Epidemiology of Fertility Treatment Use Among U.S. Women with Liveborn Infants,1997

Abstract

Objective:

This study assessed reported use of assisted reproductive technology (ART) and other (non-ART) fertility treatments among a population-based sample and examined factors related to use.

Methods:

The data for this study were collected as part of the National Birth Defects Prevention Study (NBDPS), limited to women from the control group who delivered liveborn infants with no major birth defects. We described prevalence of the use of ART and clomiphene citrate (the most commonly used non-ART treatment) by demographic and lifestyle factors and examined associations among use of fertility treatments and pregnancy outcomes, timing of prenatal care initiation, and use of prenatal testing technologies.

Results:

Overall, 4.2% of women reported any type of maternal fertility treatment use; 1.0% reported ART use, 1.6% reported clomiphene citrate use without ART, and 1.7% reported other fertility treatments. Women who reported any fertility treatment type were more likely than women with an unassisted conception to be non-Hispanic white, >30 years of age, and more highly educated. Overall, women who reported ART use were more likely than women who reported unassisted pregnancy to have an amniocentesis; however, this association was no longer evident after adjustment for maternal age.

Conclusions:

Fertility treatment use and type of treatment vary by maternal characteristics. This information may be useful to inform a broad maternal and child health audience about the growing use of fertility treatments, including who is using the treatments and the choices they are making about prenatal care.

Introduction

According to the 2002 National Survey of Family Growth (NSFG), 12% of reproductive-aged women (15–44 years) in the United States reported ever using one or more infertility-associated services.¹ Services ranged from medical advice (6.1%), diagnostic tests (4.8%), and medical help to prevent miscarriage (5.5%) to specific infertility treatments, including ovulation induction medications (3.8%), surgery or other treatment for blocked fallopian tubes (0.7%), artificial insemination (1.1%), and assisted reproductive technology (ART) (0.3%). Nearly 2% of women reported using an infertility service during the previous year.¹

ARTs are defined as procedures in which both the egg and sperm are handled outside the body for the purpose of establishing pregnancy.² As both the use and success of ART have increased, the number of live births resulting from ART has increased from 20,840 infants born in 1996 to 54,656 born in 2006.² ART accounted for >1% of the total U.S. live births in 2006.² It is well documented that ART substantially increases the risk of multiple births (twins or higher order) and associated adverse outcomes.^2

–6 Studies also suggest that even among singleton pregnancies and births, ART procedures are associated with an increased risk of adverse outcomes, such as maternal complications,⁷ preterm birth and low birth weight,^5,7

–12 fetal/infant mortality,^10

–13 and birth defects.^14

–17 Although further research is needed to determine if there is a direct treatment effect or if the underlying mechanism is related to the infertility disorders that are treated with ART, accumulating evidence suggests that ART is associated with a range of risks for both the woman and the developing fetus.

Other (non-ART) fertility treatments include surgical procedures (e.g., tubal surgery, myomectomy, surgery for endometriosis), ovulation induction medications (e.g., clomiphene citrate and medications containing follicle-stimulating hormone [FSH]), and artificial insemination (sperm, but not eggs, is retrieved and transferred medically to the woman). It is well accepted that ovulation induction medications are associated with increased risk for multiple births,^18

–22 and limited studies also suggest associations with adverse perinatal outcomes in singletons.^18,23 Although the NSFG documents that lifetime use of non-ART treatments, especially ovulation induction medications, is more than 10 times higher than lifetime ART use,¹ the frequency of U.S. births actually conceived with non-ART treatments has been studied less, and adverse effects have not been well assessed.

The NSFG provides nationally representative data on basic demographic characteristics of women who have used both ART and non-ART treatments. The U.S. National ART Surveillance System (NASS) presents some further data on maternal age, parity, and infertility diagnoses among births conceived with ART. However, there are few population-based data on maternal periconceptional exposures and other prenatal characteristics associated with U.S. births conceived with ART. Additionally, there is no U.S. population-based tracking system of births resulting from non-ART treatments; thus, little is known about how the maternal profile for these births compares with that for ART births or births conceived unassisted. In the 2003 revision of the U.S. birth certificate, questions about fertility treatment use were added, including use of fertility-enhancing drugs and ART. Because this addition is relatively new, however, no comprehensive data have been reported using this resource.²⁴

Moreover, the literature is limited concerning prenatal care choices and practices, such as prenatal testing uptake, after successful use of ART and non-ART methods. As women get older, the risk for chromosomal abnormalities in the fetus increases; women seeking ART treatment are generally older and, therefore, at greater risk of having a child affected with a chromosomal disorder.^25,26 Yet recent studies in Germany, Denmark, and Lebanon demonstrated that despite their advanced age, women who used ART were significantly less likely than women who conceived unassisted to undergo invasive prenatal testing, such as amniocentesis or chorionic villus sampling (CVS).^27

–30 Further research is specifically needed on prenatal testing uptake after both ART and non-ART treatments among a population-based sample in the United States.

In this study, we assessed the reported use of ART and non-ART fertility treatments among a population-based sample of U.S. women delivering liveborn infants with no major birth defects. We examined demographic factors and periconceptional exposures related to the use of each type of fertility treatment. We also looked at prenatal care initiation and uptake of prenatal testing after fertility treatment use.

Materials and Methods

The data for this study were collected as part of the National Birth Defects Prevention Study (NBDPS). The general protocol for this study has been described previously.^31,32 Briefly, the NBDPS is an ongoing, population-based, case-control study that includes case infants with more than 30 types of major structural birth defects identified via 10 birth defects surveillance systems in Arkansas (statewide), California (region near Fresno), Georgia (metropolitan Atlanta), Iowa (statewide), Massachusetts (eastern counties), New Jersey (statewide), New York (western NY and the Hudson valley), North Carolina (19 central counties), Texas (varying regions, currently Health Service Region 11), and Utah (statewide). The purpose is to investigate possible genetic and environmental risk factors for birth defects. Infants with major birth defects (case infants) are identified through population-based birth defects surveillance systems; liveborn infants with no major birth defects (control infants) are randomly selected from birth certificates or birth hospitals from the same source populations as the case infants. Mothers are contacted 6 weeks to 24 months after their estimated date of delivery (EDD). If the mother agrees to participate in the study, a standardized telephone interview is administered in English or Spanish by a trained interviewer to ascertain specific exposures and behaviors throughout pregnancy and the 3 months before pregnancy. Detailed questions are asked about maternal and paternal demographic factors, pregnancy history, medication use, dietary details, drug and alcohol use, occupational exposures, and reproductive factors, such as use of fertility treatments.

This analysis was limited to mothers of liveborn infants with no major birth defects (control mothers) who completed the maternal interview and had an EDD between October 1, 1997, and December 31, 2004 (n = 5871). We examined fertility treatment use among this population, including ART and other (non-ART) treatments. We conducted separate analyses of mothers who reported use of clomiphene citrate because it is the most commonly prescribed ovulation induction medication and is generally the initial treatment for anovulatory infertile women.^19,21

Exposure to infertility treatments was determined from questions in the maternal interview. First, to determine if any fertility treatment was used, mothers were asked: Did you or (Baby's name)'s father take any medications or have any procedures to help you become pregnant? We focused this study on maternal exposures to fertility treatment. A positive response to the infertility screening question prompted more questions to ascertain what form of treatment the mother used. To ascertain fertility medication use, mothers were asked: In the 2 months before you became pregnant with (Baby's name), did you take any medications to help you become pregnant? If yes: What medications or injections did you take? If fertility medication was reported, a follow-up question was asked: From what month and year to what month and year did you take the medication? To ascertain fertility treatment procedures, mothers were asked: Did you have any other procedures to help you become pregnant with (Baby's name)? If yes: Which procedure(s) did you receive in the 2 months before (Baby's name) was conceived? If the mother reported using fertility procedures, she was asked: What was the date of the last cycle? Were donor egg(s), donor sperm, or donor embryo(s) used on (DATE)? Were frozen egg(s), frozen sperm, or frozen embryo(s) used on (DATE)? Mothers with a positive response indicating any use of ART treatment—which included in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT)—were classified in the ART category. Similarly, mothers with a positive response indicating any use of clomiphene citrate were classified in the clomiphene citrate category. Table 1 is a list of all reported fertility treatments. For the remaining analyses conducted, mutually exclusive exposure categories were created. For instance, if mothers reported use of clomiphene citrate for 1 month and ART for the following month, the mother was classified into the ART group. The number of reported exposures to other fertility medications and procedures (with no reported use of ART) was insufficient to study with reasonable statistical power. We defined unassisted conception as no fertility treatment use reported by the mother or father.

Table 1.

Fertility Treatments Reported by Mothers of Liveborn Infants with No Major Birth Defects in National Birth Defects Prevention Study, 1997–2004

	With ART ^b	Without ART
	n (%)	n (%)
Fertility treatment type ^a	n = 59	n = 5812
Maternal surgeries/procedures
Opening fallopian tubes^c	0	10 (0.2)
Surgery for endometriosis-associated infertility^c	2 (3.4)	7 (0.1)
Hysterosalpingogram/laparoscopy^c	0	9 (0.2)
Other surgeries^c	0	8 (0.1)
Artificial insemination (AI)^d	1 (1.7)	36 (0.6)
Maternal medications^d
Clomiphene citrate^e	8 (13.6)	93 (1.6)
Medications containing follicle-stimulating hormone (FSH)^f	40 (67.8)	39 (0.7)
Medications containing human chorionic gonadotropin (hCG)^g	32 (54.2)	28 (0.5)
Gonadotropin-releasing hormone (GnRH) agonists^h	37 (62.7)	15 (0.3)
Medications containing progesteroneⁱ	23 (39.0)	26 (0.4)
Gonadotropin-releasing hormone (GnRH) antagonists^j	2 (3.4)	0
Other medications used in conjunction with fertility therapies^k	5 (8.5)	14 (0.2)
Total number of mothers reporting any maternal fertility treatment^l	59	187 (3.2)
Paternal surgeries^c
Varicocele surgery	0	3 (0.1)
Vasectomy reversals	0	1 (0.0)
Other surgeries/procedures	2 (3.4)	2 (0.0)
Total reporting any maternal or paternal fertility treatment^l	59	193 (3.3)

Mother could report multiple types of fertility treatment, and all responses are included in this table. The treatments reported could be consecutive treatments for the same mother.

Reported ART treatments included 58 mothers who reported in vitro fertilization (IVF), 5 mothers who reported intracytoplasmic sperm injection (ICSI), and 1 mother who reported gamete intrafallopian transfer (GIFT).

Most recent treatment that occurred within 1 year prior to conception.

Treatment occurred within the 2 months prior to conception.

Clomiphene citrate is commonly administered to induce ovulation in women who do not ovulate regularly.

Medications containing FSH stimulate the ovaries to produce eggs.

Medications containing hCG are given to complete egg maturation and trigger ovulation.

GnRH agonists suppress the production of naturally produced hormones and allow for better control over ovarian stimulation (e.g., leuprolide).

Medications containing progesterone prepare the endometrium or uterine lining for pregnancy and help prevent early pregnancy loss.

GnRH antagonists suppress the natural production of pituitary hormones (e.g., cetrorelix).

Other medications reported include metformin (used in the treatment of polycystic ovary syndrome), bromocriptine (used to suppress the hormone prolactin, often in women with high prolactin levels due to polycystic ovary syndrome), tamoxifen (used to induce ovulation), and estradiol (used to stimulate the endometrium to prepare for implantation).

The denominator for these percentages is the total number of women who completed the maternal interview and delivered a liveborn infant with no major birth defects between October 1, 1997, and December 31, 2004 (n = 5871).

ART, assisted reproductive technology.

For this analysis, we described the prevalence of use of ART and clomiphene citrate by demographic factors and periconceptional exposures. Specific characteristics examined were maternal age, race and ethnicity, education, prepregnancy body mass index (BMI), tobacco use (any use 1 month before pregnancy through month 3 of pregnancy), alcohol use (any use 1 month before pregnancy through month 3 of pregnancy), state of residence, household income, plurality, maternal folic acid use (use 1 month prior to pregnancy through month 1 of pregnancy), preexisting diabetes, gestational diabetes, and maternal hypertension during pregnancy. Prepregnancy BMI was calculated from self-reported prepregnancy weight and height (weight in kg divided by height in m²). BMI was categorized according to NIH guidelines³³: underweight, <18.5; normal weight, 18.5–24.9; overweight, 25.0–29.9; and obese, ≥30.0. The presence of maternal hypertension was based on either maternal report of the condition or use of antihypertensive medications. All other factors listed were self-reported during the interview. For analyses involving maternal state of residence, Georgia was arbitrarily chosen as the referent group because it reflected the median percentage of unassisted births. To assess the prevalence of use of donor or frozen egg(s), sperm, or embryo(s) for ART treatments, we calculated the frequency of reported methods among women who reported ART use. We examined pregnancy outcomes, including maternal weight gain during pregnancy, infant birth weight, and gestational age at delivery, among singleton and multiple births. We calculated prevalence ratios using Poisson distribution to describe the patterns of fertility treatment use with respect to these characteristics.

We also compared timing of prenatal care initiation and use of prenatal testing technologies between mothers who used fertility treatments and those who did not. Timing of prenatal care initiation included trimester and month of pregnancy when prenatal care initiation was reported. Prenatal testing uptake was ascertained from questions regarding various prenatal tests (i.e., maternal serum screening, CVS, amniocentesis). Specifically, a mother was recorded as having a prenatal maternal serum screen if she had a positive response to the question: When you were pregnant with (Baby's name), did you have any of the following blood tests: maternal serum alpha fetoprotein or MSAFP, double screen, or triple screen? Additional prenatal testing questions included: Did you have an amniocentesis or amnio? Did you have chorionic villus sampling or CVS? Prevalence ratios using Poisson distribution were calculated to describe prenatal care initiation and uptake of prenatal testing by type of fertility treatment.

We also conducted a subgroup analysis by limiting the unassisted conception group to intended pregnancies. Women were asked: At the time that you became pregnant with (Baby's name), did you want to become pregnant then, did you want to wait until later, or did you not want to become pregnant at all? Mothers who responded “want to be pregnant then” were classified as having an intended pregnancy. We then examined maternal report of amniocentesis and folic acid use among women who reported ART or clomiphene citrate use, using the intended, unassisted pregnancy group as a comparison.

All statistical analyses were performed using SAS 9.1 (SAS Institute Inc, Cary, NC).

Results

Among 5871 women who completed the maternal interview and delivered a liveborn infant with no major birth defects between October 1, 1997, and December 31, 2004, 4.2% reported any use of fertility treatment by the mother. The participation rate among control mothers was 69% during this period. Mothers could report multiple types of fertility treatment, and all responses are included in Table 1. Fifty-nine women (1.0%) reported ART use. Of the women who reported ART treatment, 15.3% used donor eggs, 3.4% used donor sperm, 3.4% used frozen sperm, and 13.7% used frozen embryo. For non-ART treatments, 101 women (1.7%) reported clomiphene citrate use, 93 (1.6%) of whom reported clomiphene citrate without ART use. Additionally, 79 women (1.3%) reported use of an ovulation induction medication containing FSH, and 39 (0.7%) used an FSH medication without an accompanying ART treatment. The most frequent maternal surgery was opening the fallopian tubes (Table 1).

Variations in the type of fertility treatment used were observed for a number of demographic and periconceptional exposures (Table 2). As expected, plurality was strongly associated with both ART and clomiphene citrate; more than half of mothers reporting ART use had a multiple birth. Twins were much more likely for pregnancy established via both ART (prevalence ratio [PR] = 39.1, 95% confidence interval (CI) 22.8-67.0) and clomiphene citrate (PR = 6.3, 95% CI 3.4-11.9). Use of fertility treatments in all categories was more common among non-Hispanic whites than among other racial and ethnic categories, and it increased with maternal age. Women who reported use of clomiphene citrate were twice as likely to be categorized as obese compared with women who reported unassisted conception (PR = 2.1, 95% CI 1.3-3.5), but ART use was not associated with maternal obesity. Women who reported clomiphene citrate use were twice as likely as women who reported unassisted conception to report gestational diabetes (PR = 2.3, 95% CI 1.3-4.3), and both ART and clomiphene citrate were associated with primiparity. ART and clomiphene citrate were also strongly associated with higher maternal education and higher household income. Women who reported ART and clomiphene citrate use were significantly more likely to report folic acid use during the month before pregnancy through month 1 of pregnancy compared with women with unassisted conception (PR = 28.8, 95% CI 7.0-118.1 and PR = 12.3, 95% CI 5.7-26.6, respectively). When we limited analysis to intended, unassisted pregnancies, women who reported use of ART and clomiphene citrate were still significantly more likely to report folic acid use during the month before pregnancy through month 1 of pregnancy (PR = 20.0, 95% CI 4.9-82.0 and PR = 8.5, 95% CI 4.0-18.4, respectively). There was significant geographic variation: women residing in Massachusetts at delivery were 8 times more likely to report ART use than women residing in metropolitan Atlanta, Georgia (PR = 8.2, 95% CI 2.5-26.9). Use of clomiphene citrate was highest in Iowa and Massachusetts (Table 2).

Table 2.

Use of Fertility Treatments Among Mothers of Liveborn Infants with No Major Birth Defects, by Demographic and Lifestyle Factors, National Birth Defects Prevention Study, 1997–2004

	Unassisted conception (n = 5611)	Assisted reproductive technologies (n = 59)		Clomiphene citrate (n = 93)
Demographic factors	n (%)	n (%)	PR (95% CI)	n (%)	PR (95% CI)
Plurality
Singletons	5493 (97.9)	27 (45.7)	1.0 (ref )	80 (86.0)	1.0 (ref )
Twins	110 (2.0)	26 (44.1)	39.1 (22.8-67.0)	11 (11.8)	6.3 (3.4-11.9)
Triplets +	2 (0.0)	6 (10.2)	153.5 (63.4-371.8)	2 (2.2)	34.9 (8.6-141.8)
Missing	6 (0.1)	0		0
Maternal race
Non-Hispanic white	3306 (58.9)	51 (86.4)	1.0 (ref )	85 (91.4)	1.0 (ref )
Non-Hispanic black	657 (11.7)	3 (5.1)	0.3 (0.1-1.0)	3 (3.2)	0.2 (0.1-0.6)
Hispanic	1301 (23.2)	2 (3.4)	0.1 (0.0-0.4)	2 (2.2)	0.1 (0.0-0.3)
Other	327 (5.9)	3 (5.1)	0.6 (0.2-1.9)	3 (3.2)	0.4 (0.1-1.2)
Missing	20 (0.4)	0		0
Maternal age, years
<24	1955 (34.8)	0	—	5 (5.4)	0.2 (0.1-0.4)
25–29	1498 (26.7)	5 (8.5)	1.0 (ref )	25 (26.9)	1.0 (ref )
30–34	1425 (25.4)	23 (39.0)	11.0 (4.2-28.8)	39 (41.9)	1.6 (1.0-2.7)
35–39	626 (11.2)	20 (33.9)	21.4 (8.1-56.8)	19 (20.4)	1.8 (1.0-3.3)
40–44	98 (1.7)	9 (15.2)	58.2 (19.8-170.6)	5 (5.4)	3.0 (1.1-7.7)
≥45	9 (0.2)	2 (3.4)	125.7 (27.2-580.3)	0	—
Prepregnancy maternal BMI
Underweight (<18.5)	312 (5.6)	2 (3.4)	0.7 (0.2-2.7)	2 (2.2)	0.5 (0.1-2.0)
Normal (18.5–24.9)	3033 (54.1)	32 (54.2)	1.0 (ref )	43 (46.2)	1.0 (ref )
Overweight (25–29.9)	1193 (21.2)	16 (27.1)	1.4 (0.7-2.5)	24 (25.8)	1.5 (0.9-2.5)
Obese (≥30)	844 (15.0)	9 (15.3)	1.1 (0.5-2.3)	24 (25.8)	2.1 (1.3-3.5)
Missing	229 (4.1)	0		0
Parity
0	2199 (39.2)	34 (57.6)	1.0 (ref )	54 (58.1)	1.0 (ref )
1	1906 (34.0)	21 (35.6)	0.7 (0.4-1.2)	24 (25.8)	0.5 (0.3-0.8)
2 or more	1503 (26.8)	4 (6.8)	0.2 (0.1-0.5)	15 (16.1)	0.4 (0.2-0.7)
Missing	3 (0.1)	0		0
Maternal preexisting diabetes
No	5586 (99.6)	58 (98.3)	1.0 (ref )	93 (100.0)	1.0 (ref )
Yes	16 (0.3)	1 (1.7)	5.7 (0.8-41.3)	0	—
Missing	9 (0.1)	0		0
Maternal gestational diabetes
No	5273 (94.0)	56 (94.9)	1.0 (ref )	81 (87.1)	1.0 (ref )
Yes	329 (5.9)	3 (5.1)	0.9 (0.3-2.7)	12 (12.9)	2.3 (1.3-4.3)
Missing	9 (0.1)	0		0
Maternal high blood pressure during pregnancy
No	5084 (90.6)	51 (86.4)	1.0 (ref )	80 (86.0)	1.0 (ref )
Yes	518 (9.2)	8 (13.6)	1.5 (0.7-3.2)	13 (14.0)	1.5 (0.9-2.8)
Missing	9 (0.2)	0		0
Folic acid use (B1-P1)^a
No	2849 (50.8)	2 (3.4)	1.0 (ref )	7 (7.5)	1.0 (ref )
Yes	2762 (49.2)	57 (96.6)	28.8 (7.0-118.1)	86 (92.5)	12.3 (5.7-26.6)
Maternal education, years
≤12	2416 (43.1)	5 (8.5)	1.0 (ref )	13 (14.0)	1.0 (ref )
13–16	2719 (48.5)	38 (64.4)	6.7 (2.6-17.0)	64 (68.8)	4.3 (2.4-7.8)
>16	466 (8.3)	16 (27.1)	16.1 (5.9-44.0)	16 (17.2)	6.2 (3.0-12.9)
Missing	10 (0.2)	0		0
Household income
<$40,000	2930 (52.2)	6 (10.2)	1.0 (ref )	23 (24.7)	1.0 (ref )
≥$40,000	2087 (37.2)	48 (81.4)	11.0 (4.7-25.7)	65 (69.9)	3.9 (2.4-6.2)
Missing	594 (10.6)	5 (8.5)		5 (5.4)
Maternal Smoking (B1-P3)^b
No	4,512 (80.4)	57 (96.6)	1.0 (ref )	81 (87.1)	1.0 (ref )
Yes	1096 (19.5)	2 (3.4)	0.1 (0.0-0.6)	12 (12.9)	0.6 (0.3-1.1)
Missing	3 (0.1)	0		0
Maternal alcohol consumption (B1-P3)^b
No	3521 (62.8)	38 (64.4)	1.0 (ref )	61 (65.6)	1.0 (ref )
Yes	2065 (36.8)	20 (33.9)	0.9 (0.5-1.5)	31 (33.3)	0.9 (0.6-1.3)
Missing	25 (0.4)	1 (1.7)		1 (1.1)
State of maternal residence
Georgia	599 (10.7)	3 (5.1)	1.0 (ref )	8 (8.6)	1.0 (ref )
Arkansas	695 (12.3)	1 (1.7)	0.3 (0.0-2.8)	13 (14.0)	1.4 (0.6-3.4)
California	773 (13.8)	2 (3.4)	0.5 (0.1-3.1)	3 (3.2)	0.3 (0.1-1.1)
Iowa	618 (11.0)	7 (11.8)	2.3 (0.6-8.7)	19 (20.4)	2.3 (1.0-5.2)
Massachusetts	680 (12.1)	29 (49.1)	8.2 (2.5-26.9)	19 (20.4)	2.1 (0.9-4.7)
New Jersey	546 (9.8)	8 (13.6)	2.9 (0.8-10.9)	7 (7.5)	1.0 (0.3-2.6)
New York	504 (9.0)	5 (8.5)	2.0 (0.5-8.2)	6 (6.5)	0.9 (0.3-2.6)
North Carolina	275 (4.9)	3 (5.1)	2.2 (0.4-10.7)	5 (5.4)	1.4 (0.4-4.1)
Texas	671 (12.0)	1 (1.7)	0.3 (0.0-2.9)	6 (6.5)	0.7 (0.2-1.9)
Utah	250 (4.4)	0	—	7 (7.5)	2.1 (0.7-5.7)
Mother born in USA?
Yes	4511 (80.4)	53 (89.8)	1.0 (ref )	89 (95.7)	1.0 (ref )
No	1093 (19.5)	6 (10.2)	0.5 (0.2-1.1)	4 (4.3)	0.2 (0.1-0.5)
Missing	7 (0.1)	0		0

Any reported use 1 month before pregnancy through month 1 of pregnancy.

Any reported use 1 month before pregnancy through month 3 of pregnancy.

PR, prevalence ratio; CI, 95% confidence interval; BMI, body mass index.

Among singleton births, about 7% of the women who reported ART use and about 8% of women who reported clomiphene citrate use reported low birth weight infants, compared with 5% of women who reported unassisted conception (PR = 1.6, 95% CI 0.4-6.8 and PR = 1.8, 95% CI 0.8-4.1, respectively); however, sample sizes were small, so the differences did not reach statistical significance (Table 3). Furthermore, among singletons, about 15% of the women who reported ART use and about 11% of women who reported clomiphene citrate use reported preterm delivery, compared with 8% of women who reported unassisted conception (PR = 2.0, 95% CI 0.7-5.7 and PR = 1.4, 95% CI 0.7-2.9, respectively).

Table 3.

Use of Fertility Treatments Among Mothers of Liveborn Infants with No Major Birth Defects, by Maternal Characteristics and Perinatal Outcomes, Stratified by Singleton vs. Multiple Births, National Birth Defects Prevention Study, 1997–2004

		Singletons
	Unassisted conception	Assisted reproductive technologies		Clomiphene citrate
	n = 5493	n = 27		n = 80
	n (%)	n (%)	PR ^a (95% CI)	n (%)	PR (95% CI)
Maternal weight gain during pregnancy, pounds
<25	1400 (25.5)	5 (18.5)	0.7 (0.2-2.0)	25 (31.3)	1.2 (0.7-2.1)
25–35	1930 (35.1)	10 (37.0)	1.0 (ref )	29 (36.2)	1.0 (ref )
>35	1941 (35.3)	11 (40.7)	1.1 (0.5-2.6)	24 (30.0)	0.9 (0.5-1.5)
Missing	222 (4.1)	1 (3.7)		2 (2.5)
Birth weight
Low birth weight (<2500 g)	251 (4.6)	2 (7.4)	1.6 (0.4-6.8)	6 (7.5)	1.8 (0.8-4.1)
Normal birth weight (2500–3999 g)	4636 (84.4)	23 (85.2)	1.0 (ref )	62 (77.5)	1.0 (ref )
Macrosomic (≥4000 g)	583 (10.6)	2 (7.4)	0.7 (0.2-2.9)	12 (15.0)	1.5 (0.8-2.8)
Missing	23 (0.4)	0		0
Gestational age
Term (≥37 weeks)	5053 (92.0)	23 (85.2)	1.0 (ref )	71 (88.8)	1.0 (ref )
Preterm (<37 weeks)	440 (8.0)	4 (14.8)	2.0 (0.7-5.7)	9 (11.2)	1.4 (0.7-2.9)
Missing	0	0		0

		Multiple birth
	Unassisted conception	Assisted reproductive technologies		Clomiphene citrate
	n = 112	n = 32		n = 13
	n (%)	n (%)	PR (95% CI)	n (%)	PR (95% CI)
Maternal weight gain during pregnancy, pounds
<25	19 (17.0)	5 (15.6)	1.1 (0.4-3.3)	3 (23.1)	1.7 (0.3-8.3)
25–35	29 (25.9)	8 (25.0)	1.0 (ref )	3 (23.1)	1.0 (ref )
>35	59 (52.7)	19 (59.4)	1.3 (0.6-2.9)	7 (53.8)	1.3 (0.3-5.1)
Missing	5 (4.5)	0		0
Birth weight
Low birth weight (<2500 g)	50 (44.6)	15 (46.9)	1.0 (0.5-2.1)	4 (30.8)	0.6 (0.2-2.0)
Normal birth weight (2500–3999 g)	59 (52.7)	17 (53.1)	1.0 (ref )	8 (61.5)	1.0 (ref )
Macrosomic (≥4000 g)	2 (1.8)	0	—	0	—
Missing	1 (0.9)	0		1 (7.7)
Gestational age
Term (≥37 weeks)	59 (52.7)	13 (40.6)	1.0 (ref )	6 (46.2)	1.0 (ref )
Preterm (<37 weeks)	53 (47.3)	19 (59.4)	1.5 (0.7-3.0)	7 (53.8)	1.3 (0.4-3.8)
Missing	0	0		0

PR, prevalence ratio; CI, 95% confidence interval.

The majority of all women in the study (86.4%) began prenatal care in the first trimester, but mothers who reported use of ART were 2.7 times more likely than women who reported unassisted conception to initiate prenatal care in the first month of pregnancy (Table 4). Uptake of prenatal testing differed depending on the test offered. There was no difference in use of maternal serum screen between women who reported use of ART or clomiphene citrate and those who did not. However, overall, women who reported ART or clomiphene citrate were more likely to have an amniocentesis (PR = 2.6, 95% CI 1.4-5.0 and PR = 1.7, 95% CI 0.9-3.0, respectively) compared with women who reported unassisted conception. Further analysis revealed that all the mothers who reported ART use and amniocentesis were ≥35 years of age at delivery, and when we limited our analyses to women <35 years or women ≥35 years of age, neither ART nor clomiphene citrate was associated with amniocentesis. Among intended pregnancies, women who reported ART use were twice as likely to have an amniocentesis (PR = 2.1, 95% CI 1.1-4.0), but again, when we stratified this subgroup by maternal age, no association between fertility treatment and amniocentesis was observed (data not shown).

Table 4.

Prenatal Care and Prenatal Testing Uptake Reported by Mothers of Liveborn Infants with No Major Birth Defects, by Fertility Treatment Type, National Birth Defects Prevention Study, 1997–2004

	Unassisted conception (n = 5611)	Assisted reproductive technologies (n = 59)		Clomiphene Citrate (n = 93)
	n (%)	n (%)	PR (95% CI)	n (%)	PR (95% CI)
Month of prenatal care initiation
First	937 (16.7)	21 (35.6)	2.7 (1.5-4.9)	21 (22.6)	1.2 (0.7-1.9)
Second	2391 (42.6)	23 (39.0)	1.0 (ref )	52 (55.9)	1.0 (ref )
Third	1499 (26.7)	13 (22.0)	1.1 (0.5-2.1)	16 (17.2)	0.6 (0.3-1.0)
Fourth	368 (6.6)	2 (3.4)	0.7 (0.2-2.8)	2 (2.2)	0.3 (0.1-1.2)
Fifth or later	221 (3.9)	0	—	0	—
No prenatal care	54 (1.0)	0	—	0	—
Missing	141 (2.5)	0		2 (2.2)
Maternal serum screen^a
No	2251 (40.1)	28 (47.5)	1.0 (ref )	46 (49.5)	1.0 (ref )
Yes	2740 (48.8)	28 (47.5)	0.8 (0.5-1.4)	43 (46.2)	0.8 (0.5-1.2)
Missing	620 (11.1)	3 (5.0)		4 (4.3)
Chorionic villus sampling
No	5423 (96.7)	56 (94.9)	1.0 (ref )	93 (100.0)	—
Yes	116 (2.1)	2 (3.4)	1.7 (0.4-6.8)	0	—
Missing	72 (1.3)	1 (1.7)
Amniocentesis
No	5101 (90.9)	47 (79.7)	1.0 (ref )	80 (86.0)	1.0 (ref )
Yes	485 (8.7)	12 (20.3)	2.6 (1.4-5.0)	13 (14.0)	1.7 (0.9-3.0)
Missing	25 (0.4)	0		0
Amniocentesis among mothers ≥35 years at delivery	n = 733	n = 31		n = 24
No	465 (63.4)	19 (61.3)	1.0 (ref )	13 (54.2)	1.0 (ref )
Yes	268 (36.6)	12 (38.7)	1.1 (0.5-2.2)	11 (45.8)	1.4 (0.6-3.2)
Amniocentesis among mothers <35 years at delivery	n = 4853	n = 28		n = 69
No	4636 (95.5)	28 (100.0)	—	67 (97.1)	1.0 (ref )
Yes	217 (4.5)	0	—	2 (2.9)	0.6 (0.2-2.6)
Missing	25 (0.5)

Includes maternal serum alpha fetoprotein (MSAFP), double screen, and triple screen.

PR, prevalence ratio; CI, 95% confidence interval.

Discussion

Our study reported population-based estimates of the frequency of use of both ART and non-ART fertility treatments among mothers of liveborn infants. In this study, about 1% of mothers of liveborn infants reported use of ART; this finding is consistent with the CDC estimate that ART accounts for about 1% of total U.S. live births.² Previous data on the frequency of use of other (non-ART) fertility treatments are limited. In our study, 1.6% of mothers reported use of clomiphene citrate (without ART), and 1.7% reported use of other non-ART fertility treatments (other than ART and clomiphene citrate).

Using a population-based sample of women who delivered liveborn infants with no major birth defects, we found that some periconceptional exposures and demographic factors were related to fertility treatment use. Mothers who reported any fertility treatment type were more likely to be non-Hispanic white, to be >30 years of age, to have completed more than 12 years of education, to have a household income of at least $40,000, and to not smoke during the time period of 1 month before pregnancy through month 3 of pregnancy. Women who reported clomiphene citrate use were more likely to be obese compared with women who reported unassisted conception. In this study, more than half of the mothers who reported ART use (54.3%) reported a multiple birth. Consistent with this estimate, CDC reported that in 2006, 48% of infants born through ART were born in multiple-birth deliveries.³⁴

In our study, use of ART varied according to maternal residence. Our findings are influenced by the particular regions included in the study. For example, the California study center, which had one of the lowest prevalences of ART use, is in the largely rural, agricultural Central Valley region of the state. Differences in geographic distribution are also likely due to differing insurance coverage among the states in the study. For example, Massachusetts, which had the highest prevalence of reported ART use, has laws requiring insurance agencies that cover pregnancy-related benefits to include comprehensive coverage for fertility services, including coverage of artificial insemination and ART treatments after 1 year of infertility.^35
–37 Arkansas, California, New Jersey, New York, and Texas also mandate agencies to offer or cover infertility-associated services, but they require less comprehensive coverage than Massachusetts. The remaining states in the study—Georgia, Iowa, North Carolina, and Utah—do not mandate coverage for infertility services.^35
–37 Previous studies have shown that state mandates that require insurance companies to offer or cover infertility-associated services cause increased use of these services; however, these mandates have had little impact on racial, ethnic, and educational disparities related to fertility treatment use.^35,38,39

The percentage of live births resulting from ART use was lower in the United States than in European countries.⁴⁰ In a 2004 report by the European Society of Human Reproduction and Embryology (ESHRE), the percentage of liveborn infants attributable to ART use ranged from 0.2% in Latvia to 4.2% in Denmark.⁴⁰ The majority of countries that reported percentages >1% publicly fund infertility treatment and have various government regulations in place to guide treatment practices.^41,42 Comprehensive coverage is associated with greater use of services, fewer embryos transferred per cycle, fewer higher-order pregnancies, and fewer multiple births.⁴³ Thus, the higher percentage of live births from ART use observed in some European countries is likely a result of federal funding for these services.

Among women who reported clomiphene citrate use, the prevalences of obesity and diabetes were twice as high as among women who reported unassisted pregnancies. Glucose intolerance and overweight and obesity are hallmark features of anovulatory infertility and polycystic ovary syndrome (PCOS).^44,45 Clomiphene citrate is a first-line treatment for infertility among women with PCOS⁴⁶; therefore, these results were not surprising and support the validity of our assessment.

In the United States, literature about prenatal testing uptake after use of fertility treatment has been scarce. In our study, prenatal testing uptake varied according to the test offered. Reported prevalence of amniocentesis among women who reported ART use was significantly higher than among women who reported unassisted conception. However, when we stratified by maternal age, no significant associations were observed for amniocentesis with ART use among women <35 years or women ≥35 years of age. Similarly, a U.S. study by Elimian et al.⁴⁷ found no significant differences in the acceptance of amniocentesis among women who reported IVF pregnancies compared with those who reported spontaneous conception. Our findings differed from those of previous international studies, however, that found reduced acceptance of invasive prenatal testing and preference for noninvasive screening after ART treatment.^27

–30 In a clinical sample of women who conceived with ART in Germany, only 17% opted for invasive prenatal tests, even though more than half had an indication for prenatal karyotyping independent of their ART, and most had received genetic counseling.³⁰

Many factors may affect the decision to undergo prenatal testing: maternal education, socioeconomic status, insurance coverage, church membership, and race and ethnicity.^47

–52 Until recently, the American College of Obstetricians and Gynecologists limited the recommendation of whom should be offered invasive diagnostic prenatal testing to women aged ≥35 years.⁵³ This recommendation could explain our finding that among women who reported ART, amniocentesis was reported only among women ≥35 years. An alternate explanation could be the increasing use of preimplantation genetic diagnosis (PGD). Currently, there are no comprehensive population-based data about PGD practices in the United States; however, PGD has been viewed as an acceptable alternative to invasive prenatal testing and may have an impact on rates of amniocentesis and CVS among women who use ART.^54
–56 Such factors as differences in healthcare practices relating to differential use of prenatal screening or CVS and differences in women's cultural values and religious beliefs could also contribute to the different findings observed for acceptance of amniocentesis in our study compared with studies from other countries.

The findings from this study should be interpreted with certain limitations in mind. Because mothers were asked to recall exposures retrospectively and the timing of the interview after delivery varied, inaccurate recall may have caused misclassification of exposures. We may have underestimated fertility treatment use because only liveborn infants were included (fetal deaths were not), and we excluded infants with birth defects. Because of small numbers for other reported fertility treatments, we were only able to include ART and clomiphene citrate in our analysis at this time. Another limitation is that we only had information on control mothers who participated in the NBDPS interview. A recent analysis by Cogswell et al.⁵⁷ suggests that differences observed between NBDPS control participants and the base population were associated with participation rather than selection because only small differences were observed between the base population and selected control mothers. This study also only used data from 10 state birth defects surveillance systems and might not be generalizable to other states or the United States as a whole. The data from the six study centers that are not statewide are not representative of their entire state; however, Cogswell et al.⁵⁷ found that the controls in the NBDPS are representative of their base population and all U.S. live births with respect to paternal and maternal age, maternal smoking status, and maternal diabetes. The control participants did differ slightly from their base population and all U.S. live births with regard to maternal race/ethnicity, education, and trimester when prenatal care began.⁵⁷

Conclusions

This study provides a population-based estimate of fertility treatment use in the United States, including both ART and non-ART treatments. Overall, 4.2% of mothers of liveborn infants reported use of fertility treatment, with about 1% who reported ART use and about 1.6% who reported clomiphene citrate use. Factors related to any type of fertility treatment use include maternal age, race and ethnicity, household income, and education; additional factors related to ART and clomiphene citrate use include maternal state of residence and maternal prepregnancy BMI, respectively. This analysis also provides important data on prenatal care choices and prenatal testing practices after successful use of ART and non-ART methods. This information may be useful to inform a broad maternal and child health audience about the growing use of fertility treatments, including who is using the treatments and how they are making choices about prenatal care.

Footnotes

Acknowledgments

We thank all collaborators from the Centers for Birth Defects Research and Prevention in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah for their significant contributions. We also thank the families that participated in the NBDPS. This project was supported in part by an appointment to the Research Participation Program for the Centers for Disease Control and Prevention administered by the Oak Ridge Institute for Science and Education through an agreement between the Department of Energy and CDC. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

K.N.D. was supported by an appointment to the Research Participation Program for the Centers for Disease Control and Prevention administered by the Oak Ridge Institute for Science and Education through an agreement between the Department of Energy and CDC.

Disclosure Statement

The authors have no conflicts of interest to report.

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Epidemiology of Fertility Treatment Use Among U.S. Women with Liveborn Infants,1997–2004

Abstract

Objective:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Results

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References