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Context: Early diagnosis and treatment of gestational diabetes (GDM) may reduce adverse obstetric and neonatal outcomes, especially in high-risk women. However, there is a lack of data for other outcomes., Objective: We compared cardiometabolic and mental health outcomes in women with early (eGDM) and classical (cGDM) GDM., Methods: This prospective cohort included 1185 All women with cGDM and 76 women with eGDM. The eGDM group had GDM risk factors (BMI >30 kg/m2, family history of diabetes, history of GDM, ethnicity), were tested at <20 weeks gestational age, and diagnosed using American Diabetes Association prediabetes criteria. All women underwent lifestyle adaptations. Obstetric, neonatal, mental, and cardiometabolic outcomes were assessed during pregnancy and postpartum., Results: The eGDM group had lower gestational weight gain than cGDM (10.7 ± 6.2 vs 12.6 ± 6.4; P = 0.03) but needed more medical treatment (66% vs 42%; P < 0.001). They had similar rates of adverse maternal and neonatal outcomes, except for increased large-for-gestational-age infants (25% vs 15%; P = 0.02). Mental health during pregnancy and postpartum did not differ between groups. eGDM had more atherogenic postpartum lipid profile than cGDM (P ≤ 0.001). In eGDM, the postpartum prevalence of the metabolic syndrome (MetS) was 1.8-fold, prediabetes was 3.1-fold, and diabetes was 7.4-fold higher than cGDM (waist circumference-based MetS: 62% vs 34%/BMI-based MetS: 46% vs 24%; prediabetes: 47.5% vs 15.3%; diabetes: 11.9% vs 1.6%, all P < 0.001). These differences remained unchanged after adjusting for GDM risk factors., Conclusion: Compared with cGDM, eGDM was not associated with differences in mental health, but with increased adverse cardiometabolic outcomes, independent of GDM risk factors and gestational weight gain. This hints to a preexisting risk profile in eGDM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Preeclampsia is a major pregnancy complication associated with long-term maternal cardiometabolic disease. Research generally is focused on metabolic and pathophysiological changes during pregnancy; however, there is much less focus on the early postpartum period in subjects who suffered preeclampsia. The aim of this study was to (1) characterize energy intake and expenditure 6 months following normotensive and preeclamptic pregnancies and (2) examine associations between energy balance, body composition, insulin resistance measures (HOMA-IR), and clinical characteristics., Design: A cross-sectional study 6 months following normotensive (n = 75) and preeclamptic (n = 22) pregnancies was performed. Metabolic measurements included anthropometrics measures, body composition via bioelectrical impedance analysis, 24-h energy expenditure via SenseWear Armbands, energy intake via a 3-day food diary, and serum metabolic parameters., Results: Six months following preeclampsia, women had a significantly higher weight (77.3 ± 20.9 kg vs 64.5 ± 11.4 kg, P = 0.01), fat mass percentage (FM%; 40.7 ± 7.4% vs 34.9 ± 8.1%, P = 0.004), and insulin resistance (HOMA-IR 2.2 ± 1.5 vs 1.0 ± 0.7, P = 0.003), as well as reduced HDL levels (1.5 ± 0.4 mmol/L vs 1.8 ± 0.4 mmol/L, P = 0.01) compared to normotensive women. Women post-preeclampsia had lower activity-related energy expenditure (P = 0.02) but a decreased total energy intake (P = 0.02), leading to a more negative energy balance compared to their normotensive counterparts (-1942 kJ/24 h vs -480 kJ/24 h, P = 0.02)., Conclusion: Increases in insulin resistance and FM%, reduced high-density lipoprotein, and more sedentary lifestyles characterize the postpartum period following preeclamptic compared with normotensive pregnancies. Early post-preeclampsia interventions, such as lifestyle behavior change, should be implemented and assessed to determine whether they reduce long-term cardiometabolic risk in women who experienced preeclampsia during pregnancy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To characterize the relationship between hemoglobin A1c (HbA1c) levels and glucose tolerance across pregnancy and postpartum., Design and Participants: In a longitudinal study of pregnant women with gestational diabetes risk factors (N = 102), we performed oral glucose tolerance testing (OGTT) and HbA1c measurements at 10-15 weeks of gestation, 24-30 weeks of gestation (N = 73), and 6-24 weeks postpartum (N = 42). Complete blood counts were obtained from clinical records. We calculated HbA1c-estimated average glucose levels and compared them with mean OGTT glucose levels (average of fasting, 1- and 2-hour glucose levels). Linear mixed effects models were used to test for longitudinal changes in measurements., Results: Mean OGTT glucose increased between 10-15 and 24-30 weeks of gestation (β = 8.1 mg/dL, P = .001), while HbA1c decreased during the same time period (β = -0.13%, P < .001). At 10-15 weeks of gestation and postpartum the discrepancy between mean OGTT glucose and HbA1c-estimated average glucose was minimal (mean [standard deviation]: 1.2 [20.5] mg/dL and 0.16 [18.1] mg/dL). At 24-30 weeks of gestation, the discrepancy widened (13.2 [17.9] mg/dL, β = 12.7 mg/dL, P < .001, compared to 10-15 weeks of gestation, with mean OGTT glucose being higher than HbA1c-estimated average glucose). Lower hemoglobin at 24-30 weeks of gestation was associated with a greater discrepancy (β = 6.4 mg/dL per 1 g/dL lower hemoglobin, P = .03 in an age- and gestational age-adjusted linear regression model)., Conclusions: HbA1c accurately reflects glycemia in the 1st trimester, but underestimates glucose intolerance in the late 2nd trimester. Lower hemoglobin level is associated with greater underestimation. Accounting for gestational age and maternal hemoglobin may improve the clinical interpretation of HbA1c levels during pregnancy., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: It is yet unknown how similar women's hormone levels are during successive pregnancies, and very little is known about the degree to which siblings experience similar prenatal environments. Given the importance of understanding how women's reproductive life histories exert cumulative effects on health via hormone exposure, and the importance of understanding how fetal programming via endocrine signaling affects sibling trait concordance, here, we address this important lacuna in the literature., Objective: This study aimed to investigate how consistent women's hormone profiles are across two successive pregnancies., Design and Main Outcome Measures: This longitudinal, prospective study followed a cohort of 28 women across two pregnancies (PREG 1 and PREG 2). Women's circulating hormone levels were assessed from blood samples at 25, 31, and 37 weeks' gestation for adrenocorticotropic hormone (ACTH), placental corticotropin-releasing hormone (pCRH), cortisol, estradiol, and progesterone. ACTH and cortisol levels were assessed 3 months postpartum. Research questions include: Are hormone levels in PREG 2 significantly different from levels in PREG 1? What proportion of variance in PREG 2 hormone levels is attributable to variance in PREG 1 levels? Are hormone levels more stable between PREG 1 and PREG 2 compared with postpartum phases following these pregnancies? Is pCRH, which is completely placentally derived, less similar than other hormones across successive pregnancies?, Participants and Setting: Pregnant women attended study visits at a university psychobiology laboratory in Southern California., Results and Conclusions: Comparisons of hormone concentrations across women's successive pregnancies via paired t test revealed substantial consistency from one pregnancy to another, with only significant differences between pregnancies for pCRH. Regressions revealed substantial predictability from one pregnancy to another, with between 17-56% of PREG 2 variances accounted for by PREG 1 values. Women exhibited lower degrees of consistency and predictability in hormone levels across postpartum phases compared with gestational concentrations. This is the first study to describe maternal and placental hormone levels across successive pregnancies.

The restoration of maternal insulin sensitivity postpartum represents an important physiological and metabolic adaptation in a woman's reproductive lifespan. The present study was conducted to examine the potential cellular mechanisms underlying the changes in insulin sensitivity from late pregnancy to postpartum in human skeletal muscle. Nine nonobese women (age, 32 +/- 2 yr; body mass index, 21.2 +/- 0.8 kg/m(2)) with normal glucose tolerance were studied during late pregnancy (30-36 wk) and again approximately 1 yr postpartum using a euglycemic-hyperinsulinemic clamp (5 mm glucose, 40 mU/m(2).min insulin) to determine insulin sensitivity. Biopsies of the vastus lateralis muscle were obtained in the basal state before each clamp. Insulin sensitivity improved by 74% from late pregnancy to 1 yr postpartum (5.5 +/- 0.6 vs. 9.6 +/- 0.9 mg/kg fat-free mass.min; P < 0.005). Skeletal muscle insulin receptor (IR) protein expression increased by 42% postpartum, as measured by ELISA (4.0 +/- 0.6 vs. 5.7 +/- 0.6 ng/g protein; P < 0.05) and by Western blotting of the IR beta-subunit (28.7 +/- 4.7 vs. 42.0 +/- 4.8 arbitrary units; P < 0.003). However, in vitro studies showed that when adjusted for IR concentration, maximal insulin-stimulated (100 nm) IR tyrosine phosphorylation (0.75 +/- 0.06 vs. 0.92 +/- 0.08 U) and IR tyrosine kinase activity (183.8 +/- 27.0 vs. 204.3 +/- 23.7 fmol ATP/ng IR) were unchanged. There was a 69% increase in IR substrate-1 (IRS-1) protein expression (P = 0.05) in muscle postpartum. In addition, the p85alpha regulatory subunit of phosphatidylinositol 3-kinase was markedly reduced by 55% (P < 0.02) postpartum. The change in insulin sensitivity from late pregnancy to postpartum correlated highly with the corresponding change in IRS-1 protein (r = 0.84; P < 0.007). Downstream signaling proteins, including total Akt and p70s6 kinase, and the glucose transporter protein GLUT-4, were similar at both time points. These data suggest that reduced IR tyrosine kinase activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. Rather, the reversal of insulin resistance 1 yr postpartum is accompanied by increased skeletal muscle IRS-1 along with a down-regulation of the p85alpha subunit of phosphatidylinositol 3-kinase. These changes may allow for greater p85/p110 binding to IRS-1 and play a significant physiological role in the underlying metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum.

Osteoprotegerin (OPG) is a soluble decoy receptor that inhibits bone resorption by binding to receptor activator of nuclear factor kappa B ligand. Murine studies suggest that OPG is elevated in pregnancy, but its role in human pregnancy is unknown. We evaluated the relationship among OPG, bone turnover, and bone density in a longitudinal study of planned human pregnancy and lactation (n = 17; age, 20-36 yr). Samples were collected before conception; at 16, 26, and 36 wk gestation; and at 2 and 12 wk postpartum. Indexes of bone resorption included serum beta C-terminal and urinary N-terminal (uNTX) telopeptides of type I collagen. OPG increased by 110 +/- 16% (mean +/- SEM) at 36 wk (P < 0.001), followed by a rapid postpartum decline in both lactating and nonlactating women. Bone resorption was elevated at 36 wk (serum beta C-terminal telopeptides by 76 +/- 17%; urinary N-terminal telopeptides by 219 +/- 41%; P < 0.001). The tissue source of OPG in pregnancy is unknown. Human breast milk contains large amounts of OPG (162 +/- 58 ng/ml in milk vs. 0.42 +/- 0.03 ng/ml in nonpregnant serum). However, the rapid postpartum decline in serum OPG and the low serum OPG in neonates suggest a placental source. There was no correlation between change in OPG and bone turnover or bone mineral density (P > 0.05), and the physiological importance of elevated OPG in human pregnancy remains uncertain.

Metastin is a novel peptide that was recently isolated from human placenta as the endogenous ligand of an orphan heptahelical receptor, hOT7T175. Metastin has been shown to suppress the motility of hOT7T175-transfected melanoma cells; however, studies of the physiological function of metastin have begun only recently. To investigate the possibility that metastin is an endocrine peptide, we determined the immunoreactive (ir-) metastin concentration in human plasma using our newly developed, sensitive, and specific two-site enzyme immunoassay. The plasma concentrations of ir-metastin in males and females were 1.30 +/- 0.14 (n = 12) and 1.31 +/- 0.37 fmol/ml (n = 10), respectively. As metastin is known to be abundant in human placenta, the ir-metastin concentration in the maternal plasma was then determined. The ir-metastin concentrations were 1230 +/- 346 fmol/ml (n = 11) in the first trimester, 4590 +/- 555 (n = 16) in the second trimester, and 9590 +/- 1640 (n = 12) in the third trimester. On d 5 after delivery, the ir-metastin concentration returned to nearly the nonpregnant level (7.63 +/- 1.33 fmol/ml; n = 10), suggesting that ir-metastin increases in pregnancy and is derived mainly from the placenta. The plasma from both nonpregnant and pregnant women showed a single ir-metastin peak at the same retention time as authentic metastin on reverse phase HPLC analysis, indicating that the major portion of the circulating metastin, as determined by our two-site enzyme immunoassay, represents endogenous metastin. Histochemical studies of human placenta localized metastin mRNA and immunoreactivity to the syncytiotrophoblasts. The present study provides evidence for metastin as a novel placenta-derived hormone in humans.

Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset, in the postpartum period. The immune basis for these phenomena is poorly understood. Recently, excessive production of IL-12 and TNF-alpha was causally linked to rheumatoid arthritis and multiple sclerosis. We studied 18 women with normal pregnancies in their third trimester and during the early postpartum period. We report that during the third trimester pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-alpha production was approximately 40% lower than postpartum values. At the same time, urinary cortisol and norepinephrine excretion and serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than postpartum values. As shown previously, these hormones can directly suppress IL-12 and TNF-alpha production by monocytes/macrophages in vitro. We suggest that a cortisol-, norepinephrine-, and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of IL-12 and TNF-alpha production may represent a major mechanism by which pregnancy and postpartum alter the course of or susceptibility to various autoimmune disorders.

Renal synthesis of the antiaggregatory and vasodilatory prostacyclin and its endogenous antagonist thromboxane A2 may be disturbed in patients with preeclampsia. We tested this hypothesis by measuring 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha; a hydration product of prostacyclin), 2,3-dinor-6-keto-PGF1 alpha (generated from 6-keto-PGF1 alpha through beta-oxidation) and thromboxane B2 (a hydration product of thromboxane A2) in the urine of healthy pregnant and preeclamptic women. Urinary excretion of 6-keto-PGF1 alpha [19.8 +/- 10.5 pmol/mmol creatinine, (mean +/- SD)] and 2,3-dinor-6-keto-PGF1 alpha (19.2 +/- 7.5 pmol/mmol creatinine) increased during normal pregnancy, reaching a maximum (about 5-fold rise) during the last month of pregnancy. No significant changes occurred in the urinary excretion of thromboxane B2. In women with severe preeclampsia (n = 17), the excretion of both 6-keto-PGF1 alpha (37.7 +/- 29.5 pmol/mmol creatinine) and 2,3-dinor-6-keto-PGF1 alpha (54.5 +/- 56.2 pmol/mmol creatinine) was lower (P less than 0.001) than in the normotensive women during the last trimester of pregnancy (80.6 +/- 43.7 and 98.7 +/- 42.9 pmol/mmol creatinine, respectively). The neonates excreted 6-25 times more 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha and thromboxane B2 than did the nonpregnant women. In contrast to the adults, neonatal 6-keto-PGF1 alpha excretion was 2-3 times greater than that of 2,3-dinor-6-keto-PGF1 alpha suggesting reduced beta-oxidation in the newborns. Infants born to preeclamptic women had reduced output of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha on the first day of life. Thus, renal prostacyclin synthesis is diminished in women with severe preeclampsia and their infants.

The concentration of immunoreactive insulin-like growth factor I (IGF-I) in human mammary secretions, assayed after acid-ethanol extraction, was high [mean, 4.1 +/- 0.5 (+/- SE) nmol/L; n = 13] for several weeks prepartum. It then decreased during the first 3 days postpartum to 1.3 +/- 0.1 nmol/L (n = 28), in parallel with changes in epidermal growth factor (EGF) and protein concentrations. However, between the first and sixth weeks postpartum, the IGF-I concentration increased to 2.5 +/- 0.2 nmol/L (n = 18), while levels of EGF and protein decreased further. Given that the volume of milk produced increases during this period, the total IGF-I output rose by up to 4-fold, while EGF output remained constant. The increase in IGF-I and decrease in EGF in milk suggest that different regulatory mechanisms control the output of different growth factors by the mammary gland.

To investigate the neuroendocrine changes that regulate initiation of normal menstrual function after parturition, serum LH, FSH, and PRL concentrations were determined at 20-min intervals for 12-24 h in eight nonlactating postpartum women on a weekly basis between postpartum days 10-26. Sleep was monitored by EEG. On postpartum day 10, serum LH concentrations were similar to early follicular phase levels in normal cycling women, while FSH concentrations were lower than early follicular phase levels. Mean LH pulse frequency during each postpartum interval was 3.6 +/- 0.6 (+/- SE), 4.4 +/- 0.6, and 4.1 +/- 0.8 pulses/12 h on postpartum days 10-11, 17-21, and 24-26, respectively. Because mean serum LH levels and LH pulse frequency did not change significantly between postpartum days 10 and 26, the results from the two or three studies in each woman were combined for the purpose of comparing LH pulse characteristics during the waking and sleeping periods. During the waking hours, mean LH pulse frequency (6.1 +/- 0.5 pulses/12 h) was significantly greater than during sleep (4.1 +/- 0.4 pulses/12 h; P less than 0.02). The amplitude of the serum immunoreactive LH pulses (P less than 0.05) and bioactive LH levels (P less than 0.05) were significantly higher during sleep than during the waking period, with five of the eight women having higher sleep-associated immunoreactive LH and bioactive LH levels between postpartum days 17-26. These changes were associated with an increase in the bioactive to immunoactive LH ratio from 3.3 +/- 0.4 (awake) to 4.5 +/- 0.5 (sleep; P less than 0.05). Although serum PRL levels remained elevated during the puerperium, the diurnal pattern of PRL secretion was conserved. With each successive week postpartum, serum PRL concentrations declined. These results suggest that the increment in LH secretion (and, by inference, increased GnRH secretion) during sleep is a feature of postpartum pituitary-ovarian reactivation. Although the mechanism(s) responsible for the increase in GnRH secretion is not known, this hormonal pattern is analogous to that during early puberty and during recovery from anorexia nervosa and hypothalamic amenorrhea. Taken together, these findings provide evidence to support the concept of a centralized preprogrammed scheme for pituitary-gonadal reactivation.