetal cells are less suitable forfluorescence in-situ hybridization (FISH) analysis than similarpreparations from other sources.     

Relationships between maternal plasma leptin, placental leptin mRNA and protein in normal pregnancy, pre-eclampsia and intrauterine growth restriction without pre-eclampsia

Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.     

A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss

Low maternal folate or vitamin B12 status has been implicated in numerous pregnancy complications including spontaneous abortion. The primary aim of this study was to test a polymorphism within the trifunctional folate enzyme MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthetase) for an association with a mother's risk of having an unexplained second trimester pregnancy loss. We genotyped 125 women who had at least one unexplained spontaneous abortion or intrauterine fetal death between 13 and 26 weeks gestation and 625 control women with no history of prior pregnancy loss. Our study is the first to identify an association between the MTHFD1 1958G-->A (R653Q) polymorphism and the maternal risk of having an unexplained second trimester pregnancy loss. Women who are MTHFD1 1958AA homozygous have a 1.64-fold increased risk of having an unexplained second trimester loss compared to women who are MTHFD1 1958AG or 1958GG [OR 1.64 (1.05-2.57), P = 0.03]. It has been reported that polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), 677C-->T (A222V), transcobalamin II (TCII), 776C-->G (P259R), are associated with pregnancy loss. Both variants were tested in this study. Neither showed evidence of significantly affecting the maternal risk of having a second trimester pregnancy loss. In conclusion, the MTHFD1 1958AA genotype may be an important maternal risk factor to consider during pregnancy.     

Lens culinaris agglutinin-reactive alpha-fetoprotein, an alternative variant to alpha-fetoprotein in prenatal screening for Down's syndrome.

BACKGROUND: Three serum tests, alpha-fetoprotein (AFP), human chorionic gonadotrophin and unconjugated oestriol, are now widely used for screening for Down's syndrome. Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) is a variant of alpha-fetoprotein with alpha1-->6 fucose appended to the reducing terminal N-acetylglucosamine. It is the most prominent AFP detected in the serum of patients with hepatocellular carcinoma. METHODS: We investigated microheterogeneities of the carbohydrate chain on AFP in fetal liver tissues, amniotic fluids and maternal sera obtained from pregnancies with Down's syndrome using lectin affinity electrophoresis with four lectins. The percentages of AFP-L3 in maternal sera from 22 Down's syndrome and 227 unaffected pregnancies were determined. RESULTS: Unlike the case with AFP concentration, the percentage of AFP-L3 in maternal serum and amniotic fluid was similar, and apparently not influenced by membrane permeability. Knowing the percentage of AFP-L3 in maternal serum was effective for discriminating between Down's syndrome-affected pregnancies and unaffected pregnancies. The percentage of AFP-L3 in maternal serum identified 55% of Down's syndrome cases with a 5% false-positive rate. CONCLUSIONS: AFP-L3 should be an effective replacement for AFP in prenatal Down's syndrome screening.     

Pregnancy: Amino acid concentrations in human embryological fluids

The concentrations of amino acids in samples of coelomic fluid(n = 15), amniotic fluid (n = 9) and maternal serum (n = 15)obtained from normal pregnancies between 7 and 12 weeks of gestationwere measured using reversed-phase chromato-graphy with pre-columnderivatization. The total molar concentration of the 18 aminoacids measured was 2.3 times higher in coelomic fluid than inmaternal serum. All amino acids except serine and tryptophanwere present in significantly higher concentrations in coelomicfluid than in maternal serum. Significant correlations betweenmaternal serum and coelomic fluid were only found for proline,tyrosine and tryptophan, suggesting that levels of the otheramino acids are mainly influenced by placental synthesis anddo not directly depend on maternal amino acid metabolism. Levelsof all amino acids were significantly higher in coelomic fluidcompared to amniotic fluid. Compared to maternal serum, theamniotic fluid contained significantly higher levels of arginine,lysine, alanine and tyrosine and lower levels of serine, glutamineand tryptophan. The total molar amino acid concentration decreasedsignificantly with gestational age in both coelomic fluid andmaternal serum. These results suggest that amino acids accumulatein coelomic fluid to support the metabolism of the secondaryyolk sac, and that the exocoelomic cavity is the reservoir formost nutrients needed by the embryo and early fetus in the firsttrimester of human pregnancy.     

Sex determination and the maternal dominance hypothesis

The maternal dominance hypothesis has been derived from workwith humans which shows that women who are more dominant thanother women are more likely to conceive sons. In both animalsand humans dominance is a characteristic or personality trait,underpinned by testosterone and responsive to a range of environmentalchanges: physical, social and psychological. Studies of thesex ratio in the social sciences and animal behaviour eithersupport or are compatible with the idea that the sex-determiningrole of X- and Y-chromosome bearing spermatozoa may be precededby factors under maternal control which provide for differentialaccess of spermatozoa. Findings in reproductive physiology andphysiological psychology suggest that folh'cular testosteroneor a related hormone may play a critical role. Reproductivephysiologists have already identified maternal mechanisms whichcould provide the context for such a model.