Outcome of pregnancies complicated by severe ovarian hyperstimulation syndrome (OHSS): a follow-up beyond the second trimester

A. Wiser, J. Levron, D. Kreizer, R. Achiron, A. Shrim, E. Schiff, J. Dor and A. Shulman1

IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer (affiliated with Sackler Faculty of Medicine, Tel Aviv University), Israel

1 To whom correspondence should be addressed. Email: adrian{at}netvision.net.il


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The main aim of this study was to assess the obstetric complications for those pregnancies that are complicated by ovarian hyperstimulation syndrome (OHSS) and continue beyond the first trimester. We checked also for other related serious events that occurred during the first trimester. METHODS: We included only patients whose pregnancies continued beyond the first trimester and compared them with IVF-treated patients displaying moderate ovarian response. RESULTS: We studied 165 patients with OHSS (101 singletons and 64 twins) and 156 IVF control patients (85 singletons and 71 twins). Two serious complications, gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH), were noted in both groups. However, the incidence of these two complications did not differ significantly between the groups. In the OHSS group, GDM presented with an incidence of 9.9% for singletons and 9.4% for twins, and 12.9% and 7.0%, respectively, for the control group. PIH presented as 6.9% for singletons and 10.9% for twins in the OHSS group, and 8.2% and 7.0%, respectively, for the control groups. During the first trimester laparoscopies for suspected ovarian torsion were performed in 13 patients, and in 10 patients the diagnosis were confirmed. CONCLUSIONS: Although patients with OHSS-complicated pregnancies previously reported a relatively high risk of GDM and PIH, the occurrence rates do not differ from a matched control group of normally responding patients who conceived after IVF.

Key words: GDM/maternal–fetal outcome/OHSS/pregnancy/second trimester


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Ovarian hyperstimulation syndrome (OHSS) is familiar to most people working in reproductive endocrinology and fertility therapy. The intensity of the syndrome is related to the degree of the follicular response to ovulation-inducing agents. OHSS is still a threat to every patient undergoing ovulation induction. Its pathophysiology is of extreme importance due to the increased use of ovulation induction agents, as well as the development of sophisticated assisted reproductive techniques (ART) (Elchalal and Schenker, 1997Go).

Many studies have addressed the clinical features of the syndrome, and assessed pregnancy rates associated with the condition, as well as pregnancy loss during the first trimester (Raziel et al., 2002Go).

There is a paucity of data about feto-maternal morbidity during the second and third trimesters of gestation among patients who develop OHSS. Abramov et al. (1998)Go described a higher rate of gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH) and abruption of placenta among patient who developed OHSS. However, they did not have a control group and did not differentiate between singleton and multiple pregnancies.

The first aim of the present study was to assess the second and third trimester morbidity of those patients who conceived and developed severe OHSS, and to compare the results with patients who conceived after ART, but did not develop OHSS and showed a normal ovarian response to the standard protocol of induction of ovulation. We also studied serious events that occurred during the first trimester.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We reviewed the medical records of all patients who were treated in our infertility unit at the Chaim Sheba Medical Center, developed severe OHSS, and were hospitalized between January 1992 and December 2001. Only pregnancies that progressed beyond the first trimester were included. All the data were obtained from our computerized database, and confirmed by a personal telephone interview conducted by one of the investigators (A.W.). Triplet or higher order pregnancies were not included in this study, including those pregnancies reduced to singletons or twins. The study group was divided in two subgroups: singleton and twin pregnancies.

The definition of severe OHSS was defined according to revised criteria proposed by Golan et al. (1989)Go and Navot et al. (1992)Go: abdominal pain, enlargement of ovary >5 cm, and ascites (ultrasonographically diagnosed) or hydrothorax. In addition, one of the following criteria had to be met: hematocrit ≥45%, white blood cells >15 000/ml, oliguria (urinary output <500 ml/24 h), elevated liver enzymes (above our laboratory normal values), dyspnoea, anasarca or acute renal failure.

All the patients in the OHSS group were hospitalized and treated with bed rest, volume expansion and drainage of ascites in cases of dyspnoea or oliguria.

The following data were collected for both groups: age, gravidity, parity, length of hospitalization due to the OHSS, complications during the hospitalization for OHSS (e.g. ovarian torsion), delivery mode, gestational age at delivery and infant's weight.

To assess the possible impact of the ART treatments, we matched the study group for treatment proximity and aetiology of infertility with a control group composed of women treated in our IVF program during the same period, but presenting with a moderate response to ovulation induction.

The mean number of retrieved eggs in our OHSS patients was 13.7±5.2, with an average estradiol (E2) level of 1906±803 pg/ml. We defined the patients with moderate response according to the number of retrieved eggs (six to eight). The control group was patients with a number of eggs that was above the accepted definition of poor responders (≤5 eggs) and up to 1 standard deviation (SD) below the mean number of our OHSS patients. The average E2 levels of the control group were 1574±643 pg/ml, significantly lower than the OHSS group.

Each patient in our infertility unit was seen 12 days after embryonic transfer for pregnancy testing. If positive, the patient was invited again 2 days later for a blood test and physical examination by one of our physicians. The follow-up was continued once a week for three consecutive weeks before they were discharged to their own gynecologist. By this follow-up we ensured that patients in the control group did not develop OHSS.

PIH was defined as blood pressure >140/90 mmHg measured on two consecutive occasions, occurring after 20 weeks of pregnancy (Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy, 2000Go).

All of our patients (like all pregnant patients in Israel) underwent similar screening for detection of GDM. They were requested to perform a glucose challenge test of 50 g glucose at 24–28 weeks of pregnancy; if the result was >140 mg/dl the oral glucose tolerance test (OGTT) was performed.

GDM was diagnosed when there were two abnormal values in the 3 h OGTT. The OGTT threshold values were 105, 190, 165 and 145 mg/dl, respectively, for the fasting, and 1, 2 and 3 h values (National Diabetes Care Group, 1979Go; ACOG Technical Bulletin, 1995Go).

Statistics
Descriptive parameters are expressed as mean±SD. Frequencies are given as percentages. Whenever a variable did not fit a Gaussian distribution, we transformed it using log10, after which all fit the Gaussian distribution. Statistical significance was tested using Student's t-test for continuous variable and {chi}2-test for categoric variable. Spearman rank correlation and Mann–Whitney tests were applied when appropriate. Age-adjusted P-values for percentages of GDM and PIH were computed using the Mantel–Haenszel method. Statistically significance differences were determined at P<0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Overall, 165 deliveries complicated by OHSS in early pregnancy were studied (101 singleton and 64 twin pregnancies). The control group comprised 156 IVF patients with normal ovarian response who did not develop OHSS (85 singleton and 71 twin pregnancies). The patients in the OHSS group were significantly younger (P=0.02) than the patients in the control group, for singletons and twins (see Tables II and III).


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Table II. Comparisons between maternal morbidity in singleton pregnancies between the two groups

 

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Table III. Comparisons between the deliveries outcome in patients with twin pregnancies between the two groups

 
The aetiology of infertility was similar in both groups, except for the number of polycystic ovary (PCO) patients, which was significantly higher in the OHSS group (Table I).


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Table I. The aetiology of infertility among patient in the two groups

 
The mean hospitalization period was 5.3±3.4 days, with a statistically significant difference (P<0.05) between patients with singletons (4.5±2.9 days) and twins (6.2±3.8 days).

In our study population, GDM and PIH were the major complications noted during the second half of pregnancy. Their incidence for the OHSS and control groups are shown in Table II (singletons) and Table III (for twins). Ten patients (9.9%) with singleton pregnancies from the OHSS group were diagnosed with GDM and 11 (12.9%) in the IVF control group; no statistical significant difference was noted. Furthermore, in twin pregnancies, no statistical differences were found between the two groups; six (9.4%) in the OHSS group and five (7.0%) in the control group. Hypertensive disorder was diagnosed in seven (6.9%) singletons and seven (10.9%) twin pregnancies in the OHSS group, with no statistical difference from the control group: seven (8.2%) and five (7.0%), respectively.

The relationship between the reason for infertility, GDM and PIH is shown in Table IV.


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Table IV. The relationship between GDM, PIH and the reason for infertility

 
Because of the statistically significant difference in age between the OHSS and the control groups, we calculated the age-adjusted P-values for the percentage of GDM and PIH computed using the Mantel–Haenszel method. The percentage of GDM and PIH remained insignificant compared with the OHSS group, for both singleton and twin pregnancies.

The singleton pregnancies in our OHSS group and the control group delivered at similar gestational age, 39±1.9 weeks [95% confidence interval (CI) 38.7–39.4], with a mean birth weight of 3045±544 g (95% CI 2936–3153) for the OHSS group and 3082±557 g for the control group [P=not significant (NS)]. Only 1% of the singleton babies were delivered at under 36 weeks of gestation in the OHSS and control groups.

Caesarean section was the mode of delivery for 24% of the singleton deliveries in the study group, and for 21.1% in the control group (P=NS).

There was no significant difference in the Apgar scores between groups at 1 and 5 min after delivery. Only three singleton babies had an Apgar score of 7 at 1 min after delivery, and improved to Apgar score 9 at 5 min after delivery (one in OHSS group and two in the control group). The rest of the singleton babies had Apgar scores of 8–10 at 1 min and of 9–10 at 5 min.

Twin pregnancies delivered at 35.3±3.4 weeks of gestation in the study group and 35.7±3.2 weeks in the control group (P=NS). Patients with twin pregnancies delivered babies with birth weights that did not differ significantly between the first and second baby; 2185±630 g and 2148±607 g for the first and second baby in the OHSS group, 2209±641 g and 2259±501 g for the first and second baby in control group. The rate of Caesarean section in twin pregnancies was 54% in the study group and 56.3% in the control group (P=NS).

In our series, there was no abruption of placenta in the study group, but there were two cases in the control group, both of which were twin pregnancies.

An interesting observation in our study was the relatively high incidence of ‘ovarian torsion’ that required laparoscopy among the patients with OHSS. In patients with exacerbated abdominal pain and signs of localized peritoneal irritation, on physical examination, the decision to perform a diagnostic laparoscopy was made according to clinical judgment. Laparoscopic intervention were performed in 13 patients (gestational age 6–10 weeks), and ovarian detorsion was required in 10 patients from the study group. Twin pregnancies [seven (10.9%)] were involved 3.5 times more than were singletons [three (3%)]. All the patients were successfully treated by means of detorsion of the involved ovary and had remaining uneventful pregnancy courses until delivery. No cases of ovarian torsion were noted in our control group.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
OHSS is an iatrogenic complication of ovulation induction. Hospitalization and conservative treatment of the patients with severe OHSS is usually the only treatment necessary and gives reasonable results (Morris et al., 1995Go). As in Morris et al.'s study, the duration of hospitalization in our cases lasted between 2 and 9 days (mean 5.3±3.4). The majority of the patients were successfully treated by bed rest, volume expansion and, if necessary, ascites and pleural effusion drainage. However, in 10 cases (6.0%) the combination of abdominal pain, nausea and signs of localized peritoneal irritation were suggestive of ovarian torsion and prompted the performance of a laparoscopy under general anaesthesia. Significantly more patients who finally delivered twins [seven of 64 (10.9%) versus three of 101 (3%)] were involved. Ovarian torsion in patients with OHSS has been already described, with an incidence varying between 3% (Gorkemli et al., 2002Go) and 16% in pregnant patients with OHSS (Mashiach et al., 1990Go). Preservation of the ovary is highly important in young fertile women. Prompt diagnosis with an immediate unwinding of the twisted adnexa by a laparoscopic technique can produce a valuable outcome (Levy et al., 1995Go). Our data confirm that OHSS patients, especially those with multiple pregnancies, are at risk for ovarian torsion. All patients in this series with OHSS and ovarian torsion had uneventful post-operative courses and delivered normal babies at term.

The obstetric outcome of pregnancies complicated by OHSS has not yet been investigated thoroughly. There are few studies that describe the obstetric outcome of these pregnancies (Abramov et al., 1998Go; Mathur and Jenkis, 2000). According to their findings, GDM and PIH were noted at high incidences in this group of patients; however, these studies were descriptive and compared the results only with the data from the literature and not with similar control group, and did not differentiate between singleton and multiple pregnancies to assess the contribution of the multiple pregnancies to developing GSM and PIH. OHSS patients in our study had an incidence of GDM similar to the control group of IVF patients who did not develop OHSS, in singleton and twins pregnancies. This rate is significantly higher than that reported in the literature for the general population. Xiong et al. (2001)Go reported a prevalence of GDM of 2.5% among 111 563 pregnant women in northern and central Alberta.

We found a similar incidence for the hypertensive disorders of pregnancies in both groups, with no differences between singletons and twins. These results are, however, higher than those reported for the general population by Ventura et al. (2000)Go, who found an incidence of PIH of 3.7% in all pregnancies that ended in live births.

An intriguing question concerns the aetiology of these high rates of GDM and PIH. Does the ART treatment itself induce higher rates of GDM and PIH or is it due to a ‘mother predisposition’. Maman et al. (1998)Go described higher rates of GDM and hypertension among IVF patients compared with the general population. However, among the IVF patients there is a large number of PCO patients. The relationship between PCO and GDM and hypertension is well established. Kashyap and Claman (2000)Go stated that patients with PCO are at very high risk of PIH during pregnancies after ovulation induction. Roach et al. (2000)Go found that patients with carbohydrate intolerance of varying severity had higher rates of PIH, and she concluded that carbohydrate intolerance and PIH share a common aetiology. However, at least two studies (Delvigne et al., 2002Go; Salamalekis et al., 2004Go) found no correlation between OHSS and hyperinsulinism. We found high rates of GDM and PIH for the OHSS group as well as for the moderate responders. The number of PCO patients among the pregnant women with GDM and PIH was small (as shown in Table IV). Therefore, PCO is not a sufficient explanation for the aetiology of these two conditions.

One can speculate that either the hormonal milieu induced during the IVF treatment and then in early pregnancy [i.e. increased estrogen, progesterone, prorenin, aldosterone, angiotensinogen, insulin growth factor I and endothelin-1 (ET-1) compared with the luteal phase and early pregnancy of spontaneous conceptions] or the preexisting metabolic-vascular state of patients undergoing IVF may be the predisposing factors to the development of GDM and/or PIH. It was found that serum levels of ET-1 were higher among women with PIH than in normotensive pregnancies (Heimarch et al., 2000Go). ET-1 is a potent vasoconstrictor that increases the capillary permeability in several tissues (Filep et al., 1993Go). High concentrations of ET-1 were found in follicular patients undergoing ovulation induction (Kamada et al., 1993Go), suggesting that ET-1 may play a role in the early pregnancy and impair normal vascular development, and express as PIH, later in pregnancy.

Further studies are needed to elucidate whether the aetiology of these disturbances during OHSS-complicated and ART pregnancies are related mainly to patient predisposition or are side-effects of the haemodynamic and metabolic changes occurring in the first trimester as a result of ART treatment. However, our data support the need for strict prenatal care in patients that conceive after ART treatment, to provide early recognition of GDM and PIH complications.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank Ms Sally Esakov for her critical comments.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on April 26, 2004; resubmitted on September 13, 2004; accepted on December 3, 2004.





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