ovarian hyperstimulation syndrome ( ohss ) is an iatrogenic complication of assisted reproductive technology ( art ) with development of multiple follicles .
ohss is characterized by cystic enlargement of the ovaries and an acute fluid shift from the intravascular compartment to the third space , which may result in ascites , pleural and/or pericardial infusion , and even generalized edema .
ohss patients suffer from lower abdominal discomfort , nausea , and vomiting . in severe cases of ohss , thromboembolic events , acute respiratory distress syndrome ( ards ) , and renal failure
clinical practitioners are unsure whether ohss and subsequent treatments , such as incessant pleural or abdominal punctures , volume expansion , and diuretics , would have an adverse effect on pregnancy outcomes of ohss patients .
previous research on this topic had a lack of an appropriate contemporaneous control group , and there were potential confounders in the research , thus making interpretation of such data unclear . in the current study , based on consistent age and count of mature ii ( m - ii ) oocytes , we compared pregnancy outcomes of patients with and without ohss , and examined the possible effects of ohss on pregnancy outcomes .
the in vitro fertilization ( ivf ) database was set up and maintained by research faculty members in our department .
ohss patients except for mild ohss patients diagnosed and treated in our hospital from 2002 to 2012 were included , and basic information was recorded in the database .
, we identified 190 ivf patients with ohss . in a total population of 5487 ivf fresh cycles ,
197 contemporaneous non - ohss cycles matched for age and count of m - ii oocytes were selected as the unexposed group .
the amount discrepancy of age and count of m - ii oocytes between the two or three matching patients was no more than 2 .
the corresponding non - ohss cycle occurred in the same or near month with the ohss cycle .
while in our study , we excluded the mild ohss patients since they were treated outpatient .
the severity of ohss was defined according to the criteria proposed by golan et al . and navot et al .
moderate ohss was characterized by abdominal distension and discomfort , nausea , vomiting or diarrhea , enlarged ovarian size ( 512 cm ) , and ultrasonic evidence of ascites .
severe ohss was characterized by variable ovarian enlargement ; massive ascites  hydrothorax ; hematocrit > 45% ; white blood cell count > 15,000/ml ; oliguria ; creatinine 1.01.5 mg / dl ; liver dysfunction ; and anasarca .
critical ohss was characterized by variable ovarian enlargement ; tense ascites  hydrothorax ; hematocrit > 55% ; white blood cell count > 25,000/ml ; oliguria ; creatinine 1.6 mg / dl ; creatinine clearance < 50 ml / min ; renal failure ; thromboembolic phenomena ; and ards .
hematocrit , white blood cell count , and liver and kidney function indices were dynamically monitored .
changes in ovarian size and abdominal or pleural fluid were monitored by ultrasound when necessary .
based on the status of disease , liver - protecting , anti - infection , and diuretic treatments , as well as drainage of abdominal and pleural fluid , were administered .
pregnancy outcomes included clinical pregnancy , miscarriage , miscarriage of one twin , fetal intrauterine death , gestational age at birth , delivery mode , neonatal birth weight , and neonatal deformity .
early miscarriage occurred before 12 gestational weeks , and late - term miscarriage was between 13 and 28 gestational weeks .
. low birth weight ( lbw ) was defined as birth weight below 2500 g , and small - for - gestational age ( sga ) was defined as a birth weight lower than the tenth percentile of the same gestational age of neonatal birth weight .
data were expressed as mean  standard deviation ( sd ) , median ( interquartile range ) , or n ( % ) .
continuous variables were compared using student 's t - test or mann  whitney u - test .
odds ratios ( ors ) and 95% confidence intervals ( cis ) were calculated after adjustment for controlled ovarian hyperstimulation ( coh ) protocol , gonadotropin ( gn ) dosage , human chorionic gonadotropin ( hcg ) dose protocol on hcg day , luteal supporting protocol , polycystic ovary syndrome ( pcos ) , and anovulation .
the in vitro fertilization ( ivf ) database was set up and maintained by research faculty members in our department .
ohss patients except for mild ohss patients diagnosed and treated in our hospital from 2002 to 2012 were included , and basic information was recorded in the database .
, we identified 190 ivf patients with ohss . in a total population of 5487 ivf fresh cycles ,
197 contemporaneous non - ohss cycles matched for age and count of m - ii oocytes were selected as the unexposed group .
the amount discrepancy of age and count of m - ii oocytes between the two or three matching patients was no more than 2 .
the corresponding non - ohss cycle occurred in the same or near month with the ohss cycle .
ohss can be classified into mild , moderate , severe , and critical ones . while in our study
the severity of ohss was defined according to the criteria proposed by golan et al . and navot et al .
moderate ohss was characterized by abdominal distension and discomfort , nausea , vomiting or diarrhea , enlarged ovarian size ( 512 cm ) , and ultrasonic evidence of ascites .
severe ohss was characterized by variable ovarian enlargement ; massive ascites  hydrothorax ; hematocrit > 45% ; white blood cell count > 15,000/ml ; oliguria ; creatinine 1.01.5 mg / dl ; liver dysfunction ; and anasarca .
critical ohss was characterized by variable ovarian enlargement ; tense ascites  hydrothorax ; hematocrit > 55% ; white blood cell count > 25,000/ml ; oliguria ; creatinine 1.6 mg / dl ; creatinine clearance < 50 ml / min ; renal failure ; thromboembolic phenomena ; and ards .
hematocrit , white blood cell count , and liver and kidney function indices were dynamically monitored .
changes in ovarian size and abdominal or pleural fluid were monitored by ultrasound when necessary .
based on the status of disease , liver - protecting , anti - infection , and diuretic treatments , as well as drainage of abdominal and pleural fluid , were administered .
pregnancy outcomes included clinical pregnancy , miscarriage , miscarriage of one twin , fetal intrauterine death , gestational age at birth , delivery mode , neonatal birth weight , and neonatal deformity .
early miscarriage occurred before 12 gestational weeks , and late - term miscarriage was between 13 and 28 gestational weeks .
premature delivery was defined as birth before 37 and after 28 completed weeks of pregnancy .
low birth weight ( lbw ) was defined as birth weight below 2500 g , and small - for - gestational age ( sga ) was defined as a birth weight lower than the tenth percentile of the same gestational age of neonatal birth weight .
data were expressed as mean  standard deviation ( sd ) , median ( interquartile range ) , or n ( % ) .
continuous variables were compared using student 's t - test or mann  whitney u - test .
odds ratios ( ors ) and 95% confidence intervals ( cis ) were calculated after adjustment for controlled ovarian hyperstimulation ( coh ) protocol , gonadotropin ( gn ) dosage , human chorionic gonadotropin ( hcg ) dose protocol on hcg day , luteal supporting protocol , polycystic ovary syndrome ( pcos ) , and anovulation .
we identified 39 moderate ( 20.5% ) , 141 severe ( 74.2% ) , and 10 critical ( 5.3% ) ohss patients .
the incidence of ohss among 5487 fresh ivf cycles was 3.46% , and the rates of serious adverse events and thromboembolism in ohss patients were 2.63% and 1.58% , respectively .
the median duration of hospitalization was 11 days ( 273 days ) and the mean number of abdominal and plural punctures was 3 ( range : 018 ) .
comparison of ivf data between ivf patients with or without ohss is shown in table 1 .
the mean dosage of gn used for ovulation induction for ohss patients was lower than that of non - ohss ( p = 0.007 ) .
the clinical characteristics , including age , body mass index , diagnosis of infertility , and duration of infertility , were not significantly different between the two groups [ table 1 ] . additionally , no significant difference was found in basal follicle - stimulating hormone or serum estradiol ( e2 ) levels on hcg day between the groups .
comparison of ivf data between ohss and non - ohss groups data were showed as mean  sd , median ( iqr ) , or n ( % ) .
ohss : ovarian hyperstimulation syndrome ; bmi : body mass index ; ivf : in vitro fertilization ; pcos : polycystic ovary syndrome ; fsh : follicle - stimulating hormone ; coh : controlled ovarian hyperstimulation ; gn : gonadotropin ; hcg : human chorionic gonadotropin ; rhcg : recombinant human chorionic gonadotropin ; m - ii : mature - ii ; iqr : interquartile range ; e2 : estradiol ; sd : standard deviation .
seven patients with ohss canceled embryo transfer ( et ) because of early - onset severe ohss , and 13 patients without ohss canceled et for a high risk of ohss . among the 183 ohss patients who did undergo et , 168 patients achieved clinical pregnancy with a clinical pregnancy rate of 91.8% , which was significantly higher than that in the control group ( 43.5% , p < 0.001 ) . the rates of multiple pregnancy and miscarriage were not significantly different between the two groups , and all the triplets and quadruplets were surgically reduced to twins during 912 weeks of gestational age .
comparison of pregnancy outcomes between ohss and non - ohss group data were showed as mean  sd or n ( % ) .
lbw : low birth weight ; sga : small - for - gestational age ; ohss : ovarian hyperstimulation syndrome ; sd : standard deviation
. the delivery outcomes of 138 ohss live births ( 84 singletons , 54 twins ) were compared with those of the control group , which were 63 live births ( 41 singletons , 22 twins ) .
we found no significant differences in the rates of live birth ( 82.1% vs. 78.8% ) , preterm delivery ( 20.9% vs. 17.5% ) , preterm birth before 34 weeks gestation ( 8.6% vs. 7.9% ) , singleton lbw ( 9.5% vs. 4.9% ) , and singleton sga ( 7.1% vs. 7.3% ) between the two groups .
pregnancy and maternal outcome of ohss patients with major complications ards : acute respiratory distress syndrome ; ohss : ovarian hyperstimulation syndrome .
thereafter , we compared ivf data of moderate ohss , severe / critical ohss with that of non - ohss patients , respectively [ table 4 ] .
the proportion of different coh protocol was statistically different between severe / critical ohss and non - ohss patients ( p = 0.039 ) .
the proportion of short protocol was comparatively higher in non - ohss than severe / critical ohss patients .
after controlling for coh protocol , gn dosage , hcg dose on hcg day , luteal supporting protocol , pcos , and anovulation , ohss was associated with increased probability of clinical pregnancy .
the adjusted ors of moderate ohss and severe / critical ohss for clinical pregnancy were 4.65 ( 95% ci , 1.8611.61 ) and 5.83 ( 95% ci , 3.459.86 ) , respectively .
comparison of ivf data among moderate , severe / critical ohss and non - ohss patients data were showed as mean  sd , median ( iqr ) , or n ( % ) .
p1 represents moderate ohss compared with non - ohss patients and p2 represents severe / critical ohss compared with non - ohss patients .
ohss : ovarian hyperstimulation syndrome ; bmi : body mass index ; ivf : in vitro fertilization ; pcos : polycystic ovary syndrome ; fsh : follicle - stimulating hormone ; coh : controlled ovarian hyperstimulation ; gn : gonadotropin ; hcg : human chorionic gonadotropin ; rhcg : recombinant human chorionic gonadotropin ; m - ii : mature - ii ; iqr : interquartile range ; e2 : estradiol ; sd : standard deviation .
clinical practitioners have always been committed to improving ovarian stimulation protocols to keep the incidence of ohss no more than 5% . however , critical ohss occasionally occurs , including acute renal failure , thrombosis , stroke , pulmonary edema , myocardial infarction , ards , and even maternal death .
considering ohss - associated complications , clinical practitioners and patients need to determine whether to terminate pregnancy because this would substantially alleviate the condition of ohss patients .
while most patients choose to continue pregnancy because this disease is self - limited , they are also wondering whether ohss would bring adverse impact to pregnancy .
a previous study has demonstrated that ohss is more likely to occur at a younger age and in treatment cycles with the highest ovarian response to stimulation .
additionally , infertility is an independent factor that appears to be involved with a poor obstetric outcome .
the oocyte yield , independent of age , shows a linear relationship with live births with up to 15 oocytes in ivf cycles .
therefore , to exclude potential bias , we matched age and count of m - ii oocytes . body mass index , causes of infertility , length of infertility , and basal ovarian function in the two groups were assessed .
we observed that the dosage of gn for ovarian stimulation and hcg for luteal support was significantly lower in ohss patients than in non - ohss patients , which suggested that ohss patients were more sensitive to stimulatory drugs .
multiple studies have reported that the clinical pregnancy rate in ohss patients is significantly higher than that in general ivf patients or non - ohss patients .
pregnancy triggers and aggravates ohss , and this is called late - term onset ohss .
late ohss is triggered by endogenous hcg release in the event of pregnancy , generally occurring after 910 days following hcg injection .
early ohss is caused by administration of exogenous hcg , which appears to be associated with an excessive ovarian response to gn stimulation , generally occurring before the 9 and 10 day after hcg injection . because we performed a retrospective study , it is difficult to define the onset model according to patients subjective recall . in terms of pregnancy outcome ,
the rates of miscarriage and perinatal complications including preterm birth , sga , pregnancy - induced hypertension and/or stillbirth were significantly higher in ohss group than non - ohss group , as reported in literature .
we analyzed that it was probably the relatively higher rate of multiple pregnancy that induced massive perinatal complications [ table 5 ] .
similar miscarriage rates between groups were observed after excluding this confounder in our study and courbiere 's series .
comparison of pregnancy outcome between ohss and non - ohss group , literature review  : data not mentioned . : compared with non - ohss patients , the multiple pregnancy rate of ohss patients increased 58%86% ; the rate of perinatal complication including preterm birth , lbw and stillbirth , of ohss patients increased 2631% . : compared with non - ohss patients , the clinical pregnancy rate of ohss patients increased 98%168% .
pih : pregnancy - induced hypertention ; lbw : low birth weight ; ohss : ovarian hyperstimulation syndrome .
some authors have postulated that systemic vascular dysfunction and microthromboembolic events might affect trophoblastic invasion , leading to placental insufficiency .
thromboembolic events occurred in four of the 40 ohss pregnant patients in courbiere 's study , characterized by increased thromboembolic events up to 10% , with a comparably higher rate of preterm than non - ohss pregnant patients .
we may hypothesize that this seemingly higher rate of preterm may be due to thrombosis .
not all of the thrombosis in ivf patients was correlated with ohss , and ivf pregnant patients complicated by ohss had an increased risk of arterial thrombosis .
therefore , ohss and pregnancy could be viewed as precipitating factors for thrombosis in ivf .
supraphysiological ovarian stimulation results in e2 levels greater than those in natural conception ( nc ) cycles and causes e2 levels in the early stage to be similar to those in the late stage of the first trimester of nc .
previous studies showed that the high maternal e2 environment in the first trimester was correlated with increased risks of lbw and sga .
additionally , the birth rates of singleton lbw and singleton sga of fresh et were significantly higher than those of frozen et and nc ( 6.3% , 4.4% , and 3.6% , and 6.9% , 5.0% , and 4.8% , respectively ) .
large - scale studies in china on the epidemiology of sga and lbw are still lacking .
some hospital - based studies and regional investigations have described that the rate of preterm birth ranges from 3.1% to 5.8% , lbw is 1.6% , and sga is 2.9% .
in the aggregate series , the rate of singleton preterm birth was 8.8% , singleton lbw was 8.0% , and singleton sga was 7.2% .
generally , rates of preterm birth and lbw or sga were higher in ivf cycles than in nc .
in conclusion , ohss , which occurs in the luteal phase or early pregnancy of ivf patients and represents transient abnormal hemodynamics , was not found to exert any obviously adverse effect on the subsequent pregnancy .
however , whether ohss would exert adverse effect on the offsprings of ivf mothers in the long - term , required further studies .
 background : the effect of ovarian hyperstimulation syndrome ( ohss ) on pregnancy outcomes of in vitro fertilization ( ivf ) patients is still ambiguous . 
 this study aimed to analyze pregnancy outcomes of ivf with or without ohss in chinese patients.methods:a retrospective cohort study was undertaken to compare pregnancy outcomes between 190 women with ohss and 197 women without ohss . 
 we examined the rates of clinical pregnancy , multiple pregnancies , miscarriage , live birth , preterm delivery , preterm birth before 34 weeks gestation , cesarean delivery , low birth weight ( lbw ) , and small - for - gestational age ( sga ) between the two groups . 
 odds ratios ( ors ) and 95% confidence intervals ( cis ) of measure of clinical pregnancy were also analyzed.results:the clinical pregnancy rate of ohss patients was significantly higher than that of non - ohss patients ( 91.8% vs. 43.5% , p < 0.001 ) . 
 after controlling for drug protocol and causes of infertility , the adjusted ors of moderate ohss and severe / critical ohss for clinical pregnancy were 4.65 ( 95% ci , 1.8611.61 ) and 5.83 ( 95% ci , 3.459.86 ) , respectively . 
 there were no significant differences in rates of multiple pregnancy ( 4.0% vs. 3.7% ) and miscarriage ( 16.1% vs. 17.5% ) between the two groups . with regard to ongoing clinical pregnancy 
 , we also found no significant differences in the rates of live birth ( 82.1% vs. 78.8% ) , preterm delivery ( 20.9% vs. 17.5% ) , preterm birth before 34 weeks gestation ( 8.6% vs. 7.9% ) , cesarean delivery ( 84.9% vs. 66.3% ) , lbw ( 30.2% vs. 23.5% ) , and sga ( 21.9% vs. 17.6% ) between the two groups.conclusion:ohss , which occurs in the luteal phase or early pregnancy in ivf patients and represents abnormal transient hemodynamics , does not exert any obviously adverse effect on the subsequent pregnancy . 
I
M
Study subjects
Inclusion and exclusion criteria
Treatments
Outcome indicators
Statistical analysis
R
D
Financial support and sponsorship
Conflicts of interest