Background
Oocyte donation is a well established-widely applied infertility treatment for women with premature idiopathic, iatrogenic and even natural menopause, with more than 30.437 cycles per year being performed in Europe during 2012 [
1]. Previous studies have reported an association between oocyte-donation pregnancies and an increased occurrence of hypertensive disorders of pregnancy [
2‐
9], gestational diabetes [
10], placental abnormalities [
9,
11,
12], preterm delivery [
2,
4,
11‐
13], prolonged maternal hospitalization after delivery and increased prevalence of caesarean section [
4,
7,
13].
Regarding neonatal complications, the outcomes seem to be overall reassuring especially among singleton deliveries. The prevalence of major congenital malformations [
6,
10] as well as the Apgar score [
2,
4,
6] were noted to be comparable to that in the general population. However conflicting findings have been reported regarding neonatal hospital stay [
2,
14,
15], birthweight [
2,
4,
5,
9,
15,
16], rate of low birthweight (i.e. birthweight <2500 gr) [
4,
5,
9,
17] and small for gestational age (SGA) infants [
5,
15,
16]. In fact, in the recent meta-analysis by Adams et al. [
18] the significant findings include being born with low birthweight (<2500 g), very low birthweight (<1500 g), preterm (<37
th week), with lower gestational age and preterm with low birthweight when compared with autologous oocyte counterparts. Some of the unfavorable outcomes have previously been attributed mostly to advanced maternal age, as well as the presence of multifetal pregnancies and prematurity as a consequence [
13,
18].
Prompted by the observations mentioned above, we aimed to examine if medically indicated oocyte donation is associated with increased risk for adverse neonatal outcomes in singleton pregnancies in a population of relatively young and healthy oocyte recipients in Sweden and whether this is affected by treatment indication.
Results
The maternal baseline characteristics of the Index and Control women are presented in Table
1. Oocyte recipients have a more advanced age compared to Comparison group B, are more often overweight or obese and deliver more often by cesarean section compared to both Comparison groups (Table
1).
Neonatal outcomes are presented in Tables
2 and
3 where infants of oocyte recipients are compared to infants who were conceived spontaneously and after conventional IVF, respectively. Regarding perinatal mortality, one neonatal death associated to chromosome deletion occurred within the Index group; the infant was delivered in the 34
th gestational week and died shortly after. No associations were found between groups regarding the prevalence of congenital malformations, neonatal jaundice, hypoglycemia, LGA diagnosis and ten-minute Apgar score. To note, no difference was observed regarding the length of neonatal hospital stay after birth between Index and Comparison groups; the latter did not differ even after studying a subgroup of solely non-healthy children (data not shown).
Table 2
Neonatal outcomes of infants conceived through oocyte donation (Index group) or conceived spontaneously (Comparison group A)
| Index group | Comparison group A | | |
| Median (IQR) | Range | Median (IQR) | Range | |
Gestational length | 40 (4) | 28–42 | 40 (3) | 28–43 | | |
Head circumference, cm | 35 (3) | 25–38 | 35 (2) | 25–40 | | |
Birth Length, cm* | 50 (3.5) | 39–54 | 51 (3) | 32–56 | | |
Birth Length term infants, cm | 50 (4) | 45–54 | 51 (3) | 42–56 | | |
Birthweight, grams* | 3238 (840) | 1105–4910 | 3495 (693) | 730–5800 | | |
Birthweight term infants, grams | 3380 (795) | 2284–4910 | 3512 (668) | 2200–5800 | | |
| n | % | n | % | Unadjusted OR (95 % CI) | Adjusteda OR (95 % CI) |
Perinatal death (<7 days after birth) | 1/76 | | 0/149 | | | |
Congenital malformationa |
No | 68/72 | 94.4 | 134/139 | 96.4 | 1.58 | 1.37 |
Yes | 4/72 | 5.6 | 5/139 | 3.6 | (0.41–6.06) | (0.23–8.14) |
5 min Apgar sa |
≥7 | 70/75 | 93.3 | 148/149 | 99.3 | 10.57 | 7.01 |
<7 | 5/75 | 6.7 | 1/149 | 0.7 | (1.21–92.20) | (0.40–123.43) |
10 min Apgar s |
≥7 | 74/75 | 98.7 | 148/148 | 100.0 | – | – |
<7 | 1/75 | 1.3 | 0 | 0.0 |
Asphyxiaa |
No | 70/76 | 92.1 | 145/149 | 97.3 | 3.11 | 2.49 |
Yes | 6/76 | 7.9 | 4/149 | 2.7 | (0.85–11.37) | (0.52–12.00) |
Preterm delivery (<37w)b |
No | 63/76 | 82.9 | 137/149 | 91.9 | 2.36 | 2.24 |
Yes | 13/76 | 17.1 | 12/149 | 8.1 | (1.02–5.45) | (0.87–5.81) |
LGAb |
No | 74/75 | 98.7 | 145/149 | 97.3 | 0.49 | 0.32 |
Yes | 1/75 | 1.3 | 4/149 | 2.7 | (0.05–4.46) | (0.03–3.46) |
SGAb |
No | 69/75 | 92.0 | 146/149 | 98.0 | 4.23 | 3.39 |
Yes | 6/75 | 8.0 | 3/149 | 2.0 | (1.03–17.42) | (0.59–19.69) |
Low birthweighta |
<2500 gr | 8/76 | 10.5 | 8/149 | 5.4 | 2.07 | 0.65 |
≥2500 gr | 68/76 | 89.5 | 141/149 | 94.6 | (0.75–5.76) | (0.10–4.30) |
Jaundicea |
No | 74/76 | 97.4 | 146/149 | 98.0 | 1.32 | 1.62 |
Yes | 2/76 | 2.6 | 3/149 | 2.0 | (0.22–8.05) | (0.23–11.68) |
Hypoglycemiaa |
No | 73/76 | 96.1 | 145/149 | 97.3 | 1.49 | 1.74 |
Yes | 3/76 | 3.9 | 4/149 | 2.7 | (0.33–6.83) | (0.25–12.03) |
Gender of the childa |
Boy | 39/76 | 51.3 | 71/149 | 47.7 | 0.86 | 0.85 |
Girl | 37/76 | 48.7 | 78/149 | 52.3 | (0.50–1.50) | (0.45–1.60) |
Infant Hospital stay, daysa |
0–2 | 41/68 | 60.3 | 102/139 | 72.3 | 1.72 | 1.13 |
≥3 | 27/68 | 39.7 | 39/139 | 27.7 | (0.94–3.17) | (0.56–2.31) |
Table 3
Neonatal outcomes of infants conceived through oocyte donation (Index group) or conceived through conventional IVF (Comparison group B)
| Index group | Comparison group B | | |
| Median (IQR) | Range | Median (IQR) | Range | | |
Gestational length | 40 (4) | 28–42 | 39 (2.3) | 36–42 | | |
Head circumference, cm | 35 (3) | 25–38 | 35 (3) | 30–38 | | |
Birth Length, cm | 50 (3.5) | 39–54 | 50 (3.3) | 44–56 | | |
Birth Length term infants, cm | 50 (4) | 45–54 | 50 (3) | 44–56 | | |
Birthweight, grams | 3238 (840) | 1105–4910 | 3545 (785) | 1985–5420 | | |
Birthweight term infants, grams | 3380 (795) | 2284–4910 | 3585 (743) | 1985–5420 | | |
| n | % | n | % | Unadjusted OR (95 % CI) | Adjusted OR (95 % CI) |
Perinatal death (<7 days after birth) | 1/76 | | 0/63 | | | |
Congenital malformationa | | | | | | |
No | 68/72 | 94.4 | 56/60 | 93.3 | 0.82 | 0.32 |
Yes | 4/72 | 5.6 | 4/60 | 6.7 | (0.20–3.44) | (0.05–2.05) |
5 min Apgar sa |
≥7 | 70/75 | 93.3 | 62/63 | 98.4 | 4.43 | 1.24 |
<7 | 5/75 | 6.7 | 1/63 | 1.6 | (0.50–38.94) | (0.11–14.18) |
10 min Apgar s |
≥7 | 74/75 | 98.7 | 61/61 | 100.0 | – | – |
<7 | 1/75 | 1.3 | 0 | 0.0 |
Asphyxia | | | | | | |
No | 70/76 | 92.1 | 63/63 | 100.0 | – | – |
Yes | 6 | 7.9 | 0 | 0.0 |
Preterm delivery (<37w)b |
No | 63/76 | 82.9 | 60/63 | 95.2 | 4.13 | 4.35 |
Yes | 13/76 | 17.1 | 3/63 | 4.8 | (1.12–15.21) | (1.08–17.52) |
LGAb |
No | 74/75 | 98.7 | 60/63 | 95.2 | 0.27 | 0.09 |
Yes | 1/75 | 1.3 | 3/63 | 4.8 | (0.03–2.67) | (0.01–1.06) |
SGAb |
No | 69/76 | 92.0 | 62/63 | 98.4 | 5.39 | 1.70 |
Yes | 6/76 | 8.0 | 1/63 | 1.6 | (0.63–46.04) | (0.16–17.72) |
Low birthweighta |
<2500 gr | 8/76 | 10.5 | 1/63 | 1.6 | 7.29 | 0.50 |
≥2500 gr | 68/76 | 89.5 | 62/63 | 98.4 | (0.89–59.99) | (0.02–13.81) |
Jaundicea |
No | 74/76 | 97.4 | 59/63 | 93.7 | 0.40 | 0.32 |
Yes | 2/76 | 2.6 | 4/63 | 6.3 | (0.07–2.25) | (0.04–2.44) |
Hypoglycemiaa |
No | 73/76 | 96.1 | 60/63 | 95.2 | 0.82 | 0.44 |
Yes | 3/76 | 3.9 | 3/63 | 4.8 | (0.16–4.22) | (0.07–2.90) |
Gender of the child |
Boy | 39/76 | 51.3 | 31/63 | 49.2 | 0.92 | 0.70 |
Girl | 37/76 | 48.7 | 32/63 | 50.8 | (0.47–1.79) | (0.32–1.52) |
Infant Hospital stay, daysa |
0–2 | 41/68 | 60.3 | 40/58 | 69.0 | 1.46 | 0.94 |
≥3 | 27/68 | 39.7 | 18/58 | 31.0 | (0.70–3.06) | (0.38–2.30) |
More specifically, mean birthweight and length differed between Index and Comparison group A as a whole [(3238 ± 840)
vs (3495 ± 693), (
p = 0.013) and (50 ± 3.5)
vs (51 ± 3), (
p = 0.011) respectively]; nevertheless no differences were noted among term infants (i.e. gestational length ≥37 weeks at birth) in these groups [(3380 ± 795)
vs (3512 ± 668), (
p = 0.126) and (50 ± 4)
vs (51 ± 3), (
p = 0.056) respectively] (Table
2). However when the effect estimate was evaluated more thoroughly in a logistic regression model, the effect size was found to be subtle (i.e. OR close to one) and disappeared after adjusting for gestational length (data not shown). Additionally, the Index group had a higher incidence of SGA diagnosis (8 %
vs 2 %,
p = 0.064) and prematurity (17.1 %
vs 8.1 %,
p = 0.041) in relation to Comparison group A. Moreover, neonates conceived after oocyte donation had more frequently five-minute Apgar score (AS) below 7 compared to spontaneously conceived infants (6.7 %
vs 0.7 %,
p = 0.017), a portion of which were also born preterm (4 out of 5 neonates conceived through OD). However, the risk for the above conditions did not remain statistically significant after adjustment for the covariates named previously (i.e. maternal age, maternal BMI, gestational age, delivery by cesarean section) (Table
2).
Regarding infants conceived through oocyte donation or autologous IVF, no differences were noted with respect to head circumference, birthweight and length, independently if infants were born at term or preterm (
p > 0.05) (Table
3). On the contrary, neonatal asphyxia (7.9 %
vs 0 %,
p = 0.032), low birthweight (<2500 gr) (10.5 %
vs 1.6 %,
p = 0.040) and prematurity (17.1 %
vs 4.8 %,
p = 0.031) were more frequently diagnosed among infants conceived through oocyte donation compared to Comparison group B; the above risks however did not differ after adjustment.
Finally, we compared the commonest neonatal outcomes after taking into account the medical indication of oocyte donation treatment. Our findings suggest that neonates born to women receiving treatment based on “other indication” have lower mean birthweight and length, as well as higher rate of SGA diagnosis, compared to neonates of women with diminished ovarian reserve or fertile women (Table
4). However no statistical difference is noted regarding birthweight and length when women with Turner syndrome are excluded from the “other indication” subgroup (data not shown). Five minute Apgar score below 7 (AS < 7 at 5 min) occurred more often on the “Diminished Ovarian Reserve” subgroup compared to “other indication of treatment” subgroup or Comparison group A (8.3 %
vs 5.9 %
vs 0.7 % respectively); a proportion of the latter can be associated to prematurity (i.e. preterm/total neonates with AS < 7 at 5 min: 2/3(66.7 %), 2/2(100 %) and 0/1(0 %) in each group respectively) (data not shown).
Table 4
Neonatal outcomes studied by indication of oocyte donation treatment compared to spontaneously conceived infants (Comparison group A)
| Comparison group A(CgA) | “Diminished ovarian reserve” subgroup (DOR) | ”OD other” subgroup (ODo) | p-value CgA vs DOR | p-value Cga vs ODo |
| n | (%) | n | (%) | n | (%) | | |
Congenital malformation | 5/139 | 3.6 % | 3/35 | 8.6 % | 1/32 | 3.1 % | 0.202 | 1.000 |
1 min Apgar s <7 | 9/149 | 6 % | 5/36 | 13.9 % | 4/34 | 11.8 % | 0.110 | 0.266 |
5 min Apgar s <7 | 1/149 | 0.7 % | 3/36 | 8.3 % | 2/34 | 5.9 % | 0.024 | 0.089 |
10 min Apgar s <7 | 0/148 | – | 0/36 | – | 1/34 | 2.9 % | – | 0.187 |
Preterm delivery (<37w) | 12/149 | 8.1 % | 6/37 | 16.2 % | 6/34 | 17.6 % | 0.133 | 0.090 |
SGA diagnosis | 3/149 | 2 % | 1/36 | 2.8 % | 5/34 | 14.7 % | 0.583 | 0.006 |
| Median (IQR) | Range | Median (IQR) | Range | Median (IQR) | Range | | |
Head circumference | 35 (2) | 25–40 | 35 (2.75) | 30–38 | 34.5 (4) | 27–38 | 0.792 | 0.107 |
Birthweight | 3472.5 (704) | 730–5800 | 3550 (913) | 2005–4910 | 3080 (801) | 1105–4670 | 0.458 | 0.004 |
Birthweight term infants | 3512 (668) | 2200–5800 | 3622.5 (931.3) | 2720–4910 | 3270 (686) | 2284–4670 | 0.898 | 0.034 |
Birth Length | 51 (3) | 32–56 | 50 (5) | 45–54 | 49 (3.25) | 39–54 | 0.662 | 0.001 |
Birth length term infants | 51 (3) | 42–56 | 51 (4.25) | 45–54 | 50 (2.75) | 45–54 | 0.832 | 0.011 |
Discussion
Our data suggest that neonates conceived through oocyte donation are more frequently born preterm (<37 weeks) and have a lower mean birthweight and length compared to infants conceived spontaneously. The somatic measurements are nonetheless improved among term infants independently of mode of conception. The results that are of borderline statistical significance indicate a notable trend but possibly reflect the limited sample size. Although our findings conform to those of previous published studies [
4‐
6], as well as with the latest and largest meta-analysis in the field [
18], one can still reflect on the clinical significance of such subtle birthweight differences. It seems however safer to conclude that there is an increasing body of evidence pointing in the direction of a pragmatic negative association between oocyte donation-gestational length and fetal growth which may be considered much more important in the long term prognosis of these infants.
Notably, a higher prevalence of hypertensive disorders of pregnancy is observed among women conceiving after oocyte donation [
7,
8]. It still remains unclear whether and at which degree hypertension or preeclampsia in relation to the mode of conception might act synergistically affecting gestational length or leading to growth restriction due to utero-placental insufficiency.
Contrary to other studies [
2,
4], a five-minute Apgar score below 7 was more frequent among infants conceived through oocyte donation; the effect, however, disappears when gestational age is taken into account, possibly reflecting the effect of prematurity. No differences were noted regarding the presence of congenital malformations in our study; one should however be cautious in the interpretation of these results since that might reflect limited statistical power.
Further analyses within the oocyte donation group revealed that birthweight and length is lower after pregnancies with treatment indications other than diminished ovarian reserve. Our finding, which comes in contrast to the study by Keegan et al. [
26], can possibly be attributed to the high proportion of women with Turner syndrome in our sample, since no neonatal somatometric differences are noted after excluding those women. However, women with Turner syndrome constitute an important part of the oocyte recipient population; we chose as a consequence not to exclude them from the study population and the analysis presented. To note, neonatal outcomes similar to those in the Turner subgroup in our study were observed in the Turner syndrome study by Hagman et al. carried out in Scandinavia [
25]. Finally, in contrast to Anttila et al. [
14] and Cobo et al. [
15], the duration of hospital stay in a newborn surveillance unit did not differ between Index and Comparison groups.
Although the exact underlying pathophysiological mechanisms remain obscure, OD pregnancies show a greater degree of antigenic dissimilarity i.e. HLA mismatch in peripheral blood compared to IVF with autologous oocytes or spontaneously conceived pregnancies [
29,
30]. Placentas from OD pregnancies, examined histologically and immunohistochemically, exhibited increased diffuse chronic deciduitis with dense fibrinoid deposition in the basal plate of the placenta, as well as increased infiltration by mononuclear cells compared to non-donor IVF pregnancies [
31]. The corresponding pattern of immune mediated placental pathology is considered a unique sign of donated oocyte conception and is postulated to be representative of a type of ”host-versus-graft reaction” [
4].
The principal strength of this report lies in its research design, being a national-level study. Since it was not carried out at a single setting for ART, the results are not reflective of specific treatment protocols or embryology laboratory techniques. Regarding reproductive health, the public health insurance program in Sweden covers all gamete donation treatment costs, providing the opportunity for citizens to equally benefit, independent of their financial ability. Moreover, the maternal health care system is organized within a well-developed and easily available primary care sector with standardized and free of charge antenatal care carried out mainly by community midwives with referral for obstetric assessment by physicians when potential complications are detected [
32]. Thus, the contrasting outcomes cannot be solely attributed to the different level of obstetric or neonatal care provided to the three study groups. Furthermore, previously reported unfavorable findings have been questioned due to the presence of multiple confounding factors (i.e. maternal comorbidities, advanced maternal age, multiple gestations) [
13,
18]. Luckily, the latter does not apply for the nationwide oocyte donation program in Sweden. The participating University clinics that make the eligibility evaluation of the recipients, seem to be in agreement regarding the importance of age and weight restrictions (age < 40 years and BMI < 35 kg/m
2), as well as good health status of the oocyte recipients [
33]. It is therefore important to note that the neonatal outcomes in our index population were observed in spite of the eligibility criteria adopted by healthcare practitioners in Sweden, introducing oocyte donation as an independent risk factor.
The limitations of the study include the limited sample size and low statistical power as seen by the wide confidence intervals; thus, further studies in similar settings are needed to confirm our findings. On the other side, there is only one similar study which comprised Finnish participants, but it was smaller, dates back to 1998, and uses only IVF pregnancies as control group [
14]. Based on the fact that most studies included in a recent meta-analysis come from the United States [
18], we feel that the information presented herein, originating from a country with a different health care system, might be a valuable input in the literature and can contribute in more robust conclusions in future review and meta-analytic approaches. Although we do not report a large enough series on infants conceived through oocyte donation treatment to permit statistically safe conclusions, our results conform to the latest international scientific data [
18].
Additionally, a possible limitation is that the birthweight analysis in this study was not adjusted for cryopreservation (i.e. fresh
vs cryopreserved embryos) or in vitro culture length, which are both believed to affect birthweight probably through epigenetic alterations. However, current data suggest that neither birthweight, nor preterm delivery among infants conceived after oocyte donation differ between fresh or frozen-thawed cycles [
15,
34,
35] or between embryos transferred at different developmental stages [
34]. Finally, although outcome variables in the Swedish national health registers are regarded as highly valid [
21], the lack of more detailed information from participants’ hospital medical records remains a limitation.
Acknowledgements
We would like to thank the statistician Marie Bladh for her contribution in data acquisition and statistical analysis, as well as the personnel at the fertility clinics of the University Hospitals in Sweden for the recruitment of participants and data collection.