In Vitro Fertilization and Complications

This paper provides a current overview of complications related to in vitro fertilization (IVF) including ovarian hyperstimulation syndrome (OHSS), heterotopic pregnancy and unlikely rare complications such as infection and bleeding.

We will discuss in detail of the pathophysiology of the ovarian hyperstimulation syndrome (OHSS), review the definition of this syndrome and the initial management of severe OHSS.

Overview of In Vitro Fertilization:

The extracorporeal fertilization of mammalian embryos was first reported more than two decades ago. The British team of Steptoe and Edwards was the first to report a pregnancy1 of a human egg and also was the first to achieve the birth2 of an in vitro fertilized baby. The birth occurred on July 25, 1978. Since then, thousands of pregnancies have been achieved worldwide by IVF. As experience has accumulated, success rates have increased.3,4

IVF procedure consists of stimulating the ovaries medically with self-administered subcutaneous gonadotropins. The stimulated ovaries produce numerous follicles, which are drained using transvaginal ultrasound guidance. The oocytes are then mixed with the prepared semen sample and then incubated. Three to five days after retrieval, the embryos are replaced through the cervix into the uterine cavity.

Overview of Complications:

IVF results in a non-physiological ovarian response and the subsequent transfer of more than 2 embryos. It may occasionally lead to the development of iatrogenic complications.

Ectopic and heterotopic pregnancies

5.5% of IVF pregnancies are ectopic3,4 and occasionally cervical5, and abdominal6 pregnancies are reported. A high index of suspicion coupled with early sonography is therefore warranted in all pregnancies resulting from IVF.7 The risk of a heterotopic pregnancy is approximately 1% which far exceeds the estimated 1/30000 incidence in spontaneous gestations.8

Multiple pregnancy

The most frequent complication of IVF is multiple gestation. According to the 2000 US registry4 and the European Society of Human reproduction and Embryology (ESHRE)3 the rate of multiple gestation was 39% and 26.3% respectively. Specifically they found 32.2%, 23.9% twins respectively, and 6.3% and 2.3% triplets, and in the US 0.5% quadruplets. Many European countries have legislation to limit the number of embryos replaced. This is reflected in the lower number of multiple births.

Multifetal pregnancies have an increased risk of preterm delivery, and have the potential for significant sequelae in the offspring. However infants delivered after IVF do not appear to be at increased risk for congenital malformations or other perinatal morbidity compared with spontaneously conceived children.9

Bleeding and Infection

The reported incidence of complications of transvaginal follicle aspiration is low10: only one series reported substantial risk of infection and their 3% incidence of infection dropped to 0% with the use of prophylactic antibiotics.11,12 Significant vaginal blood loss (>100 ml) occurred in 22 (0.8%) of the women.13 Exceptionally ovarian torsion and rupture are reported.

Ovarian Hyperstimulation syndrome

In assisted reproduction techniques (ART), ovulation induction is widely used. However, as it results in a non- physiological ovarian response it may occasionally lead to the development of ovarian hyperstimulation syndrome (OHSS).14 The development of OHSS may be exaggerated and of longer duration if the cycle has resulted in pregnancy

Classification
This iatrogenic condition is characterized by a varied spectrum of clinical and laboratory manifestations including multicystic ovarian enlargement and massive extravascular fluid accumulation, combined with intravascular depletion, hemoconcentration and electrolytic disturbances. In extreme cases it can be also accompanied by a serious and a potentially life-threatening complications. Any woman undergoing ovulation induction is at risk of severe OHSS (incidence <1%).15 In the definitive paper by Golan et al in 198915 they classified OHSS into 3 categories: mild, moderate and severe (see Table 1).

Management17,18,19

The main aim of management is:
  1. Reassurance and symptomatic relief to the patient
  2. Avoid trauma ... no pelvic exams, abstain from intercourse
  3. Avoid hemoconcentration
  4. Prevent thromboembolism
  5. Maintain cardiorespiratory and renal function
The features to note on physical examination are:
  1. General state of hydration
  2. Chest- difficulty breathing, pleural or pericardial effusion
  3. Abdomen-degree of distension
  4. Evidence of thromboembolism
  5. Avoid pelvic exam due to risk of ovarian rupture
The investigations:
  1. Sonographic measurement of ovarian dimension
  2. Chest X-ray (if dyspneic)
  3. Hemoglobin and hematocrit
  4. Urea and electrolytes
  5. Albumin and liver enzymes
  6. Clotting factor screen (INR/PTT)
  7. Quantitative bHCG
The nursing observations:
  • Blood pressure, heart rate, temperature (4 hourly)
  • Weight and abdominal girth (daily)
  • Strict fluid input/output chart
  • Consider urinary catheterization if oligouria (<30cc/hr)
Analgesia
  1. Avoid nonsteroidal anti-inflammatory drugs (NSAIDS)
Anticoagulation
  1. Full length TED stockings
  2. Prophylactic subcutaneous heparin (severe forms - 5000 IU bid)
  3. Therapeutic heparin (thromboembolism)
Diuretics
  1. Avoid all diuretics as patients are intra-vascularly depleted
The maintenance of intravascular volume will allow resumption of normal urine production (>30ml/hr)(16, Level 5)
  1. If the patient is not vomiting, encourage oral fluid intake (salt rich diet, proteins, milk)
  2. If the patient is vomiting, and serum albumin >32g/l, Hb<140 g/L then:
    normal saline 3 liters in 24 hours (avoid potassium-containing fluids because patients become often hyperkalimic)
  3. If the patient is vomiting and serum albumin<30g/L, Hb>160g/L or urea>6mmol/l then:
    q Albumin 50-100g IV every 1-12 hours (usually 1g/kg of albumin 5% IV in 500cc Ringer lactate). 1g of Albumin retains 18g of water into vascular space- ascitic fluid contains 46-53g/L Albumin. The side effects related to the injection of albumin are a "flu-like condition", low grade temperature, nausea, muscle pain or rarely a small risk of anaphylactic reaction.

Paracentesis

Indications (19, Level 3)
  • Respiratory distress
  • Hemoconcentration unresponsive to medical therapy
  • Rising creatinine
  • Oliguria

Techniques

  • Abdominal or transvaginal under ultrasound guidance

Risks

  • Rapid reaccumulation
  • Acceleration of protein loss
Surgery
  • Exceptional circumstances
  • Rupture of cyst or hemorrhage
Summary

In-vitro fertilization (IVF) can offer hope for conception to couples where this was not previously possible. Unfortunately this technology is not without inherent risk. The most serious complications that arise from IVF procedures are ectopic pregnancy and ovarian hyperstimulation syndrome (OHSS). With respect to ectopic pregnancy management should not differ from usual management, bearing in mind the increase suspicion for heterotopic pregnancy. Severe OHSS is a serious complication of IVF and patients should be monitored daily. This would be best facilitated by the reproductive endocrine clinic involved in the stimulation cycle. Important initial management prior to referral would involve fluid replacement and abstaining from vaginal exams.

- R. Bouzayen, L. Hamilton

Thanks to Dr. Tim Rowe, Reporoductive Endocrinologist at University of British Columbia, Vancouver B.C. for reviewing the draft copy of this article.

References:
  1. Steptoe PC, Edwards RG. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet 1976; 1: 880-882.
     
  2. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978; 2: 366.
     
  3. Nygen KG, Andersen AN. Assisted reproductive technology in Europe, 1998. Results generated from European registers by ESHRE. Human Reproduction 2001; 16(11): 2459-2471.
     
  4. Society for Assisted Reproductive Technology and American Society for Reproductive Medicine. Assisted reproductive technology in the United States: 1997 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2000; 74: 641-653.
     
  5. Bayati J, Garcia JE, Dorsey JH, Padilla SC. Combined intrauterine and cervical pregnancy from in vitro fertilization and embryo transfer. Fertil Steril 1989; 51: 725-727.
     
  6. Oehninger S, Kreiner D, Bass MJ, Rosenwaks Z. Abdominal pregnancy after in vitro fertilization and embryo transfer. Obstet Gynecol 1988; 72: 499-502.
     
  7. Rein MS, DiSalvo DN, Friedman, AJ. Heterotopic pregnancy associated with in vitro fertilization and embryo transfer: a possible role for routine vaginal ultrasound. Fertil Steril 1989; 51: 1057-1058.
     
  8. Dimitry ES, Subak-Sharpe R, Mills M, Margara R, Winston R. Nine cases of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril 1990; 53: 107-110.
     
  9. Buitendijk SE. Children after in vitro fertilization: An overview of the literature. Int J Technol Assess Health Care 1999; 15: 52-65.
     
  10. Evers JL, Larsen JF, Gnany GG, Sieck UV. Complications and problems in transvaginal sector scan- guided follicle aspiration. Fertil Steril 1988; 49:278-282.
     
  11. 2000;73:883-96.Howe RS, Wheeler C, Mastroianni L Jr, Blasco L, Tureck R. Pelvic infection after transvaginal ultrasound- guided ovum retrieval. Fertil Steril 1988;49:726-728.
     
  12. Meldrum DR. Antibiotics for vaginal oocyte aspiration. J In Vitro Fertil Embryo Transf 1989; 6: 1-2.
     
  13. Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound- directed follicle aspiration: a review of 2670 consecutive procedures. J.Assist Reprod Genet 1993; 10: 72-77.
     
  14. Editorial. Ovarian hyperstimulation syndrome. Lancet 1991; 338: 1111-1112.
     
  15. Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430-440.
     
  16. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992; 58: 249-261.
     
  17. Rizk, B, Aboulghar M. Modern management of ovarian hyperstimulation. Human Reproduction 1991; 6: 1082-1087.
     
  18. Delvigne A, Demoulin A, Smitz J, Donnez J, Koninckx P, Dhont M, Englert Y, Delbeke L, Doreis L, Gordts S, Puttlemans P, Gerris J, Sohoysman R, Leroy F. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features. Hum Reprod 1993; 8: 1353-1360.
     
  19. Aboulghar MA, Mansoiur RT, Serour GI, Sattar MA, Amin YM, Elattar I. Management of severe ovarian hyperstimulation syndrome by ascitic fluid aspiration and intensive intravenous fluid therapy. Obstet Gynecol 1993; 81: 108-111.
     
  20. Whelan JG 3rd, Vlahos NF.The ovarian hyperstimulation syndrome. Fertility and Sterility 200;73:883-96.

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