Abstract
Objective:
To investigate perinatal outcomes in a cohort of fertile and infertile nulliparous women.
Design:
Retrospective cohort study
Setting:
Academic medical center
Patients:
All nulliparous women delivering singletons ≥24 weeks gestation at our center from January 1- December 31, 2012 were included. Women were classified into two groups – fertile and infertile – based on a chart review at the time of delivery.
Outcome Measure:
Perinatal outcomes of interest included mode of delivery, gestational age at delivery, and birth weight.
Results:
A total of 3293 mother/infant dyads fulfilled the inclusion criteria. Of these, 277 women(8.4%) were classified as infertile. Infertile women were significantly older than fertile women. In bivariate analyses, infertile women were more likely to undergo cesarean delivery (51.8% vs. 36.1%, P<0.001) and deliver at an earlier gestational age (38.9±2.3 vs. 39.4±1.7 weeks, P<0.0001). Infertility was no longer significantly associated with cesarean delivery after adjusting for maternal age. Infertility remained associated with an earlier gestational age at delivery after adjusting for maternal age and maternal race (β coefficient −0.42, 95% CI −0.64, −0.2). There was no difference in infant birth weight. Late preterm deliveries (34 – 36 completed gestational weeks) accounted for 8.3% of deliveries for infertile women compared to 4.3% for fertile women (P=0.032).
Conclusions:
We conclude that the increased risk of cesarean section associated with infertility is driven by maternal age. Late preterm infants represent a key cohort for further evaluation in the perinatal outcomes of infertile women.
Keywords: infertility, IVF, assisted reproductive technology, preterm births
Introduction
Approximately 15% of couples experience infertility and fertility treatments are on the rise, with in vitro fertilization (IVF) contributing to 1.5% of live births in the United States and non-IVF fertility treatment (NIFT) contributing 4.61,2. NIFT includes ovulation induction agents such as clomiphene citrate, letrozole, gonadotropin hormone injections, and/or intrauterine inseminations. Multiple studies have focused primarily on IVF perinatal outcomes such as preterm delivery3, low birth weight4–6, and congenital defects7–10. Fewer studies have examined non-IVF treatment (NIFT) conceptions. A recent study demonstrated that in singletons, any fertility treatment including IVF, ovarian stimulation, and intrauterine insemination, was associated with preterm birth and low birth weight compared to women who did not use any fertility treatment11.
Although prematurity accounts for 12% of all births, over 36% of IVF infants and approximately 12% of NIFT conceptions are born premature12,13. More recently, the Institute of Medicine (US) Committee on Understanding Premature Birth coined the term “late preterm” for infants delivered between 34 and 36 6/7 weeks gestation 14. Late preterm infants make up nearly 75% of all preterm births15 and 20% to 25% of NICU admissions in the United States. Compared to full-term infants, late preterm infants are at increased risk for neonatal mortality and morbidity 14,16–18, and morbidity continues into childhood development19–22. The contribution of IVF/NIFT to late preterm births relative to early preterm births is not known.
In this study, we aim to investigate perinatal outcomes in a cohort of fertile and infertile nulliparous women at our center over a one year time period.
Materials and Methods
In this IRB-approved retrospective cohort study (Pro00031384), we reviewed the charts of all nulliparous women delivering singletons ≥24 weeks gestation at Cedars-Sinai Medical Center from January 1, 2012 through December 31, 2012. Data from the electronic medical records were abstracted for documentation of infertility and fertility treatment by extensive review of prenatal records, hospital admission notes, discharge summaries, and genetic counseling notes. This abstraction process has been described previously23. Fertility treatments were classified as IVF or NIFT, such as clomiphene citrate, gonadotropin injections, or intrauterine inseminations. The scanned prenatal record was found to be the most common source for infertility diagnosis and fertility treatment information at our institution. Preconception and prenatal care records, including genetic counseling notes and actual fertility treatment processes, were available in the electronic medical records for only a subset of patients (<50%). We did not review treatment records from outside fertility clinics. Patients were classified as infertile if the chart had provider documentation of infertility and/or use of fertility treatment. All remaining patients were classified as fertile. Data was also abstracted for socio-demographic variables, mode of delivery, gestational age at delivery, and infant birth weight.
Standard descriptive statistics were utilized to compare baseline characteristics between the infertile and fertile group. Multivariate regression models were performed to determine the independent association of infertility with outcomes of cesarean delivery and gestational age at delivery. A subset analysis of late preterm infants, delivered between 34 and 36 completed gestational weeks, was conducted. Indication for late preterm delivery was classified as 1) labor or rupture of membranes, 2) maternal indications, including hypertensive disorders (ie. preeclampsia) and placentation disorders (ie. placenta previa), and 3) fetal indications, including intrauterine growth restriction and non-reassuring fetal testing (ie. by fetal heart monitor or oligohydramnios). We also performed a sensitivity analysis to include only infertile patients who conceived with fertility treatment and fertile patients who conceived spontaneously. All analyses were performed using Stata IC 13.1 (College Station, Texas).
Results
A total of 3293 mother/infant dyads fulfilled the inclusion criteria. Of these, 277 women (8.4%) were classified as infertile. Infertile women were significantly older than fertile patients (37.4±5.3 vs. 31.5±5.3 years, P<0.0001) (Table 1). Of the infertile women, 68 (24.5%) did not have documented fertility treatment, and may represent cases of subfertility. Of the fertile patients, 8 (0.26%) had documented fertility treatment, and may represent cases in which fertility treatment was not performed for infertility (ie. IVF for single gene defects or donor inseminations). In bivariate analyses, infertile patients had a higher prevalence of cesarean delivery (51.8% vs. 36.1%, P<0.001), and also delivered at an earlier gestational age (38.9±2.3 vs. 39.4±1.7 weeks, P<0.0001). There was no difference in infant birth weight.
Table 1.
Baseline characteristics
| Infertile N=277 | Fertile N=3016 | P-value | |
|---|---|---|---|
| Maternal Age, years | 37.4±5.3 | 31.5±5.3 | <0.0001 |
| Maternal Race, n(%) | 0.023 | ||
| White | 193 (69.9) | 2066 (68.8) | |
| Black- or African-American | 16 (15.8) | 287 (9.6) | |
| Asian or Asian-American | 49 (17.8) | 391 (13.0) | |
| Other | 18 (6.5) | 260 (8.7) | |
| BMI, kg/m2 | 23.3±4.6 | 23.0±4.6 | 0.3211 |
| Mode of Conception, n(%) | <0.0001 | ||
| IVF | 136 (49.1) | 4 (0.13) | |
| NIFT | 73 (26.4) | 4 (0.13) | |
| Presumed Spontaneous | 68 (24.5) | 3008 (99.7) | |
| Cesarean Delivery, n(%) | 142 (51.8) | 1078 (36.1) | <0.001 |
| Gestational age, weeks | 38.9±2.3 | 39.4±1.7 | <0.0001 |
| Birth weight, gramsc | 3268±634 | 3317±510 | 0.1378 |
In multivariate logistic regression analyses, infertility was no longer significantly associated with cesarean delivery after adjusting for maternal age, maternal race, and gestational age at delivery (Odds Ratio 1.24, 95% CI 0.95–1.62).
In multivariate linear regression analyses, infertility remained associated with an earlier gestational age at delivery after adjusting for maternal age and maternal race (β coefficient −0.42, 95% CI −0.64, −0.2). To further explore this, we compared the prevalence of preterm, late preterm, early term, and term deliveries between infertile and fertile women (Table 2). Preterm deliveries (<34 completed gestational weeks) accounted for 2.9% of deliveries for infertile women compared to 1.3% for fertile women (P=0.032), while late preterm deliveries (34 – 36 completed gestational weeks) accounted for 8.3% of deliveries for infertile women compared to 4.3% for fertile women (P=0.003) (Table 2). Of the 200 preterm and late preterm infants, indication for delivery (rupture of membranes/labor, maternal indications, or fetal indications) did not differ between infertile and fertile women (P=0.28).
Table 2.
Infertility and Gestational Age at Delivery
| Infertile N=277 | Fertile N=3016 | P value | |
|---|---|---|---|
| <34 weeks | 8 (2.9) | 39 (1.3) | 0.0321 |
| 34– 36 6/7 weeks | 23 (8.3) | 130 (4.3) | 0.0032 |
| 37–38 6/7 weeks | 58 (20.9) | 536 (17.8) | 0.193 |
| ≥39 weeks | 188 (67.9) | 2311(76.6) | 0.0014 |
Chi square test compares deliveries <34 weeks to all deliveries ≥ 34 weeks between infertile and fertile women
Chi square test compares deliveries 34 – 36 6/7 weeks to all other deliveries between infertile and fertile women
Chi square test compares deliveries 37 – 38 6/7 weeks to all other deliveries between infertile and fertile women
Chi square test compares deliveries ≥39 weeks to all other deliveries between infertile and fertile women
In a sensitivity analysis that included only infertile patients who conceived with fertility treatment and fertile patients who conceived spontaneously, our results were unchanged.
Discussion
Our study demonstrates that women with a history of infertility are more likely to undergo cesarean delivery due to maternal age and deliver at an earlier gestational age. More notably, women with infertility are more likely to deliver a late preterm infant than women without documented infertility. This is the first study to focus on the contribution of infertility on late preterm births, and carries significant implications given the possible neonatal and childhood morbidities associated with late preterm infants.
The association between infertility and cesarean delivery is not surprising as the association is driven primarily by maternal age and the association is no longer significant after adjusting for maternal age24. We previously showed that among very advanced maternal age pregnancies, those who conceive by IVF had a two-fold increased risk of primary cesarean delivery compared to those who conceive spontaneously25. Indications for cesarean delivery included non-reassuring fetal heart rate, failure to progress, and elective procedure. Further studies are needed to guide counseling in older women, independent of fertility status, regarding the factors which contribute to an increased risk of cesarean delivery. One of the strengths of this study is that it is from a single institution, resulting in less potential for bias based on practice patterns due to geographical differences.
Prior studies suggest that IVF pregnancies, even singletons, are associated with low birthweight and preterm deliveries4,26,27. However, to our knowledge, our findings are among the first to highlight that the majority of preterm births in infertile women are categorized as late preterm. Interestingly, our study did not show a difference in birth weight, contrary to some prior studies. This may be due to a limited sample size. However, our study supports a recent larger study of 93,443 singleton IVF births reported to the Society for Assisted Reproductive Technologies which demonstrated that birth weight percentiles per completed week of gestation for IVF singletons and the general population are comparable in the third trimester28. The effect of infertility and/or fertility treatment on early development remains to be determined. Although studies on late preterm infants suggest that they are at increased risk for neonatal mortality and morbidity14,16–18, it is unknown whether infertility adds a synergistic effect. A recent prospective cohort study concluded that children’s development through age 3 years was comparable regardless of infertility or infertility treatment29.
A limitation of this study is the possible misclassification of infertile and fertile women as not all fertility treatments are uniformly documented by providers. This underscores the urgent need for improved documentation on fertility and details of fertility treatment on a national level. Existing methods such as reporting fertility treatment on birth certificates in certain states are inadequate, with some studies demonstrating that the sensitivity of reporting IVF was only 27%.28 We attempted to address the issue of misclassification by performing an sensitivity analysis on infertile patients who conceived with treatment and fertile patients who conceived spontaneously, and we obtained consistent results.
We conclude that the increased risk of cesarean section associated with infertility is driven by maternal age. We also conclude that late preterm infants represent a key cohort for further evaluation in the perinatal outcomes of infertile women.
Acknowledgments
Financial Support: This work was supported by the NICHD under Grant R01 HD074368 [to M.D.P.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Disclosure Statement: The authors have no conflicts of interest to disclose.
Contributor Information
Erica T. Wang, Cedars-Sinai Medical Center.
Lauren Ramos, Cedars-Sinai Medical Center.
Nina Vyas, UCLA David Geffen School of Medicine.
Gaisu Bhasin, Cedars-Sinai Medical Center.
Charles F. Simmons, Cedars-Sinai Medical Center.
Margareta D. Pisarska, Cedars-Sinai Medical Center.
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