Our data show that fetal size is significantly smaller at delivery and in early gestation in singleton live-births from infertile women compared to fertile women. This is the first reported comparison of fetal size both in utero and at birth between infertile and fertile women. Furthermore, this is the first ART study to our knowledge utilizing propensity scores to reduce inherent bias in observational, non-randomized studies. Comparing pregnancies in patients with multiple infertility diagnoses, who require ovulation induction therapies and in vitro technology to women who conceive without any assistance, is difficult. Although a randomized controlled study would be ideal, such an approach is nearly impossible. While still with limitations associated with retrospective studies, the propensity score matching algorithm offers a stronger analytical approach than a regression analysis in this study. It balances population characteristics and controls both known and unrecognized confounding variables that would not otherwise be controlled for in unmatched patient cohorts.
The similar neonatal size findings in offspring from infertile women who conceived with IVF as compared to WMA suggest that the mechanisms underlying the infertility may have a larger impact on alterations in fetal growth than the use of ART. This study supports previous studies suggesting that reductions in birthweight and adverse fetal outcomes are more likely in women who report prolonged times to conception, and differences between ART and spontaneous conceptions disappear when siblings born to the same mother are compared.(23
The specific findings of this study also imply that differing aspects of embryonic and in utero
growth warrant further consideration. Important size discrepancies were found in both the first trimester and at delivery but not in the mid-gestation. Alterations in fetal development in the first trimester could be significantly influenced by the underlying mechanisms of infertility. Differences in CRL size between fertile and infertile groups appeared to be most represented by the OI treatment group which may be attributed to a selection bias, demonstrated by a larger proportion of PCOS and ovulatory dysfunction patients in this group. The lack of a difference in the IVF patients could be due different infertility diagnoses, enhanced growth in in vitro
culture systems, or a potential benefit of removing the oocyte from a negative follicular environment (14
) though these hypothesis generating findings warrant follow-up. Finally, we believe that there are also likely differences in patients and outcomes within the infertility cohort based on the underlying pathologic reason for the subfertility/infertility. This may explain some of the findings within the secondary infertility subgroup comparisons. Our cohort size was too small to perform the comparisons based on infertility diagnosis and this warrants further research. Regardless of the cause, size impairments during this critical time of fetal development and the potential catch-up growth in the second trimester could be predictive of long-term health and disease later in life as previously suggested.(31
Neonatal size differences at birth may be more of a placental-mediated mechanism of growth restriction. Whether the influence comes primarily from the underlying infertility or therapies on the trophectoderm of the embryo is largely unknown. Our matched comparisons demonstrate a reduction in birthweight and higher incidence of LBW infants in pregnant women with a history of infertility as compared to fertile women. We controlled for gestational ages and excluded frozen embryo transfers, both of which could influence alternate conclusions from similar studies.(37
) The higher prevalence of LBW in infertile women, especially those who underwent IVF, could be due to selection bias of patients who required IVF (i.e. diminished ovarian reserve) as compared to other therapies, or an additive technological or therapeutic impact on gamete and fetal health.(39
) This increase in LBW infants warrants further investigation since these rates are higher than the CDC’s reported prevalence (2002 report: 7.7%) of LBW infants in the US.(44
Ultimately one could argue that differences in neonatal weight at delivery in the range of 150–300 grams, while statistically significant, may not be clinically significant. Yet, similar differences in birthweight have been reported in epidemiologic studies highlighting the powerful influence of neonatal size differences on developmental origins of disease in later life including reports from the Dutch Famine, maternal tobacco use, and studies by David Barker of populations followed from birth to adulthood. (34
) Equally relevant to the findings in our study, some of these studies demonstrated that fetal effects in early pregnancy could have long lasting impacts on health in later life independent of birthweight differences.
Our study was limited by the inability to obtain complete historical information from the patients due to the retrospective design, such as time to conception in the fertile cohort and potential iatrogenic deliveries. Exclusionary and institutional selection criteria could increase selection bias in the study, yet the database includes patients from both tertiary care and affiliated community hospitals which improves generalizability. Specifically, inclusion of only fertile controls that had both a first and second trimester ultrasound could be inherently selecting a “higher risk” control group. However, use of first trimester ultrasound by our obstetric groups has become more routine over the last decade to confirm dating and viability and we excluded patients with a more concerning indication for first trimester ultrasound. Yet, if we do assume that this control group is at higher risk of adverse outcomes, especially due to a higher preterm birth rate found, we could postulate that the differences found between infertile women and a lower risk fertile control could be even greater. Lack of BMI and weight gain in pregnancy data could also have an unappreciated role in fetal size discrepancies. Finally, we attempted to include a well-matched geographically-similar fertile control group and utilized propensity scores to account for as much unrecognized bias as possible. Our inability to find a difference in birthweight between fertile women and infertile patients who conceived spontaneously is likely due to a lack of power due to smaller numbers of patients with infertility who present for therapy but conceive spontaneously during testing or between other treatments, though we cannot exclude a true finding. Finally while we feel that the pathologic processes that underlie infertility diagnoses have a key role in fetal/neonatal health, we still cannot completely exclude a role of these therapies of interest.
Practitioners and organizations must continue to monitor the outcomes of ART pregnancies, recognizing that the technology may not be the sole reason for adverse findings. An increasing number of couples will continue to pursue IVF for a multitude of reasons. The oldest offspring from IVF in the US are nearing the age of 30 and the health of this young generation warrants our attention.