Pre-conception 25-hydroxyvitamin D (25(OH)D) and fecundability.

STUDY QUESTION: Is pre-conception 25(OH)D associated with the per cycle probability of conception, i.e fecundability, in a prospective cohort study? SUMMARY ANSWER: There are suggestive associations of high 25(OH)D (at least 50 ng/ml) with increased fecundability and low 25(OH)D (<20 ng/ml) with reduced fecundability, but the estimates were imprecise. WHAT IS KNOWN ALREADY: Vitamin D has been associated with reproductive function and fertility in animal studies, but few human studies exist. STUDY DESIGN, SIZE, DURATION: This community-based prospective cohort study included 522 women attempting to become pregnant between 2010 and 2016. The women completed online daily and monthly diaries until a positive home pregnancy test was observed or 12 months had elapsed. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women from central North Carolina who were aged 30-44 with no history of infertility, with no more than 3 months of attempt time at recruitment. Women recorded vaginal bleeding so that the ongoing number of attempt cycles could be counted and used to quantify a woman's pregnancy attempt time. Blood collected at the study entry was analysed for 25(OH)D using liquid chromatography tandem mass spectrometry. Associations with fecundability were estimated with a log-binomial discrete time-to-event model. MAIN RESULTS AND THE ROLE OF CHANCE: Among 522 women, 257 conceived during the study. The mean age was 33 years and the mean 25(OH)D was 36 ng/ml. There was an estimated 10% higher fecundability with each 10 ng/ml increase in 25(OH)D (fecundability ratio (FR) 1.10, 95% CI: 0.96, 1.25). The suggestive dose-response association with the continuous measure of 25(OH)D was driven by women in the lowest and the highest categories of 25(OH)D. Compared to women with 25(OH)D of 30-40 ng/ml, women below 20 ng/ml had an estimated 45% reduction in fecundability (FR (CI): 0.55 (0.23, 1.32)), and women with at least 50 ng/ml had an estimated 35% increase in fecundability (FR (CI): 1.35 (0.95, 1.91)). Across these three categories (25(OH)D of <20 ng/ml, 30-40 ng/ml and > 50 ng/ml), the probability of taking longer than 6 months to conceive was, respectively, 51% (17%, 74%), 28% (17%, 39%) and 15% (10%, 37%). LIMITATIONS, REASONS FOR CAUTION: While the distribution of 25(OH)D was wide, the number of observed cycles with high 25(OH)D (N = 107) or low 25(OH)D (N = 56) was small. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with prior reports of reduced fertility in women with 25(OH)D concentrations below the clinically defined deficiency level (20 ng/ml). Further studies are needed to evaluate the possible reproductive benefits of considerably higher 25(OH)D concentration (>50 ng/ml). STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683 and supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, under projects ES103086, ES049003 and ES044003. ClearBlue ovulation predictor kits were generously donated to AMZJ and AJW by Swiss Precision Diagnostics. Drs Wilcox and Jukic report non-financial support from Swiss Precision Diagnostics during the conduct of the study; Dr Jukic reports non-financial support from Theralogix, LLC, outside the submitted work. Otherwise there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Offspring birthweight by gestational age and parental cardiovascular mortality: a population-based cohort study.

OBJECTIVE: To estimate risk of parental cardiovascular disease mortality by offspring birthweight. DESIGN: Population-based cohort study. SETTING AND POPULATION: Norwegian mothers and fathers with singleton births during 1967-2002 were followed until 2009 by linkage to the Norwegian cause of death registry. METHODS: Hazard ratios by offspring absolute birthweight in grams and birthweight adjusted for gestational age (z-score) were calculated using Cox regression and adjusted for parental age at delivery and year of first birth. Stratified analyses on preterm and term births were performed. MAIN OUTCOME MEASURES: Maternal and paternal cardiovascular mortality. RESULTS: We followed 711 726 mothers and 700 212 fathers and found a strong link between maternal cardiovascular mortality and offspring birthweight but only slight evidence of associations in fathers. Adjusting birthweight for gestational age (by z-score) uncovered an unexpected strong association of large birthweight (z-score > 2.5) with mothers' cardiovascular mortality (hazard ratio 3.0, 95% CI 2.0-4.6). This risk was apparently restricted to preterm births. In stratified analyses (preterm and term births) hazard ratios for maternal cardiovascular mortality were 1.5 (1.03-2.2) for large preterm babies and 0.9 (0.7-1.2) for large term babies (P-value for interaction = 0.02), using normal weight preterm and term, respectively, as references. CONCLUSION: Women having large preterm babies are at increased risk of both diabetes and cardiovascular mortality. The birth of a large preterm baby should increase clinical vigilance for onset of diabetes and other cardiovascular disease risk factors. TWEETABLE ABSTRACT: Birth of a large preterm baby should increase vigilance for cardiovascular-disease risk factors.

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Ultrasound prediction of perinatal outcome: the unrecognised value of sibling data.

OBJECTIVE: To identify high-risk fetuses at the first routinely performed ultrasound examination by making use of information from the mother's previous pregnancy. DESIGN: A population-based cohort study. SETTING: Norway, 1999-2009. POPULATION: All singleton first live births and their second-born siblings registered in the Medical Birth Registry of Norway (166,786 eligible sibling pairs). METHODS: Odds ratios were calculated by logistic regression. MAIN OUTCOME MEASURES: Very small for gestational age (vSGA; birthweight ≤-1.96 standard deviations) and perinatal death (stillbirth at ≥22 weeks of gestation or death within 28 days of life). RESULTS: Small fetal size at ultrasound (i.e. a fetus smaller than expected by last menstrual period, LMP) is only weakly predictive of vSGA or perinatal death; however, if the firstborn sibling was vSGA at birth, ultrasound measures in the next pregnancy become strongly informative of risk. The smaller the fetal size on ultrasound, the higher its risk of vSGA (3-18%; Ptrend < 0.0001) and perinatal death (4-19 per thousand, Ptrend = 0.012). In contrast, if the first baby was not vSGA, small fetal size on ultrasound is uninformative. CONCLUSIONS: When the firstborn baby is vSGA, discrepancies between fetal size on ultrasound and LMP become highly predictive of risk of vSGA and perinatal mortality in the second-born infant. The value of combining these routinely collected clinical data has not previously been recognised.

Length of human pregnancy and contributors to its natural variation.

STUDY QUESTION: How variable is the length of human pregnancy, and are early hormonal events related to gestational length? SUMMARY ANSWER: Among natural conceptions where the date of conception (ovulation) is known, the variation in pregnancy length spanned 37 days, even after excluding women with complications or preterm births. WHAT IS KNOWN ALREADY: Previous studies of length of gestation have either estimated gestational age by last menstrual period (LMP) or ultrasound (both imperfect measures) or included pregnancies conceived through assisted reproductive technology. STUDY DESIGN, SIZE, DURATION: The Early Pregnancy Study was a prospective cohort study (1982-85) that followed 130 singleton pregnancies from unassisted conception to birth, with detailed hormonal measurements through the conception cycle; 125 of these pregnancies were included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated the length of gestation beginning at conception (ovulation) in 125 naturally conceived, singleton live births. Ovulation, implantation and corpus luteum (CL) rescue pattern were identified with urinary hormone measurements. We accounted for events that artificially shorten the natural length of gestation (Cesarean delivery or labor induction, i.e. 'censoring') using Kaplan-Meier curves and proportional hazards models. We examined hormonal and other factors in relation to length of gestation. We did not have ultrasound information to compare with our gold standard measure. MAIN RESULTS AND THE ROLE OF CHANCE: The median time from ovulation to birth was 268 days (38 weeks, 2 days). Even after excluding six preterm births, the gestational length range was 37 days. The coefficient of variation was higher when measured by LMP (4.9%) than by ovulation (3.7%), reflecting the variability of time of ovulation. Conceptions that took longer to implant also took longer from implantation to delivery (P = 0.02). CL rescue pattern (reflecting ovarian response to implantation) was predictive (P = 0.006): pregnancies with a rapid progesterone rise were longer than those with delayed rise (a 12-day difference in the median gestational length). Mothers with longer gestations were older (P = 0.02), had longer pregnancies in other births (P < 0.0001) and were heavier at birth (P = 0.01). We did not see an association between the length of gestation and several factors that have been associated with gestational length in previous studies: body mass index, alcohol intake, parity or offspring sex. LIMITATIONS, REASONS FOR CAUTION: The sample size was small and some exposures were rare, reducing power to detect weak associations. WIDER IMPLICATIONS OF THE FINDINGS: Human gestational length varies considerably even when measured exactly (from ovulation). An individual woman's deliveries tend to occur at similar gestational ages. Events in the first 2 weeks after conception are predictive of subsequent pregnancy length, and may suggest pathways underlying the timing of delivery. STUDY FUNDING/COMPETING INTEREST: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. None of the authors has any conflict of interest to declare.

Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway.

BACKGROUND: Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n = 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n = 221). The inhibition of folic acid binding to FRα was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors. RESULTS: There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0-1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FRα (CL/P aOR = 0.7, 95% CI 0.6-1.0; CPO aOR = 1.1, 95% CI 0.8-1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FRα. CONCLUSIONS: Inhibition of folic acid binding to FRα in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts.

The association of maternal factors with delayed implantation and the initial rise of urinary human chorionic gonadotrophin.

BACKGROUND Late implantation and the pattern of early rise in hCG have been associated with early pregnancy loss. We explored factors that might be predictive of these markers of poor embryonic health in spontaneously conceived pregnancies. METHODS Participants in the North Carolina Early Pregnancy Study collected daily first-morning urine specimens while attempting to conceive. Samples were assayed for estrogen and progesterone metabolites (to identify day of ovulation) and hCG (to detect conception). Data were available for 190 pregnancies, 48 of which ended in early loss (within 6 weeks of the last menstrual period). We used logistic regression to identify characteristics associated with late implantation (≥10 days post-ovulation). For pregnancies surviving at least 6 weeks (n= 142), we used linear mixed models to identify factors associated with variations in hCG rise in the first 7 days from detection. RESULTS Later implantation was associated with current maternal smoking [odds ratio (OR): 5.7; 95% confidence interval (CI): 1.1-30] and with oocytes that were likely to have been fertilized late in their post-ovulatory lifespan (OR: 5.1; CI: 1.9-16). Older women had a faster rise in hCG (P= 0.01), as did women who had relatively late menarche (P for trend = 0.02). Women exposed in utero to diethylstilbestrol showed an unusual pattern of slow initial hCG rise followed by a fast increase, a pattern significantly different from that of unexposed women (P= 0.002). CONCLUSIONS Although limited by small numbers and infrequent exposures, our analyses suggest that a woman's exposures both early in life and at the time of pregnancy may influence early development of the conceptus.

Urinary hCG patterns during the week following implantation.

BACKGROUND: Human chorionic gonadotrophin (hCG) is used to monitor pregnancy status. Yet the pattern of hCG excretion in the first week following implantation has not been adequately described. Therefore the aim of this study was to describe the average profile of hCG and its variability during the 7 days following estimated implantation in a population of naturally conceived pregnancies. METHODS: We measured daily hCG concentrations in first-morning urine for 142 clinical pregnancies from women with no known fertility problems. Mixed-effects regression models were used to estimate the hCG trajectory and its variability in relation to pregnancy outcomes. RESULTS: hCG rose 3-fold between the day of detection and the next day (95% CI = 2.7-3.4). The relative rate of rise decreased thereafter, reaching 1.6-fold (95% CI = 1.5-1.8) between days 6 and 7. HCG levels followed a log-quadratic trajectory, and the patterns of rise were unrelated to number of fetuses, risk of spontaneous abortion or sex of the baby. Later implantations (after 10 luteal days) produced slower rates of increase. CONCLUSIONS: Although mean hCG follows a log-quadratic trajectory during the first week of detectability, there is high variability across pregnancies. Later implantation may reflect characteristics of the uterus or conceptus that slow hCG production.

Bleeding following pregnancy loss before 6 weeks' gestation.

BACKGROUND: Pregnancy loss before 6 weeks' gestation is common, but little has been reported about the associated bleeding. We compared women's bleeding following a pregnancy loss before 6 weeks' gestation with their typical menstruation. METHODS: Women provided daily urine samples while trying to become pregnant and recorded the number of pads and tampons used each day. Thirty-six women had complete bleed data for a loss before 6 weeks' gestation and one or more non-pregnant cycles. RESULTS: Mean bleed length following a pregnancy loss was 0.4 days longer than the woman's average menstrual bleed (P = 0.01), primarily because of more days of light bleeding. Although there was no overall increase in the total number of pads plus tampons used, women with losses bled less than their typical menses following pregnancies of very short duration and more than usual for the pregnancies lasting the longest. CONCLUSIONS: Overall, the bleeding associated with pregnancy loss before 6 weeks' gestation is similar to menstrual bleeding and unlikely to be recognized as pregnancy loss. The intriguing finding that pregnancies of very short duration were associated with less bleeding than the woman's typical menses might reflect endometrial factors associated with loss.

On the frequency of intercourse around ovulation: evidence for biological influences.

BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for example through fluctuations in libido or by the acceleration of ovulation with intercourse. Such coordination has not been established in humans. We explored this possibility by examining patterns of sexual intercourse in relation to ovulation. METHODS: Sixty-eight sexually active North Carolina women with either an intrauterine device or tubal ligation provided data for up to three menstrual cycles. These women collected daily urine specimens and kept daily diaries of intercourse and menstrual bleeding. Major estrogen and progesterone metabolites excreted in urine were used to identify the day of ovulation. The fertile days of the cycle were defined as the 6 consecutive days ending with ovulation. Women contributed a total of 171 ovulatory cycles. Menstrual bleeding days were excluded from analysis. RESULTS: The frequency of intercourse rose during the follicular phase, peaking at ovulation and declining abruptly thereafter. The 6 consecutive days with most frequent intercourse corresponded with the 6 fertile days of the menstrual cycle. Intercourse was 24% more frequent during the 6 fertile days than during the remaining non-bleeding days (P < 0.001). CONCLUSIONS: There apparently are biological factors that promote intercourse during a woman's 6 fertile days.

Vaginal bleeding in very early pregnancy.

INTRODUCTION: Little is known about the occurrence and patterns of vaginal bleeding during the earliest stages of pregnancy. We explore this in a prospective study of early pregnancy. METHODS: A total of 221 healthy women kept daily diaries and provided daily urine samples while trying to become pregnant. Of these, 151 women became clinically pregnant [i.e. pregnancy that lasted >/=6 weeks beyond last menstrual period (LMP)] during the study. Diaries provided information on days with vaginal bleeding and sexual intercourse. Urine hormone assays were used to identify ovulation and implantation. Women were interviewed about their medical histories and lifestyle factors. RESULTS: A total of 14 women (9%) recorded at least 1 day of vaginal bleeding during the first 8 weeks of pregnancy. Twelve of these 14 pregnancies continued to a live birth. Bleeding tended to occur around the time when women would expect their periods, although rarely on the day of implantation. Bleeding was not associated with intercourse. CONCLUSIONS: Early bleeding in clinical pregnancies is generally light, and not likely to be mistaken for LMP. Thus, early bleeding is unlikely to contribute to errors in LMP-based gestational age. We found no support for the hypothesis that implantation can produce vaginal bleeding. Similarly, intercourse did not cause bleeding. Nearly all women with bleeding went on to have successful pregnancies.

Reliability of serial urine HCG as a biomarker to detect early pregnancy loss.

BACKGROUND: To examine the reliability of HCG as a biomarker for early pregnancy loss, five experienced researchers independently assessed data from 153 menstrual cycles, determining whether each cycle represented 'no conception,' a 'continuing conception' or a 'conception lost.' METHODS: Urine samples were analysed by immunoradiometric assay using a combination of capture antibodies for the intact heterodimer (B109) and for an epitope common to the beta subunit and the beta core fragment (B204). For each cycle, HCG data were presented as graphs of daily assay results. Summary statistics for HCG assays from 46 women who had undergone bilateral tubal ligation represented baseline values. RESULTS: Pairwise agreement among the assessors for any of the three options ranged from 78-89%. At least three experts agreed for 147 cycles (96%), accounting for 28 conception losses and 19 continuing conceptions. The multi-rater kappa was 0.62 for the conception lost category and 0.68 for continuing conceptions, indicating substantial agreement. CONCLUSION: The main sources of disagreement involved deciding whether there was sufficient information for assessment, interpreting cycle parameters such as cycle length or bleeding event, and interpreting a distinct HCG rise pattern that does not exceed the baseline value obtained from the sterilized women.

Natural limits of pregnancy testing in relation to the expected menstrual period.

CONTEXT: Pregnancy test kits routinely recommend testing "as early as the first day of the missed period." However, a pregnancy cannot be detected before the blastocyst implants. Due to natural variability in the timing of ovulation, implantation does not necessarily occur before the expected onset of next menses. OBJECTIVE: To estimate the maximum screening sensitivity of pregnancy tests when used on the first day of the expected period, taking into account the natural variability of ovulation and implantation. DESIGN AND SETTING: Community-based prospective cohort study conducted in North Carolina between 1982 and 1986. PARTICIPANTS: Two hundred twenty-one healthy women 21 to 42 years of age who were planning to conceive. MAIN OUTCOME MEASURES: Day of implantation, defined by the serial assay of first morning urine samples using an extremely sensitive immunoradiometric assay for human chorionic gonadotropin (hCG), relative to the first day of the missed period, defined as the day on which women expected their next menses to begin, based on self-reported usual cycle length. RESULTS: Data were available for 136 clinical pregnancies conceived during the study, 14 (10%) of which had not yet implanted by the first day of the missed period. The highest possible screening sensitivity for an hCG-based pregnancy test therefore is estimated to be 90% (95% confidence interval [CI], 84%-94%) on the first day of the missed period. By 1 week after the first day of the missed period, the highest possible screening sensitivity is estimated to be 97% (95% CI, 94%-99%). CONCLUSIONS: In this study, using an extremely sensitive assay for hCG, 10% of clinical pregnancies were undetectable on the first day of missed menses. In practice, an even larger percentage of clinical pregnancies may be undetected by current test kits on this day, given their reported assay properties and other practical limitations.

Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives.

Emergency post-coital contraceptives effectively reduce the risk of pregnancy, but their degree of efficacy remains uncertain. Measurement of efficacy depends on the pregnancy rate without treatment, which cannot be measured directly. We provide indirect estimates of such pregnancy rates, using data from a prospective study of 221 women who were attempting to conceive. We previously estimated the probability of pregnancy with an act of intercourse relative to ovulation. In this article, we extend these data to estimate the probability of pregnancy relative to intercourse on a given cycle day (counting from onset of previous menses). In assessing the efficacy of post-coital contraceptives, other approaches have not incorporated accurate information on the variability of ovulation. We find that the possibility of late ovulation produces a persistent risk of pregnancy even into the sixth week of the cycle. Post-coital contraceptives may be indicated even when intercourse has occurred late in the cycle.

Assessing human fertility using several markers of ovulation.

In modelling human fertility one ideally accounts for timing of intercourse relative to ovulation. Measurement error in identifying the day of ovulation can bias estimates of fecundability parameters and attenuate estimates of covariate effects. In the absence of a single perfect marker of ovulation, several error prone markers are sometimes obtained. In this paper we propose a semi-parametric mixture model that uses multiple independent markers of ovulation to account for measurement error. The model assigns each method of assessing ovulation a distinct non-parametric error distribution, and corrects bias in estimates of day-specific fecundability. We use a Monte Carlo EM algorithm for joint estimation of (i) the error distribution for the markers, (ii) the error-corrected fertility parameters, and (iii) the couple-specific random effects. We apply the methods to data from a North Carolina fertility study to assess the magnitude of error in measures of ovulation based on urinary luteinizing hormone and metabolites of ovarian hormones, and estimate the corrected day-specific probabilities of clinical pregnancy. Published in 2001 by John Wiley & Sons, Ltd.

Survival and reproduction among males with birth defects and risk of recurrence in their children.

CONTEXT: Few systematic data exist on survival and reproduction among males with birth defects and their contribution to occurrence of birth defects in the next generation. OBJECTIVE: To estimate survival of males with registered birth defects, their subsequent reproduction rates, and their risk of transmitting birth defects to their offspring. DESIGN AND SETTING: Population-based cohort study of data from the Medical Birth Registry of Norway. SUBJECTS: A total of 486 207 males born in Norway between 1967 and 1982, 12 292 of whom had a recorded birth defect. MAIN OUTCOME MEASURES: Survival rates through 1992, reproduction rates through 1998, and risk of birth defects among offspring of males with vs without birth defects. RESULTS: Survival through 1992 was lower among males with birth defects (84% vs 97%). Compared with males without birth defects, affected males were 28% less likely to have had a child. Among offspring of affected males, 5.1% had a registered birth defect compared with 2.1% of offspring of males without birth defects (relative risk [RR], 2.4; 95% confidence interval [CI], 1.9-3.0). Offspring of affected fathers had an increased risk of the same defect as their fathers (RR, 6.5; 95% CI, 4.0-10.4) and an increased risk of dissimilar defects (RR, 1.8; 95% CI, 1.3-2.5). CONCLUSIONS: Compared with unaffected males, males with birth defects have higher mortality and survivors are less likely to have a child. Fathers with birth defects are significantly more likely than unaffected fathers to have an affected child.

Sexual activity during late pregnancy and risk of preterm delivery.

OBJECTIVE: To examine the association between sexual activity during late pregnancy and preterm delivery. METHODS: Women at least 16 years old and carrying singleton fetuses were recruited between 24 and 29 weeks' gestation from prenatal clinics in central North Carolina. They were interviewed by telephone about sexual activity before and during pregnancy. One hundred eighty-seven women delivered between 29 and 36 weeks and had a follow-up interview after delivery. Four hundred nine women who were selected randomly from the cohort served as controls and had a follow-up interview between 29 and 36 weeks (mean gestational age 39.2 weeks). RESULTS: Intercourse during late pregnancy was associated with a reduced risk of preterm delivery. The conditional odds ratio (OR) was 0.34 and 95% confidence interval (CI) 0.23, 0.51 for preterm delivery within 2 weeks after intercourse. Similar decreased risk for preterm delivery was found with recent female orgasm. Adjusting for race, age, education, and living with a partner had little effect on results. Cases were more likely than controls to report poorer health, medical reasons for reducing sexual activity, less interest in sex, and receipt of advice to restrict sexual activity during pregnancy. Results did not differ substantially according to presence or absence of bacterial vaginosis at 28 weeks. CONCLUSION: These data provide evidence against the hypothesis that sexual activity generally increases risk of preterm delivery between 29 and 36 weeks. However, we cannot exclude the possibility that a small subgroup of susceptible women might have adverse consequences of sexual activity.

Placental abruption and perinatal mortality in the United States.

Placental abruption is an uncommon obstetric complication associated with high perinatal mortality rates. The authors explored the associations of abruption with fetal growth restriction, preterm delivery, and perinatal survival. The study was based on 7,508,655 singleton births delivered in 1995 and 1996 in the United States. Abruption was recorded in 6.5 per 1,000 births. Perinatal mortality was 119 per 1,000 births with abruption compared with 8.2 per 1,000 among all other births. The high mortality with abruption was due, in part, to its strong association with preterm delivery; 55% of the excess perinatal deaths with abruption were due to early delivery. Furthermore, babies in the lowest centile of weight (<1% adjusted for gestational age) were almost nine times as likely to be born with abruption than those in the heaviest (> or =90%) birth weight centiles. This relative risk progressively declined with higher birth weight centiles. After controlling for fetal growth restriction and early delivery, the high risk of perinatal death associated with abruption persisted. Even babies born at 40 weeks of gestation and birth weight of 3,500-3,999 g (where mortality was lowest) had a 25-fold higher mortality with abruption. The link between fetal growth restriction and abruption suggests that the origins of abruption lie at least in midpregnancy and perhaps even earlier.

On the importance--and the unimportance--of birthweight.

Birthweight is one of the most accessible and most misunderstood variables in epidemiology. A baby's weight at birth is strongly associated with mortality risk during the first year and, to a lesser degree, with developmental problems in childhood and the risk of various diseases in adulthood. Epidemiological analyses often regard birthweight as on the causal pathway to these health outcomes. Under this assumption of causality, birthweight is used to explain variations in infant mortality and later morbidity, and is also used as an intermediate health endpoint in itself. Evidence presented here suggests the link between birthweight and health outcomes may not be causal. Methods of analysis that assume causality are unreliable at best, and biased at worst. The category of 'low birthweight' in particular is uninformative and seldom justified. The main utility of the birthweight distribution is to provide an estimate of the proportion of small preterm births in a population (although even this requires special analytical methods). While the ordinary approaches to birthweight are not well grounded, the links between birthweight and a range of health outcomes may nonetheless reflect the workings of biological mechanisms with implications for human health.