Management of isoimmunization in the presence of multiple maternal antibodies.

OBJECTIVE: Evaluation and management of patients with multiple maternal antibody isoimmunization is unclear. The presence of > or = 1 maternal antibody may suggest a worse scenario. The objective of this study was 2-fold: first, to determine whether the presence of multiple antibodies predicts a more severe course than single antibodies and second, to determine the utility of the Queenan curves/protocol in evaluating multiple-antibody isoimmunization. STUDY DESIGN: Amniotic fluid DeltaOD(450) measurements were obtained from the antenatal testing logbook and confirmed by chart review. Cases were categorized by antibody type and clinical outcomes obtained by chart review. RESULTS: Twenty-four pregnancies with isoimmunization and multiple maternal antibodies were identified; of these, 17 had 2 antibodies (anti-D and -C in 13; anti-D and -E in 1; anti-D and -Jka in 1; anti-c and -E in 1; and anti-c and -Jka in 1), and 7 had > 2 antibodies (anti-D, -C, and -E in 4; anti-D, -C, and -N in 1; anti-c, -E, and -FYA in 1; and anti-E, -K, -Fya, -S, and -C in 1). Eleven patients (46%) required at least 1 intrauterine fetal transfusion (mean initial fetal hematocrit, 15%; range, 4.9%-24%). In those not transfused, no DeltaOD(450) measurements occurred in the Queenan "fetal death risk" zone. Poorest outcomes (multiple transfusions/hydrops/fetal demise) were in patients with anti-D and anti-C, with or without anti-E. The absence of anti-D was associated with no need for fetal transfusions. The overall transfusion rate was significantly higher compared with a group of 57 isoimmunization patients with only anti-D (46% vs. 25%, P < or =.05). CONCLUSIONS: The presence of anti-D appears to be the most significant factor guiding the course of isoimmunization with multiple antibodies. The presence of another antibody with anti-D appears to significantly increase the need for intrauterine fetal transfusions. The Queenan protocol can successfully treat patients with multiple maternal red blood cell antibodies.

An appreciation of modern ART.

As we have entered into the new millennium, it is difficult not to recognize ART as one of the most dynamic and rapidly emerging fields in all of medicine. What began as an experimental procedure in animals has developed into a multidisciplinary technology. A great debt is owed to the field of animal husbandry. In humans, implantation is inefficient and has been recognized as the rate-limiting step in reproduction. In vitro fertilization has allowed the observation of human gamete interaction in the laboratory. A milestone was reached when ART allowed couples with infertility to have success rates that exceeded those associated with normal human fecundity. Continued innovations are improving the rate of embryonic implantation. Blastocyst transfer will have a major role in the future of ART. It is common for the couple with infertility to battle their problem by increasing the frequency of intercourse because it is the only weapon at their disposal. So, too, did clinicians increase the number of embryos transferred to the uterus. New developments promise to challenge the long-held contention that successful IVF/embryo transfer is positively correlated with the number of oocytes retrieved or the number of embryos transferred. More accurate reporting will enable us to measure the impact of technologic improvements that improve implantation rates and decrease multiple gestations. The future holds the promise of some tangible goals. The development of in vitro maturation of immature oocytes could lead to an era in which oocytes are harvested without the need for controlled ovarian hyperstimulation. This would provide for the possibility of the banking of gametes. Women could preserve or store their fertility at a young age in a manner similar to that which has been possible for men for decades. They could avoid the increased risk for aneuploidy seen with the age of 35, and theoretically, they should have a lower risk for miscarriage. The future is near. One day, ART will be perfected so that a single embryo transfer will be the standard of care. Soon it will be possible to know all about the genetic makeup of that embryo and it will be routinely selected from its cohort by virtue of those genetic traits.

Embryo freezing to prevent ovarian hyperstimulation syndrome.

One of the primary goals of ART is to achieve some degree of supraphysiologic ovarian stimulation. Too vigorous a response can lead to ovarian hyperstimulation syndrome (OHSS), which is potentially life threatening. The incidence of severe OHSS is low, yet global proliferation of ART suggests that the absolute number of cases will be increasing. The clinical course of OHSS is more severe in patients who conceive. Should gonadotropin therapy induce too great a response, OHSS can best be prevented via cycle cancellation and withholding HCG. An alternative, which would not forfeit oocyte retrieval, is to perform elective cryopreservation of all resulting pre-embryos. This requires a strategy to identify patients at risk accurately. Several centers have bypassed fresh embryo transfer to lessen the risk of OHSS. By consensus it appears that this approach reduces but does not eliminate the risk of severe OHSS. Chances of pregnancy are excellent in subsequent cryo thaw transfers.

Elevated serum Chlamydia trachomatis IgG antibodies. Association with decreased implantation rates in GIFT.

OBJECTIVE: To analyze the impact of elevated Chlamydia IgG antibody (Ab) titers on the outcome of gamete intrafallopian transfer (GIFT) cycles. STUDY DESIGN: We retrospectively evaluated all the GIFT cycles in a five-year period performed at our center. One hundred one women under 40 years of age undergoing a total of 112 consecutive GIFT cycles were included. RESULTS: Twenty-six cycles (23.2%) were in women with elevated serum Chlamydia IgG Ab, and 86 (76.8%) were in women with negative titers. There were no significant differences in mean age, number of mature oocytes obtained or number of oocytes transferred between the two groups. Patients with elevated IgG Ab had clinical and ongoing pregnancy rates (PR) of 34.6% and 23.1%, respectively, and an implantation rate (IR) of 7.1% (13/184) as compared to a clinical and ongoing PR of 47.7% and 40.7%, respectively, and an IR of 16.5% (61/369) in the negative Ab group, respectively (P = NS for clinical and ongoing PR, P = .003 for IR). No ectopic pregnancies were noted in either group. The incidence of early pregnancy loss was 33.3% (3/9) and 14.6% (6/41) in the positive and negative Ab groups, respectively (P = .40). CONCLUSION: The presence of elevated serum Chlamydia IgG Ab was associated with a significantly lower implantation rate, a trend toward a lower PR and a trend toward a higher early pregnancy loss rate as compared to women with negative Ab titers. This group may represent a subset of assisted reproductive technology patients who are less likely to benefit from GIFT.

Knowledge of likely time of ovulation and contraceptive use in unintended pregnancies.

This investigation analyzed social and demographic characteristics of women having an unwanted or mistimed pregnancy (unintended pregnancies at the current time) in South America. A sample of 5135 women having had a normal non-malformed live-born infant were interviewed immediately postpartum at 18 hospitals participating in the Latin American Collaborative Study of Congenital Malformations (Spanish acronym: ECLAMC). Half (2568/5135 = 50%) reported that their pregnancies had been unintended, and, of those, 59.3% (1522/2568 = 59.3%) declared that they were trying to avoid conception. The latter group (n = 1522) was the main sample for this study. Patients were asked about their knowledge of when during the menstrual cycle conception is most likely to occur, their biomedical and social characteristics, the type of contraceptive methods used, their opinion of reasons for contraceptive failure, and their reasons for not using contraceptive methods. Among women with unintended pregnancies who attempted to avoid conception, only 61.6% were using contraceptive methods. Reasons given for not using contraceptives included health problems, lack of knowledge and lack of access to contraception. Women with unintended pregnancies who had not attempted to avoid conception were younger, often primigravid, less educated, and less knowledgeable concerning when during the cycle pregnancy is most likely to occur. Thus, reproductive health policies should be aimed at this target group.

PIP: This study analyzes the social and demographic characteristics of women having an unwanted or unintended pregnancy in South America between 1992 and 1994. The study was conducted among 5135 women who had a normal non-malformed live-born infant and were interviewed at 18 hospitals participating in the Latin American Collaborative Study of Congenital Malformations. Patients were asked about their knowledge of when conception is most likely to occur during the menstrual cycle, their biomedical and social characteristics, the type of contraceptive methods used, their opinion and reasons for contraceptive failure, and their reasons for failing to use contraceptive methods. Results indicate that 50% of the respondents had unintended pregnancies, and about 59% declared that they were trying to avoid conception. However, among women with unintended pregnancies who attempted to avoid conception, only 61.6% were using contraceptive methods. Reasons for failure to use contraceptives include health problems, lack of knowledge, and lack of access to contraception. Meanwhile, women with unintended pregnancies who had not attempted to avoid conception were younger, often primigravid, less educated, and less knowledgeable concerning the likelihood that pregnancy will occur during menstrual cycle. This study implies that reproductive health policies should be aimed at this target group.

Unintended pregnancies in women delivering at 18 South American hospitals. NFP-ECLAMC Group. Latin American Collaborative Study of Congenital Malformations.

Unintended pregnancies are accepted as associated with social, maternal and perinatal risks, but few data exist in South America. In a selected network of hospitals participating in the ECLAMC (Spanish acronym for Latin American Collaborative Study of Congenital Malformations), the frequency of unintended pregnancies was 49.8% in 5155 mothers of normal liveborns, as interviewed in the post-partum period (1992-1994). Compared with the intended pregnancy group, these mothers were more frequently multiparous, conceived easily, had a surprisingly higher mean maternal age, lower educational level, and Black ancestors. The frequency of mistimed pregnancies was the highest among primiparae. No adverse perinatal outcome could be found with regard to low birthweight (< 2500 g), prematurity (< 37 weeks), and early neonatal death. The rates of Caesarean delivery, twinning and sex ratio were similar in intended and unintended groups. Logistic regression analysis showed that maternal education could be a confounding factor associated with other maternal variables. The rate of unintended pregnancies in the present study is significantly higher than that described for other regions. Knowledge of the characteristics of women experiencing unintended pregnancies would allow proper public health strategies.

Sex ratio associated with timing of insemination and length of the follicular phase in planned and unplanned pregnancies during use of natural family planning.

This was a multicentred, prospective study of pregnancies among women using natural family planning. The women maintained natural family planning charts of the conception cycle, recording acts of intercourse and signs of ovulation (cervical mucus changes, including peak day and basal body temperature). Charts were used to assess the most probable day of insemination relative to the day of ovulation and length of the follicular phase of the cycle. The sex ratio (males per 100 females) for 947 singleton births was 101.5, not significantly different from the expected value of 105. The sex ratio did not vary consistently or significantly with the estimated timing of insemination relative to the day of ovulation, with the estimated length of the follicular phase or with the planned or unplanned status of the pregnancy. Although these findings may be affected by imprecision of the data, the study suggests that manipulation of the timing of insemination during the cycle cannot be used to affect the sex of offspring.

PIP: In the context of ongoing debate over the determinants of sex ratio, the authors used data from a multinational study of pregnancies among natural family planning (NFP) users to investigate the association between timing of conception or follicular phase and length and the sex ratio at birth. They also explored whether a pregnancy's planned or unplanned status affects those associations. A multicenter, prospective study of pregnancies among women using NFP was conducted. The women maintained NFP charts of their conception cycles, recording acts of intercourse and signs of ovulation such as cervical mucus changes and basal body temperature. Charts were used to identify the most probable day of insemination relative to the day of ovulation and length of the follicular phase of the cycle. The sex ratio (number of males per 100 females) for 947 singleton births was 101.5, not significantly different from the expected value of 105. The sex ratio did not vary consistently or significantly with the estimated timing of insemination relative to the day of ovulation, with the estimated length of the follicular phase, or with the planned or unplanned status of the pregnancy. Study findings suggest that manipulating the timing of insemination during the cycle cannot be used to affect the sex of offspring.

The performance of subcutaneously injected Fertinex when used as the sole gonadotropin for in vitro fertilization stimulation.

OBJECTIVE: To assess the performance of Fertinex (urofollitropin; Serono Laboratories, Norwell, MA) in stimulating the development of multiple follicles and initiating subsequent pregnancy in patients undergoing controlled ovarian hyperstimulation (COH) for IVF. DESIGN: Prospective observational study. SETTING: Private assisted reproductive technology (ART) center. PATIENT(S): Ninety-three women who underwent an IVF cycle of COH in which Fertinex was used as the sole gonadotropin. INTERVENTION(S): The COH protocol included Fertinex with leuprolide acetate down-regulation in the late luteal phase or the early follicular phase. Embryo transfer was performed after 3 days of culture. MAIN OUTCOME MEASURE(S): Stimulation parameters, embryologic data, and pregnancy rates (PRs). RESULT(S): Ninety-three patients underwent 97 cycles of COH, with a cancellation rate of 13.4%. The clinical PR was 42% per initiation, 49% per retrieval, and 51% per transfer. Shorter stimulation periods, lower estradiol levels either per follicle punctured or per oocyte retrieved, and slower embryo development were observed. Patients responded to Fertinex in three distinct stimulation patterns: escalating response with a peak estradiol level of < or =3,000 pg/mL, escalating response with a peak estradiol level of >3,000 pg/mL, or escalating response characterized by a drop in the estradiol level or a plateau before hCG administration. All three responses had similar PRs. CONCLUSION(S): Fertinex can be used successfully as the sole gonadotropin for COH in ART without compromising high PRs. Traditional estradiol response curves or cancellation criteria may not apply when Fertinex is used as the sole gonadotropin for COH in ART.

Perinatal medicine: a look to the future.

There have been many advances in perinatal medicine, but few as impressive as those in Rh-disease. Over several decades, we have seen a disease, which once caused the perinatal death of half of all Rh-immunized pregnancies, almost disappear. The success of this medical campaign should serve as a model for the conquering of other perinatal problems.

The frequency and spectrum of congenital anomalies in natural family planning users in South America: no increase in a case-control study. NFP-ECLAMC Group. Natural Family Planning. Latin-American Collaborative Study of Congenital Malformations.

Users of natural family planning (NFP) practice periodic abstinence, leading many to reason that such couples should show increased anomalies in offspring as a result of fertilization involving aging gametes. In an effort to complement our NFP cohort study, we currently conducted a case-control study in the same region (South America) in which the largest number of cases have been recruited for our cohort NFP study. During 1992-94, 5324 case-control pairs of mothers were interviewed during the immediate postpartum period in 18 maternity hospitals participating in the Latin-American Collaborative Study of Congenital Malformations: ECLAMC (Spanish acronym for Latin-American Collaborative Study of Congenital Malformations). Natural family planning (NFP) usage was recorded in 6% of mothers in the ECLAMC sample studied (n = 10,648). Overall, no significant differences in frequency of NFP usage were observed between malformed cases (349/5324 = 6.6%) and normal controls (303/5324 = 5.7%) (chi 2 = 3.3; df = 1; p > 0.05). No significant differences in sex ratios were observed between children of NFP user and non-user mothers. Of special interest is the lack of association between NFP and Down syndrome, the sentinel phenotype for the hypothesis of delayed fertilization (aging gametes).

Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers.

In-vitro fertilization patients (n = 15) at risk of ovarian hyperstimulation syndrome (OHSS) (oestradiol > or =4500 pg/ml on the day of human chorionic gonadotrophin administration and 25 or more follicles of intermediate or large size) underwent aspiration of all follicles and cryopreservation of all fertilized oocytes at the pronuclear stage. Patients were monitored for up to 2 weeks post-retrieval. Subsequent transfer of cryopreserved-thawed embryos was performed in programmed cycles using exogenous oestrogen and progesterone for endometrial preparation. Two patients (13%) developed OHSS necessitating hospitalization and vaginal aspiration of ascitic fluid. Two other patients (13%) developed moderate OHSS requiring ascitic fluid vaginal aspiration in the office setting, with dramatic improvement of the condition. Subsequent transfer of cryopreserved-thawed embryos yielded a clinical pregnancy rate of 58% per transfer and ongoing or delivery rates of 42 and 67% per transfer and per patient respectively. By eliminating pregnancy potential with cryopreservation of all prezygotes and examining the pregnancy potential with subsequent cryopreserved-thawed transfers, it is concluded that OHSS is reduced, but not eliminated for patients at risk. Subsequent transfer of cryopreserved-thawed prezygotes in a programmed cycle with exogenous steroids yields an excellent pregnancy rate.

Transfer of cryopreserved-thawed pre-embryos in a cycle using exogenous steroids without prior gonadotrophin-releasing hormone agonist suppression yields favourable pregnancy results.

We have analysed the use of a programmed cycle of administration of exogenous steroids without prior suppression with a gonadotrophin-releasing hormone agonist (GnRHa) for the transfer of cryopreserved-thawed pre-embryos. From July 1992 to June 1994, 199 cycles (162 patients) were studied. Pre-embryos had been previously cryopreserved at the pronuclear stage using 1.5 M 1,2-propanediol as a cryoprotectant. Preparation of the endometrium was achieved in a step-up regime with transdermal oestradiol patches (0.1 to 0.4 mg). Progesterone in oil (50 mg i.m.) was started on cycle day 13. Pre-embryos were thawed on day 14 and transferred on day 15 after evidence of survival and cleavage. The mean (+/- SD) age of patients undergoing transfer was 35.4 +/- 4.3 years. The mean number of pre-embryos thawed was 4.7 +/- 1.8 with a mean of 3.3 +/- 1.4 pre-embryos being transferred. Eight of the cycles demonstrated follicular development >16 mm prior to thaw and transfer; however, these patients did not demonstrate a luteinizing hormone surge. Mean endometrial thickness on day 13 was 10.8 +/- 2.1 mm. Overall pregnancy rate was 29.2% (57/195). The ongoing or delivery rate was 16.1% (32/195). The rate of preclinical losses per transfer was 6.2% (12/195). Overall, the implantation rate was 6.2% (47/757). Thus, the use of a programmed cycle for cryopreserved embryo transfer yields favourable pregnancy outcome and offers practical advantages to patients. Prior suppression with a GnRHa is not necessary for endometrial preparation.

Effects of timing of conception on birth weight and preterm delivery of natural family planning users.

OBJECTIVE: Various birth defects and untoward perinatal outcomes have been claimed to be associated with pregnancies conceived by gametes aged in vivo before fertilization. Thus, these outcomes were systematically assessed in pregnancies occurring in natural family planning (NFP) users. Our international multicenter cohort study of NFP pregnancies (n = 877) is by far the largest systematic study designed to assess pregnancy outcome and is of sufficient power to allow us to address the concern of low birth weight (< 2500 g) and preterm delivery (< 37 weeks gestation). STUDY DESIGN: In addition to gathering baseline medical data, evaluation was performed at 16 weeks, 32 weeks and at term. Data were collected in a systematic cohort fashion, verified by the five collaborating international recruiting centers, and analyzed by investigators in the US. Most recruiting center principal investigators are obstetrician-gynecologists and, if not, have integral relationships with such specialists. Standard criteria could thus be applied within and among centers. In our cohort, birth weight was recorded accurately at delivery. Almost all of the deliveries occurred in hospitals; thus, data should be quite reliable. Neonatal examination for anomalies was usually conducted immediately after delivery, when birth weight was recorded. RESULTS: Analysis of risk factors for low birth weight and preterm delivery showed that this population had a low risk profile. Low birth weight infants (< 2500 g) and preterm deliveries were increased among women with a history of either prior low birth weight or preeclampsia in the index pregnancy. However, mean birth weight was unaffected by the timing of conception vis à vis ovulation or pregnancy history. Mean birth weight for the 877 singleton NFP pregnancies was 3349.6 g. The risk of preterm delivery was increased among older women who drank alcohol, but there were no significant effects of timing of conception vis à vis ovulation on preterm delivery. Results held when analysis was stratified according to whether NFP was being used for contraception or to achieve pregnancy. CONCLUSIONS: Our data do not appear to show striking differences between 877 NFP pregnancies and the general obstetric population. The timing of conception vis à vis ovulation does not exert significant effects on the birth weight or preterm delivery of resulting pregnancies, a reassuring finding for NFP users.

Pregnancy complications in natural family planning users.

A multicenter cohort study was designed to assess pregnancy outcome among natural family planning (NFP) users, and provide the opportunity to address complications in NFP users by planning status and by timing of conception with respect to day of ovulation. There were 877 singleton births in this sample. Complications evaluated were abnormal vaginal bleeding, urinary tract infection, vaginal infection, hypertension of pregnancy, proteinuria, glycosuria, and anemia. There was no significant difference in the mean age, number of prenatal visits or birth weight among optimally and non-optimally timed pregnancies or for planned and unplanned pregnancies. There were higher incidences of "parity 2 or more" and current smokers in the non-optimally timed pregnancies and lower incidences of prior pregnancy loss and "currently employed" in the non-optimally timed pregnancies. There was little difference in pregnancy complications with respect to pregnancy timing, with the exception of a significant increased risk of vaginal bleeding late in pregnancy among non-optimally timed conceptions (11.5%) compared to optimally timed pregnancies (5.2%, RR = 2.2, 95% CI 1.3-3.7). More differences were observed in pregnancy complication rates by planning status. Unplanned pregnancies were associated with significantly more late pregnancy bleeding, vaginal infections, proteinuria, glycosuria and medication use than planned pregnancies. Unplanned pregnancies had lower incidences of maternal anemia. Complications of pregnancy were low in this NFP population, irrespective of planned versus unplanned status. Women with planned pregnancies had even fewer complications during pregnancy than women with unplanned conceptions, suggesting that women using NFP to plan their reproduction may be at particularly low risk.