Even High Normal Blood Pressure Affects Live Birth Rate in Women Undergoing Fresh Embryo Transfer

Huijun Chen; Xiaoli Zhang; Sufen Cai; Jian Li; Sha Tang; Carl-Friedrich Hocher; Benjamin Rösing; Liang Hu; Ge Lin; Fei Gong; Bernhard K. Krämer; Berthold Hocher

Disclosures

Hum Reprod. 2022;37(11):2578-2588.

Abstract and Introduction

Abstract

Study Question: Do differences in blood pressure within the normal range have any impacts on the live birth rate (primary outcome) or biochemical pregnancy rate (beta-hCG positivity), clinical pregnancy rate (heart beating in ultrasound), abortion rate and ectopic pregnancy rate (secondary outcomes) of fresh embryo transfer in women undergoing their IVF/ICSI treatment?

Summary Answer: Even rather small differences in baseline blood pressure in women with normal blood pressure according to current guidelines undergoing fresh embryo transfer after IVF/ICSI affects substantially the live birth rate.

What is Known Already: Pre-pregnancy hypertension is a well-known risk factor for adverse pregnancy events such as preeclampsia, fetal growth restriction, placental abruption and adverse neonatal events. It is likewise well known that hypertension during pregnancy in women undergoing ART is associated with adverse pregnancy outcomes. However, whether blood pressure at the high end of the normal range has an impact on ART is unknown.

Study Design, Size, Duration: It is a prospective observational cohort study based on a single IVF center between January 2017 and December 2018.

Participants/Materials, Setting, Methods: Two thousand four hundred and eighteen women with normal blood pressure undergoing fresh embryo transfer after IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya were enrolled in this study.

Main Results and the Role of Chance: Blood pressure was measured at the first visit when women consulted the IVF center due to infertility. In women with a successful pregnancy outcome (1487 live births out of 2418 women undergoing fresh embryo transfer after IVF/ICSI), systolic blood pressure (SBP) (114.1 ± 9.48 mmHg versus 115.4 ± 9.8 mmHg, P = 0.001) and diastolic blood pressure (DBP) (74.5 ± 7.5 mmHg versus 75.3 ± 7.34 mmHg, P = 0.006) were lower than in those who did not achieve live births. Multivariate logistic regression analysis revealed that SBP (OR: 0.987, 95% CI: 0.979–0.996, P = 0.004) and DBP (OR: 0.986, 95% CI: 0.975–0.998, P = 0.016) were negatively associated with live birth. Similarly, SBP was significantly negatively related to clinical pregnancy rate (OR: 0.990, 95% CI: 0.981–0.999, P = 0.033), while for DBP the association was not statistically significant (OR: 0.994, 95% CI: 0.982–1.006, P = 0.343). However, both SBP and DBP were positively associated with miscarriage OR: 1.021 (95% CI: 1.004–1.037, P = 0.013) and OR: 1.027 (95% CI: 1.005–1.049, P = 0.014), respectively. Both SBP and DBP were unrelated to biochemical pregnancy (hCG positivity), implantation and ectopic pregnancy rate.

Limitations, Reasons for Caution: Whether lowering blood pressure before initiating ART treatment in women with SBP or DBP higher than the thresholds defined in our study will confer a benefit is unknown. Also, we cannot exclude bias due to different ethnicities. Moreover, participants in our study only received fresh embryo transfer, whether the results could apply to frozen embryo transfer is unclear.

Wider Implications of the Findings: Our study challenges the current blood pressure goals in women undergoing fresh embryo transfer after IVF/ICSI. Further studies are needed to figure out the mechanism and effective approach to increase IVF/ICSI pregnancy outcomes.

Study Funding/Competing Interest(S): Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare that there were no conflicts of interest in this study.

Trial Registration Number: N/A.

Introduction

ART has been developed rapidly over the past few decades. Currently, the overall clinical pregnancy rate of ART is over 50% (Niederberger et al., 2018). Many factors influence the success of a clinical pregnancy such as maternal age, ovarian reserve, infertility duration and type, hormone levels and endometrial receptivity (Hu et al., 2018; Hwang et al., 2020; Xie et al., 2020). However, there are still some unknown risk factors that could affect the pregnancy outcomes of ART.

Pre-pregnancy hypertension is a well-known risk factor for adverse pregnancy events such as preeclampsia, fetal growth restriction, placental abruption and adverse neonatal events (Bramham et al., 2014; Magee et al., 2016). A cohort study on 109 932 pregnancies including 1417 (1.3%) women with chronic hypertension reported that maternal hypertension at conception was associated with increased risk of stillbirth, small for gestational age (SGA), gestational diabetes mellitus, iatrogenic preterm birth (PTB) <37 weeks and elective cesarean section (CS), decreased risk of large for gestational age and had no significant effect on late miscarriage, spontaneous PTB or emergency cesarean section (Panaitescu et al., 2017). Similarly, another study on 352 patients with chronic hypertension found that maternal chronic hypertension was also associated with lower birth weight, lower Apgar score and the number of intrauterine complications such as intrauterine growth restriction (IUGR), stillbirth and placental abruption (Akbar et al., 2019).

It is likewise well known that hypertension during pregnancy in women undergoing ART is associated with adverse pregnancy outcomes. Women with hypertension who conceive may experience even more placental complications, in particular SGA, as well as other adverse maternal and neonatal outcomes (such as prematurity and cesarean delivery) than do similar women with unassisted conceptions (Dayan et al., 2016). Pregnancy-induced hypertension after frozen embryo transfer (FET) and oocyte donation is associated with a substantially increased rate of PTB (Stern et al., 2021). In addition, a meta-analysis including 66 longitudinal studies showed that all pregnancy-related hypertensive disorders were increased following any invasive ART (Thomopoulos et al., 2017).

The standard definition of diagnostic criteria for hypertension does not consider outcome data of pregnancy. Hypertension was defined as systolic blood pressure (SBP) over 140 mmHg, diastolic blood pressure (DBP) over 90 mmHg or taking antihypertensive medicine (Liu, 2020). They are based on the relationship between cardiovascular/renal diseases and blood pressure. The optimal blood pressure at conception for major pregnancy outcomes such as live birth rate especially in women undergoing ART is simply unknown. The aim of our prospective observational study was thus to analyze the relationship between blood pressure before initiation of ART and major birth outcomes such as live birth rate.

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Table I. Demographic and baseline clinical characteristics of participants according to live birth.
	Live birth (n = 1487)	No-live birth (n = 931)	P-value
Age years, mean (SD)	29.1 (3.40)	29.6 (3.84)	<0.01
Menstrual cycle days, mean (SD)	35.2 (16.77)	37.5 (21.57)	<0.01
Infertility reason
Fallopian tube abnormalities	92.3 (1372/1487)	90.8 (845/931)	0.19
Ovulation disorders (PCOS)	26.7 (397/1487)	29.2 (272/931)	0.18
Infertility type
Primary	55.2 (821/1487)	48.9 (455/931)	<0.01
Secondary	44.8 (666/1487)	51.1 (476/931)	0.14
Parity	15.5 (230/1487)	17.7 (165/931)
Pre-existing diseases			0.78
Diabetes	0.5 (8/1487)	0.4 (4/931)	0.67
HBV carrier	3.6 (54/1487)	4.0 (37/931)
Previous history			0.94
Tuberculosis	2.1 (31/1487)	2.0 (19/931)	0.85
Heart diseases	0.1 (2/1487)	0.1 (1/931)	0.79
Urinary tract affection	0.3 (4/1487)	0.2 (2/931)	0.25
Treponema pallidum affection	0.8 (12/1487)	1.3 (12/931)	0.66
Condyloma acuminatum	0.3 (4/1487)	0.1 (1/931)	0.79
Pelvic inflammatory disease	8.5 (126/1487)	8.2 (76/931)
BMI kg/m², mean (SD)	21.4 (2.4)	21.5 (2.39)	0.32
Waist circumference cm, mean (SD)	73.9 (7.71)	74.4 (7.74)	0.12
Hip circumference cm, mean (SD)	90.6 (7.05)	90.8 (6.68)	0.57
Waist-to-hip ratio, mean (SD)	0.8 (0.05)	0.8 (0.05)	0.08
Infertility duration years, mean (SD)	3.5 (2.28)	3.6 (2.40)	0.27
AMH ng/ml, mean (SD)	7.1 (4.79)	7.2 (5.26)	0.81
AFC	24.9 (11.66)	25.3 (12.73)	0.45
Basal FSH mIU/ml, mean (SD)	5.8 (1.63)	5.8 (1.50)	0.99
Basal LH mIU/ml, mean (SD)	4.5 (4.95)	4.3 (2.89)	0.27
Basal FSH/LH, mean (SD)	1.8 (1.79)	1.7 (0.93)	0.61
Basal E2 pg/ml, mean (SD)	40.1 (37.72)	38.6 (27.77)	0.30
Basal P ng/ml, mean (SD)	0.4 (1.28)	0.4 (1.19)	0.62
Basal T ng/ml, mean (SD)	0.5 (2.89)	0.3 (0.97)	0.08
Total 25(OH)D, ng/ml mean (SD)	20.1 (4.87)	19.9 (5.23)	0.48
Free 25(OH)D pg/ml, mean (SD)	4.8 (1.03)	4.8 (1.02)	0.36
Pulse beats/min, mean (SD)	81.9 (9.79)	81.6 (9.98)	0.52
Systolic blood pressure mmHg, mean (SD)	114.0 (9.48)	115.4 (9.80)	<0.01
Diastolic blood pressure mmHg, mean (SD)	74.5 (7.50)	75.3 (7.34)	<0.01
Pulse pressure mmHg, mean (SD)	39.6 (7.11)	40.1 (7.35)	0.11
Mean arterial pressure mmHg, mean (SD)	87.7 (7.50)	88.7 (7.48)	<0.01

PCOS, polycystic ovary syndrome; AMH, anti-Müllerian hormone; AFC, antral follicle count; E₂, estradiol; P, progesterone; T, testosterone.
Data are given as % (n/N) unless stated otherwise.
More baseline characteristics of the study population are given in in Supplementary Table SI.

Table II. Controlled ovarian hyperstimulation characteristics and laboratory outcomes in participants according to live birth.
	Live birth (n = 1487)	No-live birth (n = 931)	P-value
Protocol
Long protocol	77.34 (1150/1487)	76.69 (714/931)	0.71
Ultra-long protocol	22.63 (337/1487)	23.31 (217/931)
Gn dosage IU, mean (SD)	2226.26 (935.95)	2304.30 (918.80)	0.03
Gn duration days, mean (SD)	10.76 (1.84)	10.83 (1.82)	0.46
E2 on hCG day pg/ml, mean (SD)^a	3660.26 (1334.54)	3579.36 (1360.32)	0.14
P on hCG day ng/ml, mean (SD)^a	0.64 (0.28)	0.64 (0.29)	0.65
LH on hCG day mIU/ml, mean (SD)^a	1.70 (0.87)	1.68 (0.75)	0.70
hCG dosage for triggering IU, mean (SD)	6263.28 (1499.82)	6272.82 (1419.22)	0.21
No. of oocytes retrieved, mean (SD)	12.35 (4.68)	11.68 (4.72)	0.48
No. of MII oocytes^b, mean (SD)	10.98 (4.37)	10.31 (4.32)	<0.01
No. of 2PN zygotes, mean (SD)	7.16 (3.40)	6.71 (3.50)	<0.01
Fertilization methods
IVF	68.33 (1016/1487)	71.43 (665/931)	0.22
ICSI	16.81 (250/1487)	15.90 (148/931)
IVF+ICSI	14.86 (221/1487)	12.67 (118/931)
Fertilization rate (%), mean (SD),	66.42 (20.30)	65.33 (20.82)	0.21
Day 3 good-quality embryo rate	65.38 (5905/9032)	64.49 (3355/5202)	0.29
Blastocyst formation rate	35.74 (1770/4952)	33.04 (1021/3090)	0.01
EM thickness before ET mm, mean (SD)	13.52 (2.09)	13.14 (2.14)	<0.01
Number of embryos transferred, mean (SD)	1.91 (0.29)	1.89 (0.32)	0.06
Day3 embryo	1.98 (0.13)	1.97 (0.18)	0.02
Blastocyst	1.56 (0.50)	1.55 (0.50)	0.90
Top embryo transfer rate (%)	82.22 (2335/2840)	77.96 (1369/1756)	<0.01

D3, Day 3; E₂, estradiol; Gn, gonadotropin; EM, endometrium; GV, germinal vesicle; MI, metaphase I; MII, metaphase II; 2PN, pronucleus; ET, embryo transfer; good-quality embryo, D3 embryo ≥7C-II, blastocyst ≥4BB; fair embryo, D3 embryo <7C-II, blastocyst <4BB.
^ahCG day: the last day of ovarian stimulation, hCG was injected to trigger the final maturation of oocytes.
^bReflects oocytes quality, only MII oocyte can be fertilized.
Data are given as % (n/N) unless stated otherwise.

Table III. Multivariate logistic regression analysis for live birth according to systolic blood pressure (stepwise regression).
	B	P-value	Odds ratio	95% CI of odds ratio
	B	P-value	Odds ratio	Lower bound	Upper bound
Age (years)	−0.03	<0.01	0.97	0.94	0.99
Menstrual cycle (days)	−0.01	0.03	0.99	0.99	1.00
Systolic blood pressure (mmHg)	−0.01	<0.01	0.99	0.98	1.00
ESR (mm/h)	−0.01	0.01	0.99	0.98	1.00
Endometrial thickness (mm)	0.08	<0.01	1.1	1.04	1.12
The number of top embryos transferred	0.14	<0.01	1.15	1.04	1.28
Constant	0.03	0.01	1.03	1.01	1.05

We added factors to the regression models that were significantly different in the baseline characteristics according to live birth yes/no (see also Tables I and II as well as Supplementary Table SI): age, menstrual cycle length, systolic blood pressure, diastolic blood pressure, mean arterial pressure, ESR, PLT, gonadotrophins dosage, the number of MII oocytes, the number of 2PN zygotes, endometrial thickness before embryo transfer, the number of Day 3 embryo transferred and the number of top embryos transferred into regression stepwise forward model. All these variables are continuous variables. Considering the interaction effect of systolic, diastolic blood pressure and mean arterial pressure we put them into the regression model separately.
ESR, erythrocyte sedimentation rate; PLT, platelets.

Table IV. Multivariate logistic regression analysis for live birth according to diastolic blood pressure (stepwise regression).
	B	P-value	Odds ratio	95% CI of odds ratio
	B	P-value	Odds ratio	Lower bound	Upper bound
Age (years)	−0.04	<0.01	0.97	0.94	0.99
Menstrual cycle (days)	−0.01	0.02	1.00	1.00	1.00
Diastolic blood pressure (mmHg)	−0.01	0.02	0.99	0.98	1.00
ESR (mm/h)	−0.01	0.01	0.99	0.98	1.00
Endometrial thickness (mm)	0.08	<0.01	1.08	1.04	1.12
The number of top embryos transferred	0.14	0.01	1.15	1.04	1.28
MII oocytes	0.03	0.01	1.03	1.01	1.05
Constant	1.35	0.04	3.84

ESR, erythrocyte sedimentation rate.

Table V. Multivariate logistic regression analysis for live birth according to mean arterial pressure (stepwise regression).
	B	P-value	Odds ratio	95% CI of odds ratio
	B	P-value	Odds ratio	Lower bound	Upper bound
Age (years)	−0.04	<0.01	0.97	0.94	0.99
Menstrual cycle (days)	−0.01	0.03	1.00	0.99	1.00
Mean arterial pressure (mmHg)	−0.02	<0.01	0.98	0.97	1.00
ESR (mm/h)	−0.01	0.01	0.99	0.98	1.00
Endometrial thickness	0.08	<0.01	1.08	1.04	1.12
The number of top embryos transferred	0.14	0.01	1.15	1.04	1.28
MII oocytes	0.03	0.01	1.03	1.01	1.05
Constant	1.75	0.01	5.72

ESR, erythrocyte sedimentation rate.

Table VI. Pregnancy outcomes and prenatal outcomes of participant according to systolic and diastolic blood pressure cut-off value.
	SBP < 119.5 mmHg (n = 1797)	119.5 ≤ SBP < 140 mmHg (n = 621)	P-value	DBP < 69.5 mmHg (n = 557)	69.5 ≤ DBP < 90 mmHg (n = 1861)	P-value
hCG positive rate	72.51 (1303/1797)	69.73 (433/621)	0.18	74.51 (415/557)	70.98 (1321/1861)	0.11
Clinical pregnancy rate	69.67 (1252/1797)	64.73 (402/621)	0.02	72.71 (405/557)	67.11 (1249/1861)	0.01
Implantation rate	52.56 (1799/3423)	50.81 (596/1173)	0.30	54.01 (572/1059)	51.54 (1823/3537)	0.16
Ectopic pregnancy rate	2.00 (25/1252)	1.74 (7/402)	0.75	1.98 (8/405)	1.92 (24/1249)	0.95
Ongoing pregnancy rate	65.83 (1183/1797)	60.55 (376/621)	0.02	69.66 (388/557)	62.92 (1171/1861)	<0.01
Early miscarriage rate	9.58 (120/1252)	14.18 (57/402)	0.01	6.67 (27/405)	12.01 (150/1249)	<0.01
Live birth rate	63.05 (1133/1797)	57.00 (354/621)	0.01	67.50 (376/557)	59.70 (1111/1861)	<0.01
Singleton	65.31 (740/1133)	66.10 (234/354)	0.79	65.96 (248/376)	65.35 (726/1111)	0.83
Twins	34.69 (393/1133)	33.90 (120/354)		34.04 (128/376)	34.65 (385/1111)
Number of boys	52.10 (795/1526)	53.16 (252/474)	0.68	54.17 (273/504)	51.74 (774/1496)	0.35
Number of girls	47.90 (731/1526)	46.84 (222/474)		45.83 (231/504)	48.26 (722/1496)
Birthweight (all live birth)
<2500 g	24.57 (375/1526)	25.53 (121/474)		29.37 (148/504)	23.26 (348/1496)	0.02
2500–4000 g	72.87 (1112/1526)	70.68 (335/474)	0.31	67.66 (341/504)	73.93 (1106/1496)
≥4000 g	2.56 (39/1526)	3.80 (18/474)		2.98 (15/504)	2.81 (42/1496)
Birthweight (full-term live birth)
<2500 g	12.27 (144/1174)	13.90 (51/367)		14.29 (53/371)	12.14 (142/1170)	0.49
2500–4000 g	84.41 (991/1174)	81.20 (298/367)	0.24	81.67 (303/371)	84.27 (986/1170)
≥4000 g	3.32 (39/1174)	4.90 (18/367)		4.04 (15/371)	3.59 (42/1170)
Gestation weeks
<37 weeks	17.48 (198/1133)	17.80 (63/354)	0.89	19.95 (75/376)	16.74 (186/1111)	0.16
≥37 weeks	82.52 (935/1133)	82.20 (291/354)		80.05 (301/376)	83.26 (925/1111)
Delivery methods
Natural labor	29.21 (331/1133)	26.55 (94/354)	0.33	28.99 (109/376)	28.44 (316/1111)	0.84
Cesarean section	70.79 (802/1133)	73.45 (260/354)		71.01 (267/376)	71.56 (795/1111)
Prenatal complications
Gestational diabetes mellitus	10.07 (181/1797)	10.31 (64/621)	0.87	9.69 (54/557)	10..26 (191/1861)	0.70
Hypertensive disorders complicating pregnancy	1.73 (31/1797)	2.74 (17/621)	0.12	1.80 (10/557)	2.04 (38/1861)	0.71
Anemia	8.63 (155/1797)	6.44 (40/621)	0.09	10.05 (56/557)	7.47 (139/1861)	0.05
Edema	9.35 (168/1797)	8.05 (50/621)	0.33	11.13 (62/557)	8.38 (156/1861)	0.05
Polyhydramnios	0.17 (3/1797)	0	0.18	0.36 (2/557)	0.05 (1/1861)	0.07
Oligohydramnios	0.83 (15/1797)	0.48 (3/621)	0.36	0.90 (5/557)	0.70 (13/1861)	0.63
Placenta previa	0.39 (7/1797)	0.81 (5/621)	0.20	0.90 (5/557)	0.38 (7/1861)	0.12
Placenta abruption	0.11 (2/1797)	0.16 (1/621)	1.00	0	0.16 (3/1861)	0.79
Intrauterine hypoxia	0.39 (7/1797)	0.16 (1/621)	0.69	0.72 (4/557)	0.21 (4/1861)	0.16
Respiratory tract infection	0	0	NS	0	0	NS