Olga Basso

Infertility, infertility treatment, and congenital malformations: Danish national birth cohort

Abstract Objectives To examine whether infertile couples (with a time to pregnancy of > 12 months), who conceive naturally or after treatment, give birth to children with an increased prevalence of congenital malformations. Design Longitudinal study. Setting Danish national birth cohort. Participants Three groups of liveborn children and their mothers: 50 897 singletons and 1366 twins born of fertile couples (time to pregnancy ≤ 12 months), 5764 singletons and 100 twins born of infertile couples who conceived naturally (time to pregnancy > 12 months), and 4588 singletons and 1690 twins born after infertility treatment. Main outcome measures Prevalence of congenital malformations determined from hospital discharge diagnoses. Results Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations—hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins. Conclusions Hormonal treatment for infertility may be related to the occurrence of malformations of genital organs, but our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants. The association between untreated infertility and congenital malformations warrants further examination.

On the Pitfalls of Adjusting for Gestational Age at Birth

Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified.

Higher risk of pre-eclampsia after change of partner. An effect of longer interpregnancy intervals?

Epidemiologic studies have shown that pre-eclampsia is mainly a disease of first pregnancy, possibly associated with primipaternity. The interpregnancy interval, which is strongly associated with change of partner, has received little attention. In this study, based on Danish hospital records, we evaluated whether the interpregnancy interval may confound or modify the paternal effect on pre-eclampsia. We studied the outcome of the second birth in a cohort of Danish women with pre-eclampsia in the previous birth (8,401 women) and in all women with pre-eclampsia in second (but not first) birth together with a sample of women with two births (26,596 women). A long interpregnancy interval was associated with a higher risk of pre-eclampsia in women with no previous pre-eclampsia when the father was the same. We estimated the risk of pre-eclampsia in second birth according to paternal change in different models. Although partner change was associated with an increased risk of pre-eclampsia in women with no history of pre-eclampsia, this effect disappeared after adjustment for the interpregnancy interval. We saw, however, different results when we stratified on the length of the interval. Our results indicate that the interval between births should be taken into consideration when studying the effect of changing partner on pre-eclampsia.

Infertility and the risk of adverse pregnancy outcomes: a systematic review and meta-analysis

STUDY QUESTION Do women who conceive without treatment after a long time to pregnancy (TTP) have an increased risk of preterm birth compared with women in the general obstetric population? SUMMARY ANSWER Based on this meta-analyses of 14 studies, women with a long TTP are at an increased risk of preterm birth: pooled crude odds ratio (OR): 1.38 (95% CI: 1.25-1.54). WHAT IS KNOWN ALREADY Several studies have shown that women who conceive without treatment after >12 months of trying have an elevated risk of poor pregnancy outcomes. To date, no systematic review or meta-analysis of this evidence has been published. STUDY DESIGN, SIZE, DURATION This systematic review identified literature from Embase, Medline and Popline published between January 1974 and October 2011, on the association between infertility in a non-treated population and the risk of preterm birth, low birthweight (LBW), small-for-gestational age and birthweight deficits. PARTICIPANTS/MATERIALS, SETTING, METHODS Two authors independently conducted the searches, selected the studies and abstracted the data. A total of 89 full-text articles were assessed for eligibility and 17 met the inclusion criteria. The pooled analysis of the primary outcome led to a total sample size of 1 269 758 births: 19 983 in the exposed/infertile group and 1 249 775 in the unexposed/fertile group. There were a total 68 885 preterm births in the overall sample: 1644 (8.2%) and 67 241 (5.4%) among the infertile and reference groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE A moderate increase in the risk of preterm birth persisted irrespective of the type of pooling. The common OR of the pooled crude preterm birth data compared with the pooled regression-adjusted analysis was modestly attenuated: from 1.38 (95% CI: 1.25, 1.54) to 1.31 (95% CI: 1.21, 1.42), with I² decreasing from 53.2 to 3.9% in the crude to adjusted results, respectively. An association of a similar magnitude was seen between infertility and LBW, due in part to overlapping of outcomes. LIMITATIONS, REASONS FOR CAUTION Consistency of the estimates across various types of pooling, including the more restricted sensitivity analyses of higher quality studies, is reassuring. While it is possible that systematic error may have been present through misclassification of exposure and confounding, these findings suggest that it would need to be of the same magnitude across diverse studies, which seems unlikely. WIDER IMPLICATIONS OF THE FINDINGS A long TTP is only a symptom, research is needed to assess whether specific groups of infertile couples are at increased risk of adverse outcome, or whether the increased risk is due to characteristics common to most infertile couples. As long as the contribution of infertility is not clarified, the risks due to assisted reproductive technologies cannot be properly assessed. STUDY FUNDING/COMPETING INTEREST(S) C.M. was supported by a Canadian Institutes of Health Research doctoral research award at the time of this study. No competing interests are declared.

Sex ratio and twinning in women with hyperemesis or pre-eclampsia.

We examined twinning and fetal gender in births of women with a hospital diagnosis of pre-eclampsia or hyperemesis. We also investigated sex ratio in infants whose mothers had had hyperemesis or pre-eclampsia in a different pregnancy. From all the hospitalized cases in Denmark between 1980 and 1996 we extracted 6,227 births with hyperemesis and 24,764 with pre-eclampsia. Twins were more frequent in pregnancies with either condition. The male to female sex ratio was 1.04 (95%CI = 1.02–1.05) in the reference population, 0.87 (95% CI = 0.82–0.91) in births with hyperemesis, and 1.10 (95% CI = 1.07–1.12) in births with pre-eclampsia. Women with pre-eclampsia had slightly more males also in non-affected pregnancies.

Low birth weight and preterm birth after short interpregnancy intervals

OBJECTIVE Our purpose was to study low birth weight and preterm birth after short interpregnancy intervals. STUDY DESIGN Follow-up of a cohort of a register-based random sample of women who had at least two live births in Denmark between 1980 and 1992. Frequency of preterm birth (gestational age <37 weeks) and low birth weight (<2500 gm) were studied as a function of the interpregnancy interval in 10,187 women. RESULTS Short interpregnancy intervals (< or =8 months) were associated with preterm birth but not with low birth weight. The adjusted odds ratios for preterm birth were 3.60 (95% confidence interval 2.04 to 6.35) for intervals up to 4.00 months and 2.28 (1.49 to 3.48) for intervals between 4.01 and 8.00 months compared with deliveries after 24 to 36 months, in which the risk of preterm birth was 3.5%. Risks were higher in women with a previous pregnancy at term. Social status, age, and parity were adjusted for. CONCLUSIONS Short interpregnancy intervals were associated with an increased risk of premature delivery. This risk should be taken into account when planning a new pregnancy.

Risk of recurrence of prolonged pregnancy

Paternal genes as expressed by the fetus play a role in the timing of birth and in the risk of repeating a prolonged pregnancy Prolonged pregnancy—a pregnancy with a gestational length of 294 days or more—occurs in about 5% of all births. It is associated with a higher frequency of obstetric complications and perinatal morbidity,1 and little is known about its aetiology.2 We studied the risk of recurrence of prolonged pregnancy as a function of change in partner or change in social conditions. We obtained data recorded in the Danish medical birth registry on all women with a prolonged pregnancy in the first delivery and in a subsequent delivery, during 1980-94, and a 5% sample of all women with two or more pregnancies recorded in the period 1980-92 (only the first two deliveries were used for analysis). The information on gestational age in the registry was obtained from birth records that had been …

United States Birth Weight Reference Corrected For Implausible Gestational Age Estimates

OBJECTIVES: To provide an updated US birth weight for gestational age reference corrected for likely errors in last menstrual period (LMP)-based gestational age dating, as well as means and SDs, to enable calculation of continuous and categorical measures of birth weight for gestational age. METHODS: From the 2009–2010 US live birth files, we abstracted singleton births between 22 and 44 weeks of gestation with at least 1 nonmissing estimate of gestational age (ie, LMP or obstetric/clinical) and birth weight. Using an algorithm based on birth weight and the concordance between these gestational age estimates, implausible LMP-based gestational age estimates were either excluded or corrected by using the obstetric/clinical estimate. Gestational age– and sex-specific birth weight means, SDs, and smoothed percentiles (3rd, 5th, 10th, 90th, 95th, 97th) were calculated, and the 10th and 90th percentiles were compared with published population-based references. RESULTS: A total of 7 818 201 (99% of eligible) births were included. The LMP-based estimate of gestational age comprised 85% of the dataset, and the obstetric/clinical estimate comprised the remaining 15%. Cut points derived from the current reference identified ∼10% of births as ≤10th and ≥90th percentiles at all gestational weeks, whereas cut points derived from previous US-based references captured variable proportions of infants at these thresholds within the preterm and postterm gestational age ranges. CONCLUSIONS: This updated US-based birth weight for gestational age reference corrects for likely errors in gestational age dating and allows for the calculation of categorical and continuous measures of birth size.

Paternal age and preterm birth.

Background: There is growing evidence that advanced paternal age can be a reproductive hazard. Methods: We studied couples and their first children using nationwide registers in Denmark between 1980 and 1996. We restricted the analysis to mothers age 20–29 years. We estimated odds ratios (ORs) of preterm (<37 weeks gestation) and very preterm birth (<32 weeks) as a function of paternal age using logistic regression to adjust for potential confounding variables. Results: The risk of preterm birth increased with paternal age, almost entirely resulting from an association for very preterm birth. Compared with fathers age 20–24 years, ORs for very preterm birth were 1.3 (age 25–29), 1.4 (age 35–39), 1.7 (age 40–44), 1.6 (age 45–49), and 2.1 (age 50+) (test for trend: P = 0.01). Conclusions: Risk of very preterm birth increases among older fathers, perhaps as a result of a paternal placental effect.

Carbonated beverages and chronic kidney disease.

Background: Carbonated beverage consumption has been linked with diabetes, hypertension, and kidney stones, all risk factors for chronic kidney disease. Cola beverages, in particular, contain phosphoric acid and have been associated with urinary changes that promote kidney stones. Methods: We examined the relationship between carbonated beverages (including cola) and chronic kidney disease, using data from 465 patients with newly diagnosed chronic kidney disease and 467 community controls recruited in North Carolina between 1980 and 1982. Results: Drinking 2 or more colas per day was associated with increased risk of chronic kidney disease (adjusted odds ratio = 2.3; 95% confidence interval = 1.4–3.7). Results were the same for regular colas (2.1; 1.3–3.4) and artificially sweetened colas (2.1; 0.7–2.5). Noncola carbonated beverages were not associated with chronic kidney disease (0.94; 0.4–2.2). Conclusions: These preliminary results suggest that cola consumption may increase the risk of chronic kidney disease.