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The process of fertilization is intricate and is dependent on factors such as ovulation, the sperm viability and transportation, and the passage of the cleaving embryo to the uterine cavity where it develops following implantation. For conception to occur, several other factors such as age, frequency and timing of sexual intercourse come into play. Based on this, infertility has been defined as the inability to conceive following continuous unprotected sexual intercourse after a period of one to two years (NICE Clinical Guidelines, 2004).
Infertility is a condition affecting one in every seven couples in Europe, with a prevalence of 14% (Boivin et al., 2007). Following a consultation, the supposed infertile couple is provided with information on conception and if needed, further enquiry is made into their pregnancy, contraceptive, sexual, surgical and medical history and abnormalities are checked for by carrying out a general physical examination including calculation of BMI (Cahill and Wardle, 2002).
Assisted reproductive technology involves the use of embryos or both sperm and oocytes in procedures or treatments in order to purposefully establish a pregnancy (Min et al., 2004). ART may also be used when a natural conception may present with severe risks associated with the infant. Several types of procedures exist and they include, but are not limited to, in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI) and frozen embryo transfer (FET), gestational surrogacy, zygote intrafallopian transfer (ZIFT) and gamete intrafallopian transfer (GIFT) (Zegers-Hochschild et al., 2009).
In vitro fertilization (IVF)
This is the most common form of ART. The first child born following IVF was Louise Brown who was born 1978 in England. Her birth brought with it hope for infertile couples and three years later, another IVF-induced birth Elizabeth Carr In America further advertised the IVF profile. IVF is carried out in a laboratory and involves the ferltilisation of a harvested preovulatory oocyte with a sperm and the subsequent transfer of the resulting embryo to the uterine cavity (Picaud et .al., 2012). The IVF process follows steps which are:
Stimulation of ovaries with medication to induce multiple ovarian follicle development,
Aspiration of the follicles ( done with the use of a transvaginal ultrasound),
Classification of oocyte based on maturation,
Preparation of Sperm usually derived from ejaculate
Insemination of the Oocyte,
Culture of the Embryo and
Transfer of the Embryo.
Indications for the use of IVF include an unsuccessful therapy of intrauterine /gonadotropin insemination, endometriosis, infertility of unknown aetiology and pelvic disease (van den Boogaard, 2012). IVF can be done with Intracytoplasmic sperm injection (ICSI), a specialized procedure which involves the injection of a single sperm into an egg. The resulting embryo is then placed either in the fallopian tube or the uterus. The combination of IVF and ICSI has been described as a suitable solution for infertility resulting due to male factor infertility (Speroff and Fritz, 2005)
1.2 Gamete intrafallopian transfer
This procedure was developed for women with infertility of unknown causes in 1984. It involves the extraction of eggs from the ovaries, their introduction into flexible catheters (tubes) containing sperm and their injection into the fallopian tube. The insertion is made with the patient under general anaesthesia and is carried out laparoscopically. The choice of GIFT amongst couples has been seen to be influenced by both ethnic and religious beliefs (Gardner et al.,2009)
Zygote intrafallopian transfer (ZIFT)
This is considered to be the most invasive of all ART treatments. Here, the egg and sperm are harvested following IVF techniques and they are combined in the laboratory, in a medium with suitable nutrients to support development. After fertilization, the embryos are relocated and left to grow before a few are carefully selected and laparoscopically placed in the fallopian tubes. Hence it is also known as tubal embryo transfer (TET). The advantage of ZIFT is that confirmation of fertilization before implantation leads to the use of fewer embryos and hence reduces the possibility of multiple pregnancy. However, ZIFT compared to GIFT has been seen to have a more successful result (Weissman, et al., 2013).
Although these procedures have been very effective means of conception for couples considered to be subfertile, they have unfortunately been linked to several complications. A few of which are discussed below.
2.1 Multiple pregnancies
The rate of multiple gestation pregnancy increased greatly since the development of ART and it is the most documented risk associated with ART (Reed and Sutcliffe, 2012 ). This was noted because it was the previous practice to transfer as many suitable embryos as available in other to improve the chances of conception, hence three or more embryos were transferred, leading to an increase in the percentage of twins, triplets, quadruplets or higher number of multiple gestation pregnancy conceptions.
Multiple gestational pregnancies are associated with an increase in both fetal and maternal perinatal complications and can be mainly attributed to a greater risk of preterm birth, low birth weight and infant mortality (Rao et al., 2004). Maternal complications include caesarean section, postpartum and antepartum haemorrhage, gestational diabetes, polyhydramnios, gestational hypertension, anemia placenta previa and also stress brought on by parenting. Furthermore, the need for neonatal care and antenatal hospitalization to be prolonged in multiple pregnancies is a financial burden (ARSM, 2004).
Studies have shown that on average, compared to ART and spontaneous singletons, twins are born three weeks earlier and have a lower mean birth weight which varies between 800g - 1kg (Jauniaux, 2012). Some studies have also seen the number of fetuses to be directly linked to perinatal risks. A retrospective cohort study carried out by Salihu et al., 2003 showed an increasing risk of early death with each additional fetus and the relative risk compared to twins were 2.4 for triplets, 3.3 for quadruplets and 10.3 for quintuplets.
In order to control and minimise multiple births due to ART, several countries now promote single embryo transfer (SET) to limit the number of embryos transferred , for example from 2001, the United Kingdom set a limit of two embryos for transfer (Braude, 2006). However even with all the controversy surrounding multiple pregnancies achieved through ART, there is a suggestion that it may not necessarily be viewed as an adverse outcome for infertile couples (Jauniaux, 2012).
2.2 Ovarian hyperstimulation syndrome (OHSS)
This is an iatrogenic condition which could occur as a result of controlled stimulation of the ovaries following ART. It is characterized by both an increase in the size of the ovaries (due to multiple ovarian cysts and fluid) as well as noticeable ovarian angiogenesis (Shmorgun and Claman, 2011). The condition typically develops after the administration of gonadotropin therapy (human chorionic gonadotropin, hCG) believed to be linked to the angiogenic molecule, VEGF, production (Pietrowski et al., 2011). OHSS could be an early form (occurring within days of hCG administration due to the response of the ovaries to the stimulation by gonadotropin) and a late form (occurring up to 10days after hCG administration and brought about due to the release of hCG by the placenta) (Shmorgun and Claman, 2011).
OHSS presents with several clinical features which include abdominal pain, nausea and vomiting, ascites and tense distension, localized or generalized peritonitis, acute abdominal pain, dyspnea, hypotension, hypovolemia, a hypercoagulable state, acute renal failure and electrolyte imbalance. Risk factors which predict OHSS include previous OHSS, polycystic ovary syndrome and young age (Lee et al., 2008). It can be classified into mild, moderate, severe and critical based on the severity.
2.3 Congenital anomalies.
Several studies have been carried out to show the link between the use of ART and congenital anomalies. In a general population, 3% of neonates who survive are born with a congenital anomaly, and they are usually caused by genetic defects which may lead to neonatal death (5% of the time) and spontaneous abortions (50% of the time) (Mozafari et al., 2012). Mechanisms believed to lead to congenital malformations in children conceived by ART include epigenetic abnormalities, chromosomal abnormalities (i.e. aneuploidy and ring Y) and point mutations (cystic fibrosis). However in ART, some factors such as the by passing of natural selection and changes of the status of hormones in the laboratory have been believed to also play roles in the incidence of congenital anomalies (Pinborg et al., 2013).
Congenital disorders which have been reportedly linked to ART in several studies:
Renal agenesis, anal atresia, diaphragmatic defects, tracheoesophageal fistula, vertebral segmentation defects, neural tube defects and abdominal wall defects (Halliday et al, 2010).
Cardiovascular malformations (Wen et al., 2010).
Congenital heart disease and malformation of ventriculoarterial connections (Tararbit et al, 2011).
Cerebral palsy cases in children conceived through IVF reported by Hvidtjorn et al. (2010) and Zhu et al. (2010)
And a meta-analysis performed by Rimm et al. in 2011 showed a 40-50% higher rate of malformations resulting from ART. Furthermore, as a woman's age increases, she has an increased risk of having a child with congenital abnormalities and this increased risk is also seen in women using ART as the quality and quantity of eggs decreases with increasing age. And in addition, the success rates of births have been seen to decrease steadily after the age of 35 (Speroff and Fritz, 2005)
2.4 Placenta Previa and First -Trimester Bleeding
Bleeding has been noted in the first trimester following assisted reproductive. In their study, De Sutter et al., (2006) identified the complications posed by first trimester bleeding and outcomes such as second and third trimester bleeding , preterm labour and pregnancy duration were measured. The results showed an association between first-trimester bleeding and adverse outcome of pregnancy. Bleeding could also occur after transvaginal oocyte retrieval and this process could lead to infection and ovarian torsion. Although mild bleeding usually resolves itself, a presentation of anemia symptoms and worsening lower abdominal pain may suggest hematomas (Sarhan and Muasher, 2007)
A meta-analysis carried out by Jackson et al. (2004) reported that treatments with ART are three times more likely to result in placenta previa when compared to spontaneous pregnancies. A population-based study carried out by Romundstad et al. (2006) to investigate this further showed that it may be directly related to the infertility treatment. The effects of maternal factors as confounding effects was taken into account as they also made a comparison of assisted fertilization and natural conception in the same woman. This also showed a close to three-fold increased risk placenta previa in ART pregnancies. The presence of placenta previa may be a risk factor for vasa previa (Al-Turki, 2010).
Although ART is a suitable solution for subfertile couples like Mrs. Z and her husband, several studies mentioned above have linked ART to several adverse outcomes for both the mother and infant. The bleeding which Mrs. Z experienced could be as a result of several factors. One theory explaining this is that due to the use of catheters in replacing the embryos in the uterine cavity, the process might induce contraction of the uterus, leading to the lower uterine implantation seen in ART pregnancies. This low implantation predisposes the mother to conditions associated with abnormal placenta presentation, including bleeding which could occur early in pregnancy an seen (Romundstad et al., 2006). Another possible explanation could be the process of transvaginal oocyte retrieval which has been reported by Sarhan and Muashaer (2007) to result in bleeding following a follicle puncture. As Mrs. Z had tried the procedure severally, it is possible that this may have also led to her bleeding. The risk of bleeding caused by this could however be controlled by reducing the vaginal punctures and with the aid of a color Doppler, viewing peripheral follicles as stated by Sarhan and Muashaer (2007). I believe that these two reasons may be the two main factors that could account for Mrs. Z's bleeding.
Further more, since Mrs. Z repeatedly received IVF-ICSI treatments, over 9months, there are several other factors that could have affected the outcome of the pregnancy. It is possible that in order to ensure a successful implantation, the number of embryos transferred back into her uterus could have been increased, which may have led to a multiple gestational pregnancy. She could have also developed OHSS due to an increased administration of hormonal drugs such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), human menopausal gonadotropin (hMG) and human chorionic gonadotropin (HCG) given to stimulate oocyte production. However as Mrs. Z was not followed up in order to dismiss or support this, it remains a speculation. Also another speculation can be made for the explanation of the several failed attempts at IVF. For this, Mrs. Z's age could be taken into account. Although at 32 she may not be considered significantly advanced, it is worth considering that her chance of success at ART is reduced. However the limitation here is that it requires further research.
Assisted reproduction technique (ART) is a very effective course of treatment in couples considered to be subfertile and there are several types which exist including IVF, ICSI, ZIFT and GIFT. Mrs. Z underwent IVF-ICSI, a form of ART to conceive and experienced first-trimester bleeding which may have occurred as a result of the treatment. Although no adverse outcomes are reported in Mrs. Z's case, there are several studies which have investigated and reported the association between ART and several risks such as birth defects, bleeding OHSS and MGD exist. These links therefore suggest that before ART is commenced, infertile couples and particularly women should be extensively educated about the treatment options and their resulting complications to ensure that they make informed decisions. Healthcare professionals should also be fully aware of said complications in order offer relevant information and advice regarding measures which they could take to improve outcomes such as regular follow ups. The necessity of this was made even more evident on interviewing Mrs. Z as she reported feeling 'relaxed, confident and comfortable' following the information session with her obstertician.