Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling.

BACKGROUND: Postpartum depression (PPD) affects approximately 13% of women and has a negative impact on mother and infant, hence reliable biological tests for early detection of PPD are essential. We aimed to identify robust predictive biomarkers for PPD using peripheral blood gene expression profiles in a hypothesis-free genome-wide study in a high-risk, longitudinal cohort. METHOD: We performed a genome-wide association study in a longitudinal discovery cohort comprising 62 women with psychopathology. Gene expression and hormones were measured in the first and third pregnancy trimesters and early postpartum (201 samples). The replication cohort comprised 24 women with third pregnancy trimester gene expression measures. Gene expression was measured on Illumina-Human HT12 v4 microarrays. Plasma estradiol and estriol were measured. Statistical analysis was performed in R. RESULTS: We identified 116 transcripts differentially expressed between the PPD and euthymic women during the third trimester that allowed prediction of PPD with an accuracy of 88% in both discovery and replication cohorts. Within these transcripts, significant enrichment of transcripts implicated that estrogen signaling was observed and such enrichment was also evident when analysing published gene expression data predicting PPD from a non-risk cohort. While plasma estrogen levels were not different across groups, women with PPD displayed an increased sensitivity to estrogen signaling, confirming the previously proposed hypothesis of increased sex-steroid sensitivity as a susceptibility factor for PPD. CONCLUSIONS: These results suggest that PPD can be robustly predicted in currently euthymic women as early as the third trimester and these findings have implications for predictive testing of high-risk women and prevention and treatment for PPD.

Dehydroepiandrosterone sulfate and anovulation increase serum inhibin and affect follicular function during administration of gonadotropins.

To test the hypothesis that testosterone (T) derived from circulating dehydroepiandrosterone sulfate (DS) or produced in excess within the anovulatory ovary is a follicular regulator capable of stimulating inhibin secretion. DS and inhibin were determined by RIA in residual serum samples from in vitro fertilization cycles and analyzed along with other parameters using analysis of variance and stepwise multiple linear regression after log transformation of the RIA data. It was predicted that the serum concentration of inhibin would be higher in women with anovulation than in normal subjects and that the serum inhibin concentration would have a positive regression coefficient on the serum DS concentration. The serum concentrations of inhibin (P < 0.01) and estradiol (P < 0.001) on the day of hCG treatment were higher in women with anovulation than in normal subjects, as was the number of oocytes retrieved (P < 0.001). The FSH and LH doses (both P < 0.005) and age (P < 0.001) were significantly lower, and the average duration of gonadotropin therapy was 1 day shorter (P < 0.001) in anovulatory patients. There was no significant difference in serum DS (P > 0.2). Regression analysis showed that serum inhibin was positively related to the number of oocytes (P < 0.001) and serum DS (P = 0.05), with an increase in anovulatory subjects (P < 0.025). The duration of treatment with gonadotropins was related positively to the patient's age (P < 0.001) and negatively to serum DS (P < 0.025), with a decrease in anovulatory subjects (P < 0.025). The number of oocytes obtained was negatively related to age (P < 0.001) and positively to serum DS (P < 0.005). These data are consistent with a stimulatory effect of follicular T derived from either circulating DS or the anovulatory ovary, which affects the secretion of inhibin, the duration of gonadotropin treatment, and the number of oocytes retrieved.

Serum triple-marker screening in in vitro fertilization and naturally conceived pregnancies.

OBJECTIVE: To determine whether results of second-trimester maternal serum triple-marker screening for Down syndrome and open neural tube defects in singleton pregnancies conceived from in vitro fertilization (IVF) differ from those of pregnancies conceived spontaneously. METHODS: The screen-positive rates and triple-marker levels of patients conceiving singleton pregnancies by IVF were compared to age-adjusted standards. RESULTS: Sixty-nine singleton IVF pregnancies with maternal serum screening were identified. Twenty-one (30.4%) of the 69 IVF singleton pregnancies had a positive screen for Down syndrome compared with a 14.4% expected screen-positive rate for the maternal age distribution in our observed sample (P = .013). The screen-positive rate for open neural tube defects in the measured population was similar to anticipated values based on historic controls (5.8% in IVF patients versus 5.3% in the total population). The median levels of the triple markers were 0.95 multiples of the median (MoM) for alpha-fetoprotein (AFP), 0.90 MoM for unconjugated estriol (E3), and 1.22 MoM for hCG. CONCLUSION: The increased hCG levels as well as the slightly lower AFP and unconjugated E3 levels may contribute to the higher Down syndrome screen-positive rate in this IVF singleton population. These results may be due to the number of embryos transferred, the maternal hormonal environment of the IVF process, or other factors. Pregnancies conceived by IVF may be twice as likely to have a positive maternal serum screening test. As additional data are collected, corrected standards should be determined.

Effects of fetal number and multifetal reduction on length of in vitro fertilization pregnancies.

OBJECTIVE: To determine the effects of multifetal reduction and other variables on the duration of gestation of in vitro fertilization (IVF) pregnancies. METHODS: All 274 IVF pregnancies from the inception of the Women and Infants' Hospital IVF Program on May 26, 1988, until December 31, 1993, were evaluated. RESULTS: Spontaneous reduction occurred in ten pregnancies, and multifetal reduction was elected in 28 multiple gestations. Among 260 pregnancies that remained viable beyond 20 weeks, 162 singletons (37.9 +/- 0.29 weeks; mean +/- standard error) had a longer mean gestation than did 64 twins (34.6 +/- 0.61 weeks), 25 pregnancies reduced to twins (33.4 +/- 1.0 weeks), or nine triplets (29.7 +/- 1.9 weeks). Triplets delivered 4.9 weeks earlier than nonreduced twins (P < .05) and 3.7 weeks before twins resulting from multifetal pregnancy reduction (P < .05). Regression analysis showed that at the 8-week ultrasound, each viable fetus could be expected to reduce the duration of the gestation by about 3.6 weeks, and each fetus reduced medically or as a result of natural causes could be expected to prolong the gestation by approximately 3.0 weeks. Only 14% of triplet pregnancies underwent spontaneous multifetal reduction. CONCLUSION: Multifetal reduction of pregnancies with three or more fetuses was beneficial and increased the duration of gestation.

Predicting probabilities of pregnancy and multiple gestation from in vitro fertilization--a new model.

OBJECTIVE: To develop a statistical model that adjusts for variation between patients and adequately predicts the observed distribution of pregnancies among singletons and multiple gestations of various orders. METHODS: All in vitro fertilization (IVF) cycles from the inception of the IVF program at Women and Infants' Hospital on May 26, 1988, until December 31, 1993, were evaluated using logistic regression in selected subsets. RESULTS: A new cycle-one specific model uses three different probabilities: P1, the probability of pregnancy (predicted by age and total embryo score); P2/P1, the conditional probability of finding a second implantation in those who had become pregnant with at least one (predicted by total embryo score); and P3/P2, the conditional probability of finding a third implantation in those who had become pregnant with at least two (with no significant predictors). This is the first model to use these three adjusted probabilities. CONCLUSION: P1 increases with increasing total embryo score but decreases with increasing age. P2/P1 increases with increasing total embryo score but does not depend on age. Embryo scoring is useful because the total embryo score is a better predictor of P1 and P2/P1 than the number of embryos alone. By using patient-specific information (age and total embryo score) and cycle-specific tables, an estimate of the probability of pregnancy and multiple gestation can be provided before embryo transfer.

Hematosalpinx after methotrexate treatment of unruptured ectopic pregnancy.

A large asymptomatic hematosalpinx followed single low-dose MTX treatment of an unruptured EP, a previously unreported complication. Management and implications are discussed.

Triplet tubal pregnancy treated by outpatient laparoscopic salpingostomy.

To our knowledge, this represents the first case of a laparoscopically treated triplet EP and the first time that a double EP in the same tube was treated conservatively (with preservation of the tube). Multiple EPs may be more common than currently thought, and our report offers an alternative explanation for at least some cases of persistent EP after conservative surgical therapy. Finally, given the substantial cost savings and reduced postoperative recovery time associated with operative laparoscopy, when the patient is stable and the surgeon experienced, the laparoscopic approach should be tried, regardless of the number of EPs or their size.

Evaluation of Astroglide, a new vaginal lubricant: effects of length of exposure and concentration on sperm motility.

Traditional vaginal lubricants have been shown to adversely affect sperm motility. Astroglide, a new vaginal lubricant, and K-Y Jelly were tested at varying concentrations to assess their suitability for infertility patients requiring a lubricant. The vaginal lubricants tested impaired sperm motility in a concentration-dependent but not time-dependent manner. We conclude that all traditional vaginal lubricants should be avoided in patients desiring conception. Future studies should attempt to mimic in vivo conditions and focus on concentration-dependent effects.

Serum inhibin levels are lower in ectopic than intrauterine spontaneously conceived pregnancies.

OBJECTIVE: To determine if serum inhibin concentrations are lower in ectopic (EP) versus intrauterine pregnancies (IUPs) that are conceived spontaneously. DESIGN: Case-control study. SETTING: Academic clinical practice. PATIENTS: Serum samples were obtained from 19 women who had EP confirmed at surgery and by pathology. For comparison, serum samples were collected from 24 women of similar chronological and gestational age with sonographic evidence of an IUP. MAIN OUTCOME MEASURE: Serum dimeric inhibin-A, total inhibin, P, and hCG. RESULTS: Serum total and dimeric inhibin concentrations in women with EP were < 60% of the concentrations for women with single IUPs. Total inhibin, but not dimeric inhibin-A, was elevated in maternal serum before week 8 of gestation relative to normal menstrual cycle levels. CONCLUSIONS: Serum inhibin concentrations are lower in EP as compared with IUPs that are spontaneously conceived and the relative amounts of dimeric inhibin-A, B, and alpha inhibin subunit in maternal serum may change throughout gestation.

The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro fertilization.

OBJECTIVE: To determine the impact of hydrosalpinx on pregnancy rates in patients undergoing IVF for infertility caused by tubal disease. DESIGN: Review of the records of all patients who had undergone IVF for tubal factor infertility at our institution between May 1988 and October 1994. SETTING: A university-sponsored, hospital-based IVF facility. PATIENT(S): Two hundred fifty patients were identified with infertility due to tubal disease; 67 of these had at least one documented hydrosalpinx whereas the remaining 183 did not. MAIN OUTCOME MEASURE(S): Numbers of oocytes retrieved and fertilized, the number of embryos transferred and implanting, and resulting pregnancy rates. RESULT(S): The groups were similar in age and cycle cancellation rates. The patients with hydrosalpinx had greater numbers of oocytes retrieved per cycle (15.0 versus 11.6) and embryos transferred per cycle then those without hydrosalpinges (4.21 versus 3.98). The hydrosalpinx group also undertook more cycles per patient (2.31 versus 1.96). Fertilization rates between the two groups were similar, but implantation rates were decreased in those with hydrosalpinx (8.5% versus 11.2%). CONCLUSION(S): Hydrosalpinx did not result in impaired ovarian stimulation or decreased oocyte fertilization. It did, however, interfere with implantation and reduce to some degree the success of IVF in achieving an ongoing pregnancy. The validity of routine salpingectomy for hydrosalpinx is debatable, but its use in selected individuals may well be appropriate.

Hulka Clip application as a potential cause of chronic pelvic pain.

A case report of an isolated hydrosalpinx resulting from the placement of two Hulka Clips on the same fallopian tube is presented. This is a previously unreported complication of mechanical sterilization and is suggested as a possible cause of chronic pelvic pain.

Closure of Pfannenstiel skin incisions. Staples vs. subcuticular suture.

OBJECTIVE: To compare skin closure with staples and subcuticular suture. STUDY DESIGN: Obstetric patients undergoing cesarean section with a Pfannenstiel incision were prospectively randomized to skin closure with staples or subcuticular suture. Pain and cosmesis were assessed postoperatively. RESULTS: Patients reported significantly less pain following subcuticular closure at both the time of discharge (P < or = .01) and the postoperative visit (P < or = .002). Incisions closed with subcuticular suture were found to be more cosmetically attractive by both patients (P = .04) and physicians (P = .01) at the postoperative visit. CONCLUSION: Pfannenstiel skin incisions closed with subcuticular closure following cesarean section result in less postoperative discomfort and are more cosmetically appealing at the six-week postoperative visit as compared to incisions closed with staples.

Folic acid. Preconception knowledge and use by infertile women.

OBJECTIVE: To assess knowledge of preconception folic acid intake (PFAI) and its use by infertile women and to compare it to results from a national survey of reproductive-age women. STUDY DESIGN: New patients presenting to a reproductive medicine practice were surveyed regarding their knowledge and use of PFAI. Results were compared to those of a national survey of reproductive age women. RESULTS: Eighty-six women were surveyed. Infertile women were more aware of the benefits of PFAI than the control population (65% vs. 13%) and used it more frequently (52% vs. 29%). Although infertile women knowledgeable about PFAI were more likely to take folic acid (chi 2 = 24.90, P < .001), 30% of women who were aware of the benefits of PFAI did not take it. CONCLUSION: Preconception folic acid knowledge and use were higher among infertility patients presenting to a reproductive medicine practice than in the general population. Nonetheless, in this highly motivated population, only half were taking folic acid, and knowledge alone did not ensure usage. To effectively decrease the incidence of neural tube defects, food fortification may be more effective than education focusing on vitamin supplementation.

Efficacy of oral micronized progesterone in the treatment of luteal phase defects.

OBJECTIVE: Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects. STUDY DESIGN: Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation. RESULTS: On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration. CONCLUSION: We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.

Preoperative versus postoperative dextran 70 for preventing adhesion formation.

Since serosal drying and tissue abrasion play an important role in adhesion formation, we tested the hypothesis that the peritoneal instillation of 32% high-molecular-weight dextran 70 (H) before, rather than after, a surgical procedure results in less postoperative adhesion formation and reformation. Twenty rabbits were subjected to a standardized surgical injury on one ovary, the ipsilateral uterine horn and adjacent parietal peritoneum. Three weeks later the animals underwent a second laparotomy to blindly score the adhesions and subsequently lyse them using microsurgical techniques. The animals were randomly assigned to one of two treatment groups, with H administered either before or at the end of each surgical procedure. Three weeks after the second surgical procedure, the animals were killed to blindly score adhesions. There was no difference in the mean adhesion scores between the two groups after either the first (2.0 versus 2.9, NS) or second surgical procedure (5.5 versus 5.1, NS). Thus, we conclude that preoperative instillation of H does not offer any advantage over postoperative instillation in the prevention of either adhesion formation or reformation.

The hot flash: pathophysiology and treatment.

Hot flashes are the most frequent somatic complaint of women going through the menopause. Although the exact pathophysiology of the hot flash remains unknown, it appears to be related to an alteration in the set point of the hypothalamic thermoregulatory center. With the withdrawal of estrogen, some event parallel to the release of GnRH (and subsequent release of LH) causes a decrease in the set point of the thermoregulatory center. The hot flash, with its characteristic sweating and vasodilation, represents the attempt to decrease the body core temperature and restore equilibrium. Estrogen therapy reliably treats hot flashes in the majority of women in addition to its proven beneficial effect on heart disease and osteoporosis. It is rare that health care providers can so reliably and safely positively impact on a patient's symptoms and overall health.