Adjustment for time-invariant and time-varying confounders in 'unexplained residuals' models for longitudinal data within a causal framework and associated challenges.

'Unexplained residuals' models have been used within lifecourse epidemiology to model an exposure measured longitudinally at several time points in relation to a distal outcome. It has been claimed that these models have several advantages, including: the ability to estimate multiple total causal effects in a single model, and additional insight into the effect on the outcome of greater-than-expected increases in the exposure compared to traditional regression methods. We evaluate these properties and prove mathematically how adjustment for confounding variables must be made within this modelling framework. Importantly, we explicitly place unexplained residual models in a causal framework using directed acyclic graphs. This allows for theoretical justification of appropriate confounder adjustment and provides a framework for extending our results to more complex scenarios than those examined in this paper. We also discuss several interpretational issues relating to unexplained residual models within a causal framework. We argue that unexplained residual models offer no additional insights compared to traditional regression methods, and, in fact, are more challenging to implement; moreover, they artificially reduce estimated standard errors. Consequently, we conclude that unexplained residual models, if used, must be implemented with great care.

Placental protein 14 secretion during in vitro fertilization cycles with and without human chorionic gonadotropin for luteal support.

OBJECTIVE: To investigate levels of placental protein 14 (PP14) in in vitro fertilization (IVF) patients with and without exogenous human chorionic gonadotropin (hCG) for luteal support. DESIGN, PATIENTS: Thirty-one women undergoing IVF were studied. For 18 women, hCG was administered in the luteal phase, and 12 became pregnant. Five pregnancies occurred in 13 women not receiving exogenous hCG. SETTING: All the patients attended the University of Southampton/Chalybeate Hospital IVF program. RESULTS: There was no change in PP14 levels 2 days after embryo transfer (ET), but small significant rises were noted by day 8 in all patients. Thereafter, levels rose further in pregnant subjects but showed no change in nonpregnant patients. The highest level of PP14 was seen in the group of women on hCG support, but there was no overall statistical difference between those on support and those not. In the nonpregnant group, there was no significant correlation between progesterone (P) and PP14 8 days from ET, whereas a highly significant correlation was noted in the pregnant group. CONCLUSIONS: Neither hCG nor P are primary factors in the control of endometrial PP14 secretion, but PP14 and P may have common underlying control mechanisms.

Comparison of 'poor' responders with 'good' responders using a standard buserelin/human menopausal gonadotrophin regime for in-vitro fertilization.

This study identifies a group of 87 patients, who demonstrated a 'poor' response to a standard buserelin/human menopausal gonadotrophin (HMG) regime. The subsequent outcome in 61 of these 'poor' responders when treated with a higher dose of HMG to achieve a satisfactory response was compared with 250 patients, who showed a 'good' response to the standard regime. 'Poor' responders were significantly older than 'good' responders (P less than 0.001), but no significant difference was demonstrated in the indication for in-vitro fertilization (IVF). Even on higher doses of HMG, 'poor' responders took longer for their follicles to achieve maturity than the 'good' responders (P less than 0.01). 'Poor' responders produced 8.9 oocytes per oocyte collection compared to 11.8 in the 'good' responders (P less than 0.01). The fertilization rate was significantly lower in the 'poor' responders compared to the 'good' responders (P less than 0.01). Although there was no significant difference in morphometric grading between 'poor' responder embryos and 'good' responder embryos, the rate of cell division was significantly slower in embryos of the 'poor' responders than the 'good' responders (P less than 0.01). The pregnancy rate per oocyte retrieval was 9% in the 'poor' responders compared to 29% in the 'good' responders (P less than 0.01). The implantation rate in the 'poor' responders was 4.4% compared to 16.1% in the 'good' responders (P less than 0.001).

Biochemical monitoring during hormone replacement therapy cycles for transfer of cryopreserved embryos in patients with functional ovaries.

Biochemical monitoring was undertaken in 22 treatment cycles for women with normal ovarian function who underwent pituitary suppression with buserelin and administration of exogenous oestradiol (E2) and progesterone (P) for cryopreserved embryo transfer (ET). Eighteen transfers of 1-4 thawed embryos, on the third day of exposure to progesterone, resulted in five clinical pregnancies (27.8%) and one biochemical pregnancy. There was no difference between pregnant and non-pregnant patients in the number and quality of embryos transferred, age, weight or infertility diagnosis. Serum E2 level from days 10-17 (the late proliferative phase) of the therapy cycle were significantly higher in the pregnant group compared with the non-pregnant group (P less than 0.05--P less than 0.005). There were no significant differences in P levels between the two groups from the onset of progesterone administration to the end of the cycle. However, as might be expected, the mean E2/P molar ratio in the pregnant group was significantly higher at the time of ET (P less than 0.02). It is concluded that biochemical monitoring during the embryo replacement cycle is necessary to tailor drug dosages for individual requirements to achieve adequate E2 levels before ET. Alternative routes of oestradiol administration need to be considered in patients with poor E2 profiles.

Lack of placental protein 14 production in pregnancy after frozen embryo transfer, down-regulation of anterior pituitary and administration of exogenous oestradiol and progesterone.

The circulating levels of placental protein 14 (PP14) and progesterone were measured in three pregnancies resulting from the transfer of cryopreserved embryos. Two of these women had suppressed ovarian activity as a result of pituitary down-regulation with the luteinizing hormone-releasing hormone agonist (buserelin) prior to treatment with exogenous oestradiol and progesterone. After 14 days of oral oestradiol treatment and if the endometrial thickness was greater than 7 mm, progesterone was given intramuscularly for a further 14 days with embryo transfer on the third day of this treatment. On confirmation of pregnancy by human chorionic gonadotrophin analysis, progesterone administration was altered to transvaginal pessaries for maintenance of adequate progesterone levels and endometrial support. In the two women with ovarian suppression, PP14 levels remained below the 2.5th centile of the normal range for pregnancy. In the third pregnancy, embryo transfer was performed 3 days after a spontaneous luteinizing hormone surge in a normal menstrual cycle. In this pregnancy, PP14 levels were within the normal range. Ultrasonic examination confirmed three normal ongoing singleton pregnancies. These results suggest that the majority of PP14 production in normal pregnancy is under ovarian or anterior pituitary control and that the influence of progesterone is of a secondary nature.

Trial of support treatment with human chorionic gonadotrophin in the luteal phase after treatment with buserelin and human menopausal gonadotrophin in women taking part in an in vitro fertilisation programme.

OBJECTIVE: To evaluate the effect of support with human chorionic gonadotrophin in the luteal phase in women taking part in an in vitro fertilisation programme after buserelin and human menopausal gonadotrophin were used to hyperstimulate their ovaries. DESIGN: Controlled group comparison. SETTING: Outpatient department of a private hospital. PATIENTS: 115 Women with indications for in vitro fertilisation, all of whom had at least one embryo transferred. INTERVENTIONS: After suppression of the pituitary with buserelin the ovaries of all the women were stimulated with human menopausal gonadotrophin on day 4 of the luteal phase. Human chorionic gonadotrophin (10,000 IU) was given to induce ovulation, and oocytes were recovered 34 hours later. Embryos were transferred 46 to 48 hours after insemination. Women who had received the 10,000 IU of human chorionic gonadotrophin on a date that was an uneven number (n = 61) were allocated to receive support doses of 2500 IU human chorionic gonadotrophin three and six days after that date. The remaining 54 women did not receive hormonal support. END POINT: Determination of the rates of pregnancy. MEASUREMENTS and main results--Support with human chorionic gonadotrophin did not significantly alter the progesterone or oestradiol concentrations in the early or mid-luteal phase. The mean (range) progesterone concentrations in the late luteal phase in women who did not become pregnant were, however, significantly higher in those who received support (16(9-110) nmol/l nu 8(4-46) nmol/l), and the luteal phase was significantly longer in this group (14 days nu 12 days). The rate of pregnancy was significantly higher in the women who received support than in those who did not (25/61 nu 8/54). CONCLUSIONS: When buserelin and human menopausal gonadotrophin are used to hyperstimulate ovaries support with human chorionic gonadotrophin in the luteal phase has a beneficial effect on in vitro fertilisation.

Augmentation by epidermal growth factor of basal and stimulated progesterone production by human luteinized granulosa cells.

Human granulosa cells were prepared from follicular aspirates obtained during oocyte collection for in vitro fertilization. Following several days in culture, cells were washed and then progesterone output was measured in 2-h incubations. After culture for 3 days, incubated cells responded well to human chorionic gonadotrophin (hCG) and prostaglandin (PG) E2 with similar levels of maximum response. Exposure of cultured cells to epidermal growth factor (EGF) for 2 days (days 3-5) led to substantial increases both in basal production and in responses to hCG and PGE2 during subsequent incubations. These effects of EGF were not accompanied by measurable increases in DNA levels in cultures over this time. Results may point to a possible paracrine role for EGF-like factors modulating the activity of cells forming the early corpus luteum.