Pregnancy in women after infertility treatment

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1 Archives of Perinatal Medicine 20(2), 73-77, 2014 ORIGINAL PAPER Pregnancy in women after infertility treatment MIROSŁAW WIELGOŚ, IWONA SZYMUSIK Abstract From the biological point of view the pregnancy achieved after infertility treatment is identical with naturally conceived one. However, due to medical, psychological, social and financial burden pregnancies after infertility treatment (especially in vitro fertilization; IVF) are considered high risk and of special care. The literature concerning pregnancies after ovarian stimulation and/or IUI is scarce it seems that they are very similar to natural conception. IVF pregnancies are generally considered to have an increased risk of complications and worse perinatal outcome. Nevertheless, it should be remembered that the infertile population is often different from fertile couples, not only because they are older, but also because of the background of infertility. The article discusses the influence of IVF on various pregnancy complications, especially preterm deliveries and multiple gestations. It also reviews shortly the impact of treatment on children s development. Key words: pregnancy complications, in vitro fertilization; infertility treatment, IVF children, multiple gestations Procreation is considered one of the main human necessities. Therefore, it is obvious that infertility results in great psychological burden, psychosocial and personal frustration. The process of diagnosis and therapy itself aggravates the problem, especially if the treatment is unsuccessful. There is a variety of ways of infertility treatment, depending on the cause and duration of the problem and patient s age: ovulation induction, intrauterine insemination (IUI) with/without stimulation and in vitro fertilization (IVF) with all its modifications. It should be taken into account that from the biological point of view the pregnancy achieved by infertility treatment is identical with naturally conceived one. However, due to medical, psychological, social and financial burden pregnancies after infertility treatment (especially IVF) are considered high risk and of special care [1, 2]. The literature concerning pregnancies after ovarian stimulation and/or IUI is scarce it seems that they are very similar to natural conception. Fahri and Fisch suggested that supraphysiological concentrations of gonadotrophins used for ovulation induction may result in an increased risk of congenital malformations both when IVF and stimulation with/without IUI were performed [3]. Intrauterine insemination is an easy, relatively cheap, acceptable and accessible method of infertility treatment, although currently of controversial meaning because of its unsatisfactory efficacy. Multicenter data published by ESHRE (European Society of Human Reproduction and Embryology) in 2006 revealed its efficacy of 11-16% in younger patients and only around 6-7% in women over 40 years of age. The rate of multiple gestations (around 10%), greatly exceeding the population rate, is the major complication of such a pregnancy [4]. According to the latest ESHRE data, the delivery rate after IUI in Europe reached 8.3% (IUI by husband) and 13.4% (IUI by donor) [5]. It is difficult to affirm if pregnancies after ovulation induction or IUIs have an increased risk of other complications and literature data is of conflicting evidence. In one multicenter study it was suggested that infertility treatment results in higher risk of an early miscarriage, however, the differences were insignificant when groups were adjusted by age and cause of infertility [6]. It is also suggested that pregnancies achieved after clomifen citrate stimulation result in a higher risk of miscarriages because of the detrimental effect of the drug on endometrium. On the other hand it seems reasonable to take the primary cause of infertility into consideration. It was reported that the history of endometriosis was related to an increased risk of preterm deliveries, placental complications and preeclampsia, regardless of the way of conception. Similarly, pregnancies in patients with the polycystic ovary syndrome were associated with an increased risk of gestational diabetes, hypertension and preterm delivery [7, 8]. As mentioned above, literature regarding pregnancies after ovarian stimulation and IUI is scarce and conflicting. Therefore, the following part of the article discusses only pregnancies achieved by in vitro fertili- 1 st Department of Obstetrics and Gynecology, Medical University of Warsaw

2 74 M. Wielgoś, I. Szymusik zation. According to general belief, IVF pregnancies are considered to have an increased risk of complications and worse perinatal outcome. Nevertheless, it should be remembered that the infertile population is often different from fertile couples, not only because they are older, but also because of the background of infertility. IVF and early pregnancy losses The follow-up of early miscarriages after IVF is rather difficult and national reports vary greatly: from 15 to 30%. It has not been verified whether classic IVF or ICSI (intracytoplasmic sperm injection) is related to higher percentage of pregnancy loss. The influence of the cause of infertility on miscarriages is also unclear. Both women s age and increased BMI have detrimental effect, but the same is observed in fertile population. Additionally, one of the Polish publications reported that the history of endometriosis increased the risk of early pregnancy losses the same can be found in foreign literature [9-11]. Assisted reproduction technologies (ART) increase the risk of ectopic pregnancies, especially a very rare case of heterotopic gestation. The published rates again vary greatly from 0.7 to 4.5% for ectopic and around % for heterotopic pregnancy. It is suggested that the history of PID (pelvic inflammatory disease), tubal factor of infertility and embryo transfer technique could favor the above mentioned complications [12, 13]. IVF and multiple gestations The increasing rate of multiples in the world is indisputably related to ART. According to the latest ESHRE monitoring, the total multiple delivery rate after IVF in Europe in 2009 was 20.2% [5]. Due to the economical and health consequences of prematurity, multiple pregnancies are currently considered one of the greatest complications of infertility treatment. Therefore, an elective transfer of a single embryo should be pursued all over the world. The course and complications of pregnancy should always be analyzed separately for singletons, twins and higher order gestations. Papers published prior to 2000 covered study groups of hardly 200 patients. The majority of them concluded that perinatal outcome of IVF twins is worse than spontaneously conceived twins because of higher risk of complications and increased risk of preterm delivery [14, 15]. Nevertheless, papers published in the last decade analyzed much bigger study groups. All of them (including one meta-analysis) concluded that obstetric outcome of IVF twins was comparable to spontaneously conceived twins, especially with regard to the risk of prematurity [16-18]. The article published in 2012, based on own material, also had similar conclusions the method of conception seemed not to have a negative impact on the course of pregnancy, risk of preterm delivery and obstetric outcome, while neonatal complications of IVF and spontaneous twins were mostly a result of prematurity [19]. IVF and preterm delivery First reports on an increased risk of preterm deliveries after IVF were published in 1980 s. The following years only reaffirmed earlier information [15, 20, 21]. Dhont et al. analyzed a group of over 3000 singleton IVF pregnancies and revealed higher rates of preterm labors and low birth weights in newborns, even after age and parity adjustment [22]. Helmerhorst et al. published a systematic review of 25 case-controlled studies from and also proved the above [16]. The meta-analysis of 15 papers by Jackson et al. confirmed once again the higher risk of preterm delivery and lower neonatal birth weight in IVF singletons in comparison to spontaneously conceived pregnancies [23]. The risk has not been proven for twins. Some authors tried to find other independent factors influencing the risk of prematurity in IVF singletons. Ochsenkuhn et al. reported that hypertension was an independent risk factor of low neonatal birth weight and hypotrophy as well [24]. Nevertheless, there are also papers reporting similar perinatal outcome in IVF and spontaneously conceived singletons [25, 26]. IVF and first trimester bleeding The majority of available literature indicates that the rate of first trimester bleeding in IVF pregnancies is higher than in controls the rates vary from 19.6 to 32.3%. The reason of the above is unknown, however the influence of ovarian stimulation, luteal insufficiency and spontaneous embryo reduction are suggested. The technique of fertilization (IVF or ICSI) does not seem to be relevant [11, 24, 27]. IVF and placenta previa There is conflicting evidence regarding placenta previa, nevertheless the majority of publications conclude that the above complication is more frequently diagnosed in IVF singletons [11, 20, 21, 26, 28]. Jackson et al. reported that the risk of placenta previa for IVF

3 Pregnancy in women after infertility treatment 75 triples [23]. It is suggested that not the procedure of fertilization, but the technique of embryo transfer might be significant [29]. IVF and gestational diabetes The influence of in vitro fertilization on gestational diabetes is unclear. The majority of papers reported that the risk of the above complication is similar for IVF and spontaneously conceived pregnancies. However, Maman et al. suggested that the risk of gestational diabetes doubled in IVF pregnancies and it might be due to the causes of infertility (especially PCOS) or drugs used for ovulation induction [30]. Their results have not yet been proven. IVF and gestational hypertension, preeclampsia and intrauterine growth restriction (IUGR) The above pregnancy pathologies are commonly analyzed together and again the evidence for IVF is conflicting. Some authors indicate that hypertension, preeclampsia and IUGR are more often diagnosed in IVF pregnancies, especially among multiples [15, 20, 21, 23, 25, 29]. Primiparity is an additional unfavorable factor in IVF population. IVF and intrahepatic cholestasis of pregnancy The literature regarding cholestasis is very scarce. Pinborg et al. reported higher risk of this particular complication in IVF pregnancies, especially in multiples [29]. The highest calculated risk reached 3.8 for IVF gestations [31]. IVF donation pregnancies Oocyte and embryo recipients are usually older patients, POF (premature ovarian failure) women, patients with decreased ovarian reserve or genetic abnormalities carriers. They are reported to be at high risk of first trimester bleeding, gestational hypertension and IUGR, especially if POF was diagnosed. POF is also a single independent risk factor of SGA (small for gestational age) with OR 8.24 (95%CI ) [32]. Stoop et al. even confirmed that the risk of first trimester bleeding and hypertension remained when compared with autologous IVF pregnancies matched for age, parity and race [33]. IVF pregnancies with ovarian hyperstimulation syndrome (OHSS) OHSS is a very unique ART complication alongside multiple pregnancies its prevention strategy is nowadays considered top priority. Various literature reports suggest poorer perinatal outcome when pregnancy is complicated by OHSS. Authors reported higher rates of miscarriages (27-29%), preterm deliveries (38-44%), low neonatal birth weight (27-62%), gestational hypertension (6.9-13%), multiple pregnancies (40-46%), placental abruption (4.4%) and intrahepatic cholestasis. The influence of OHSS (hemoconcentration, hypoxemia, increased cytokine, angiotensin and renin concentration) on organogenesis is unknown, however, the rate of congenital malformations in pregnancies complicated by OHSS reaches 2-2.8% [34-36]. IVF and the mode of delivery The vast majority of papers covering the mode of delivery in IVF pregnancies reported a very high rate of cesarean sections, both among singletons and twins. In 2004 Polish Gynecological Society published recommendations in which experts suggested to perform cesarean delivery on IVF multiples and also to consider cesarean delivery on request in IVF singletons [2]. Nowadays we do know more about IVF pregnancies, since they became more common in our daily practice. Perhaps the time has come to reconsider and replace doctor s and patient s anxiety with scientific data. IVF, congenital malformation and the development of children The association of IVF and congenital malformations has always been controversial. It especially applies to severe male factor, lack of natural sperm selection during ICSI and in vitro culture. The age of women is also not negligible. According to ASRM statement (American Society for Reproductive Medicine) patients undergoing ICSI procedure should be informed about an increased risk of congenital malformation in children, alongside the possibility of hereditary male infertility. Meta-analyses from the last decade are unfavorable for IVF pregnancies even after maternal age and parity adjustment (OR for IVF and congenital malformations) [37-39]. There are also some alarming reports on DNA imprinting disorders the risk of rare diseases such as Beckwith-Wiedemann syndrome seems to be increased in IVF children [40, 41]. Nevertheless, a lot of attention has also been paid to neurological and psychomotor development of IVF children and the results are satisfactory. The systematic review of literature covering the above subject proved that, regardless of the laboratory technique, IVF does

4 76 M. Wielgoś, I. Szymusik not influence the risk of neurological sequelae, cerebral palsy nor psychomotor development [42, 43]. It is worth remembering that generally, once we prevent prematurity, the development of IVF and spontaneously conceived children is comparable. Since in the developed countries ART infants represent over 1% of birth cohorts, their proportion is no longer negligible. References [1] Jaroszewicz P. (2006) Czynniki psychologiczne związane z leczeniem zaburzeń płodności. Gin. po Dypl., pp (Zeszyt Edukacyjny: Techniki rozrodu wspomaganego medycznie w leczeniu niepłodności). [2] Rekomendacje Polskiego Towarzystwa Ginekologicznego w zakresie wybranych patologii wczesnej ciąży oraz postępowania w ciąży po zapłodnieniu in vitro (2004). Ginekol. Pol. 75: [3] Farhi J., Fisch B (2007). Risk of major congenital malformations associated with infertility and its treatment by extent of iatrogenic intervention. Pediatr. Endocrinol. 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