By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships relevant to this field of study.
Women undergoing infertility treatment, particularly in vitro fertilization, are at higher risk of severe maternal morbidity, but the overall risk remains low.
Dayan N, Joseph KS, Fell DB, et al. Infertility treatment and risk of severe maternal morbidity: A propensity score-matched cohort study. CMAJ 2019;191:E118-E127.
Although it is known that infertility therapy increases the risk for the resulting fetuses, the extent to which infertility treatment predicts severe maternal morbidity is not as well appreciated. Canadian investigators examined the association between infertility treatment and severe maternal morbidity during pregnancy and the immediate postpartum period. They identified all live births and stillbirths at ≥ 20 weeks’ gestation (numbering 11,965 women with a pregnancy conceived through infertility treatment and 448,198 women with a spontaneously conceived pregnancy) in Ontario between April 1, 2006, and March 31, 2012, randomly selecting only one live birth per woman. The women who underwent infertility treatment were older and had higher incomes, and a greater percentage were nulliparous or pregnant with multiple pregnancies. Consequently, each pregnancy resulting after infertility treatment was matched with about five untreated pregnancies using a propensity score generated using all baseline characteristics in a logistic regression model, resulting in 11,546 pregnancies from infertility treatment and 47,553 untreated pregnancies.
Before propensity score matching, 387 pregnancies achieved through infertility treatment were affected by severe maternal morbidity or death (32.3 per 1,000) compared with 6,689 women with severe morbidity or death in the untreated group (14.9 per 1,000), for a crude relative risk (RR) of 2.17 (95% confidence interval [CI], 1.96-2.40). Using the propensity-matched cohort, severe maternal morbidity or death occurred in 356 infertility-treated pregnancies (30.8 per 1,000) and in 1,054 untreated pregnancies (22.2 per 1,000), resulting in an adjusted RR of 1.39 (95% CI, 1.23-1.56). Moreover, the absolute risk of severe morbidity or death related to infertility treatment was more pronounced in women ≥ 40 years of age (RR, 1.64; 95% CI, 1.25-2.16). Severe maternal morbidity or mortality occurred in 121 pregnancies achieved through noninvasive infertility treatment (defined as intrauterine insemination or ovulation induction alone) and 235 pregnancies achieved through invasive treatment (in vitro fertilization [IVF] with or without intracytoplasmic sperm injection; 21.7 and 39.3 per 1,000, respectively), for adjusted RRs of 0.98 (95% CI, 0.81-1.18) and 1.77 (95% CI, 1.54-2.03).
The most common individual indicators of severe maternal morbidity in pregnancies resulting from infertility treatment were severe postpartum hemorrhage (requiring transfusion of red blood cells or other interventions; adjusted RR, 1.70, 95% CI, 1.39-2.08), maternal admission to an intensive care unit (adjusted RR, 1.51; 95% CI, 1.17-1.94), and puerperal sepsis (adjusted RR, 1.54; 95% CI, 1.13-2.10). Of note is the fact that significant associations between infertility treatment and these three indicators of severe maternal morbidity were observed among pregnancies achieved through invasive treatment but not in pregnancies resulting following noninvasive treatment. The adjusted odds ratio (OR) for having three or more such indicators was 1.65 (95% CI, 1.18-2.30) among women who used infertility treatment compared to those who did not. Women who had invasive treatment had the highest OR for having three or more indicators of severe maternal morbidity (adjusted OR, 2.28; 95% CI, 1.56-3.33) compared to no association for noninvasive treatment (adjusted OR, 0.99; 95% CI, 0.57-1.72).
Commentary
Severe maternal morbidity and death are uncommon, but clearly do occur. This large, well-controlled Canadian cohort study suggests that women undergoing IVF are at somewhat higher risk, whereas women undergoing noninvasive infertility treatment are not at increased risk compared to women who conceive spontaneously. These data also are consistent with previous reports. In 2016, a retrospective study using data from 14,761 IVF pregnancies from U.S. centers collected by the Centers for Disease Control and Prevention reported that the adjusted RR for severe maternal morbidity was 2.3 (95% CI, 2.1-2.7) when comparing IVF pregnancies with pregnancies achieved without treatment.1 Another cohort study from Massachusetts compared women conceiving through assisted reproductive technologies (ART) with those who were subfertile, untreated, and pregnant. The authors found an increased risk of severe maternal morbidity among ART singletons for both vaginal deliveries (OR, 1.97; 95% CI, 1.30-3.00) and cesarean deliveries (OR, 1.75; 95% CI, 1.30-2.35).2 One other small study using data from a single center reported an increased risk of severe maternal morbidity related to infertility treatment (OR, 2.40; 95% CI, 1.10-5.23).3
Several studies have focused on fetal outcomes following infertility treatment. Using data from 1996-1997, investigators reported in 2002 that singleton infants born at ≥ 37 weeks’ gestation following IVF had a 2.6-fold (95% CI, 2.4-2.7) increased risk of low birth weight (≤ 2,500 g).4 Subsequently, a meta-analysis using data from 15 studies comprising 12,283 IVF and 1.9 million spontaneously conceived singletons reported that IVF singletons had significantly higher odds of perinatal mortality (OR, 2.2; 95% CI, 1.6-3.0), preterm delivery (OR, 2.0; 95% CI, 1.7-2.2), low birth weight (OR, 1.8; 95% CI, 1.4-2.2), very low birth weight (OR, 2.7; 95% CI, 2.3-3.1), and small for gestational age (OR, 1.6; 95% CI, 1.3-2.0) compared to the spontaneously conceived infants.5 More recently, a population-wide cohort study from a single Australian state conducted over 17 years including more than 308,000 births, with > 6,100 from assisted reproductive technologies, found that the ART mothers were more likely to have a stillbirth and to have singleton infants with lower mean birth weight — but were more often nulliparous, older, and of higher socioeconomic status.6 After multivariate adjustment for several potential confounders, the OR for birth defects in the ART infants (n = 513; 8.3%) was 1.28 (95% CI, 1.16-1.41) compared to the spontaneously conceived pregnancies (n = 17,546; 5.8%). When the ART pregnancies were examined in more detail, the risk was increased only in pregnancies resulting after IVF with intracytoplasmic sperm injection (OR, 1.57; 95% CI, 1.30-1.90). Pregnancies in women with infertility conceiving without ART had only a borderline increased risk of birth defects that was not significant (OR, 1.29; 95% CI, 0.99-1.68). This study has been criticized because the incidence of birth defects is higher than usually reported, but there is no consensus as to what defects to include in any study. Both the women undergoing ART and the controls were evaluated for defects in the same manner.
These data indicate that there are increased risks to both the mothers and infants of infertile women undergoing IVF. It is also important to recognize that the absolute risks must be small because there have been more than 6 million births worldwide and almost all the pregnancies and the resulting infants have been entirely normal. However, these increased risks for both the infants and the mothers indicate the need for heightened surveillance during pregnancy, labor, and following delivery. These are high-risk pregnancies and should be treated as such.
REFERENCES
- Martin AS, Monsour M, Kissin DM, et al. Trends in severe maternal morbidity after assisted reproductive technology in the United States, 2008-2012. Obstet Gynecol 2016;127:59-66.
- Belanoff C, Declerq ER, Diop H, et al. Severe maternal morbidity and the use of assisted reproductive technology in Massachusetts. Obstet Gynecol 2016;127:527-534.
- Wang ET, Ozimek J, Greene N, et al. Impact of fertility treatment on severe maternal morbidity. Fertil Steril 2016;106:423-426.
- Shieve LA, Meikle SF, Ferre C, et al. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731-737.
- Jackson RS, Gibson KA, Wu YK, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: A meta-analysis. Obstet Gynecol 2004;103:551-563.
- Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366:1803-1813.
