Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008–2016): A cohort study

Gizachew A Tessema; Siri E Håberg; Gavin Pereira; Annette K Regan; Jennifer Dunne; Maria C Magnus

doi:10.1371/journal.pmed.1004129

. 2022 Nov 22;19(11):e1004129. doi: 10.1371/journal.pmed.1004129

Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008–2016): A cohort study

Gizachew A Tessema ^1,^2,^3,^*, Siri E Håberg ³, Gavin Pereira ^1,³, Annette K Regan ^1,^4,⁵, Jennifer Dunne ¹, Maria C Magnus ³

Editor: Gordon C Smith⁶

PMCID: PMC9681073 PMID: 36413512

Abstract

Background

The World Health Organization recommends to wait at least 6 months after miscarriage and induced abortion before becoming pregnant again to avoid complications in the next pregnancy, although the evidence-based underlying this recommendation is scarce. We aimed to investigate the risk of adverse pregnancy outcomes—preterm birth (PTB), spontaneous PTB, small for gestational age (SGA) birth, large for gestational age (LGA) birth, preeclampsia, and gestational diabetes mellitus (GDM)—by interpregnancy interval (IPI) for births following a previous miscarriage or induced abortion.

Methods and findings

We conducted a cohort study using a total of 49,058 births following a previous miscarriage and 23,707 births following a previous induced abortion in Norway between 2008 and 2016. We modeled the relationship between IPI and 6 adverse pregnancy outcomes separately for births after miscarriages and births after induced abortions. We used log-binomial regression to estimate unadjusted and adjusted relative risk (aRR) and 95% confidence intervals (CIs). In the adjusted model, we included maternal age, gravidity, and year of birth measured at the time of the index (after interval) births. In a sensitivity analysis, we further adjusted for smoking during pregnancy and prepregnancy body mass index. Compared to births with an IPI of 6 to 11 months after miscarriages (10.1%), there were lower risks of SGA births among births with an IPI of <3 months (8.6%) (aRR 0.85, 95% CI: 0.79, 0.92, p < 0.01) and 3 to 5 months (9.0%) (aRR 0.90, 95% CI: 0.83, 0.97, p = 0.01). An IPI of <3 months after a miscarriage (3.3%) was also associated with lower risk of GDM (aRR 0.84, 95% CI: 0.75, 0.96, p = 0.01) as compared to an IPI of 6 to 11 months (4.5%). For births following an induced abortion, an IPI <3 months (11.5%) was associated with a nonsignificant but increased risk of SGA (aRR 1.16, 95% CI: 0.99, 1.36, p = 0.07) as compared to an IPI of 6 to 11 months (10.0%), while the risk of LGA was lower among those with an IPI 3 to 5 months (8.0%) (aRR 0.84, 95% CI: 0.72, 0.98, p = 0.03) compared to an IPI of 6 to 11 months (9.4%). There was no observed association between adverse pregnancy outcomes with an IPI >12 months after either a miscarriage or induced abortion (p > 0.05), with the exception of an increased risk of GDM among women with an IPI of 12 to 17 months (5.8%) (aRR 1.20, 95% CI: 1.02, 1.40, p = 0.02), 18 to 23 months (6.2%) (aRR 1.24, 95% CI: 1.02, 1.50, p = 0.03), and ≥24 months (6.4%) (aRR 1.14, 95% CI: 0.97, 1.34, p = 0.10) compared to an IPI of 6 to 11 months (4.5%) after a miscarriage. Inherent to retrospective registry-based studies, we did not have information on potential confounders such as pregnancy intention and health-seeking bahaviour. Furthermore, we only had information on miscarriages that resulted in contact with the healthcare system.

Conclusions

Our study suggests that conceiving within 3 months after a miscarriage or an induced abortion is not associated with increased risks of adverse pregnancy outcomes. In combination with previous research, these results suggest that women could attempt pregnancy soon after a previous miscarriage or induced abortion without increasing perinatal health risks.

In a Norwegian cohort study, Dr Gizachew Tessema and colleagues investigate the association between interpregnancy interval and adverse pregnancy outcomes, among pregnancies following miscarriages or induced abortions.

Author summary

Why was this study done?

The World Health Organization recommends to wait at least 6 months after miscarriage and induced abortion before becoming pregnant again to avoid complications in the next pregnancy, although the evidence-based underlying this recommendation is scarce.
The differences in pregnancy outcomes according to interpregnancy interval (IPI) after miscarriage as opposed to induced abortions remains unclear.

What did the researchers do and find?

Using data linkage from registry data in Norway, we explored the risks of adverse pregnancy outcomes for births after a miscarriage and after an induced abortion separately. While 3 out of 5 women with previous miscarriages conceive within 6 months, 1 out of 5 women with previous induced abortions conceive within 6 months.
Our study suggests that conceiving within 6 months after a miscarriage or an induced abortion is not associated with increased risks of adverse pregnancy outcomes. The results are consistent for IPI as short as 3 months.
There was no evidence of higher risks of adverse pregnancy outcomes among women with an IPI of greater than 12 months after a miscarriages or induced abortions, with the exception of a modest increased risk of gestational diabetes mellitus.

What do these findings mean?

Our results do not support current international recommendations to wait at least 6 months after a miscarriage or an induced abortion.
In combination with previous research, our results are reassuring for families who attempt pregnancy soon after a miscarriage or induced abortion.
These findings motivate a review of current international guidelines for birth spacing after a miscarriage or an induced abortion.

Introduction

Miscarriage or the loss of the fetus before viability occurs in 12% to 15% of recognised pregnancies [1–3], and induced abortions occur in up to 15% of pregnancies in high-income countries [4]. Miscarriage causes significant psychological distress for couples [5], and induced abortions are performed for many different reasons including medical, financial, or social reasons [6,7]. The optimal interpregnancy interval (IPI)—the time between the end of one pregnancy and the start of the next—after pregnancy loss remains unclear. Based on a single study from Latin America, which reported that an IPI less than 6 months following miscarriages and induced abortions was associated with increased risk of adverse perinatal outcomes in the next pregnancy (odds ratio (OR) > 2.0 for preterm birth (PTB) and low birth weight (LBW)) [8], the World Health Organization (WHO) has recommended since 2007 that women wait at least 6 months before trying to become pregnant again after a miscarriage or induced abortion [9]. The study from Latin America did not distinguish between miscarriages and induced abortions, which is likely to have resulted in substantial heterogeneity in the underlying risk profile. Furthermore, when large cohort studies from Scotland (OR 0.89, 95% confidence interval (CI): 0.81, 0.98 for PTB; OR 0.84, 95% CI: 0.71, 0.89 for LBW; and OR 1.18, 95% CI: 0.82, 1.23 for preeclampsia) and California (OR 0.87, 95% CI: 0.81, 0.94 for PTB) subsequently evaluated this research question, they observed no increased risk of adverse pregnancy outcomes in births that followed a short IPI (<6 months) after a miscarriage [10,11]. However, an increased risk of adverse pregnancy outcomes in pregnancies that followed a short (<6 months) IPI after induced abortions was observed in Finland (OR 1.44, 95% CI: 1.10, 1.88 for PTB) [12]. Studies investigating risks of maternal complications after long IPI following a live birth indicated increased risks of gestational diabetes mellitus (GDM) in Canada (OR 1.66, 95% CI: 1.39, 2.00) and preeclampsia in Australia (OR 1.28, 95% CI: 1.17, 1.41) [13,14]. The differences in pregnancy outcomes according to IPI after miscarriage as opposed to induced abortions therefore remains unclear. Besides the available large cohort studies described above, other studies with smaller sample size (n < 1,100) were conducted to explore pregnancy outcomes after a miscarriage; however, these studies investigated limited outcomes such as recurrent miscarriage and PTB [15–18]. Therefore, there is a dearth of research exploring the subsequent risks of other pregnancy outcomes including preeclampsia and GDM following miscarriage or induced abortion. Our objective was therefore to investigate the risk of a broad range of adverse pregnancy outcomes such as PTB, spontaneous PTB, small for gestational age (SGA), large for gestational age (LGA), preeclampsia, and GDM according to IPI for pregnancies that follow miscarriages or induced abortions separately, with the intention of informing intrapartum care following early pregnancy loss.

Methods

Study design and data sources

We conducted a retrospective cohort study using 3 Norwegian national health registries: the Medical Birth Registry of Norway (birth registry) [19], the Norwegian Patient Registry (patient registry), and the General Practitioner database [20]. Using these 3 registries, we identified all registered pregnancies in Norway with an estimated date of conception between January 1, 2008 and December 31, 2016. The birth registry includes mandatory notifications on pregnancies in Norway ending after 12 gestational weeks and provided information on live births, stillbirths, miscarriages, and late induced abortions.

The patient and general practitioners’ registries provided information on induced abortions and miscarriages irrespective of gestational weeks. A detailed description of the processes for identification of miscarriage and induced abortions and data linkage procedures have been described previously [21]. In summary, we used primary and secondary diagnostic codes indicating the presence of a miscarriage or induced abortions. From the patient registry, information on miscarriages before 12 completed gestational weeks were captured using the following International Classification of Diseases version 10 (ICD-10) codes: missed abortion (O02.1); other specified abnormal products of conception (O02.8); abnormal product of conception, unspecified (O02.9); spontaneous abortion (O03); and threatened abortion (O20.0). Similarly, induced abortions were identified using the following ICD-10 codes: medical abortion (O04), other abortion (O05), and unspecified abortion (O06). In the general practitioner database, we captured information on miscarriages before 12 completed gestational weeks using the following ICPC-2 codes: bleeding in pregnancy (W03) and spontaneous abortion (W82). We only counted registrations of threatened abortion and bleeding in pregnancy codes as miscarriage or induced abortions if they did not subsequently end in a registration in the birth registry.

In this study, a fetal death at 20 gestational weeks or later or with a birthweight of 400 grams or more was considered a stillbirth, while fetal deaths prior to 20 gestational weeks with a birthweight less than 400 grams were defined as miscarriages. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline [22] (S1 STROBE Checklist).

Participants and exclusions

In the study period, there were a total of 108,444 miscarriages of which 75,059 were followed by subsequent pregnancies, and 127,912 induced abortions of which 57,282 were followed by subsequent pregnancies. After excluding pregnancies ended prior to 20 weeks, we were left with 50,343 births after miscarriages and 24,248 births after induced abortions. By further excluding multiple births, births with gestational age ≥45 weeks, late induced abortions, births with missing maternal age, and births with missing information on birthweight or offspring sex, we had a sample size of 49,058 index births after previous miscarriage and 23,707 index births after previous induced abortions. The index birth was defined as the birth after the IPI. A total of 1,647 (3.4%) women after miscarriages and 552 (2.3%) women after induced abortions contributed more than one birth in the study population (Fig 1).

Exposure

IPI was defined as the time between the date of previous miscarriage or induced abortion and date of the conception (date of birth minus gestational age) of the subsequent live or stillbirth recorded in the birth registry. The gestational age estimation was largely based on ultrasound estimates (99%). We categorised IPI into 6 categories: <3, 3 to 5, 6 to 11, 12 to 17, 18 to 23, and ≥24 months, with 6 to 11 months as the reference category, consistent with the WHO guidelines and literature [9,10,23].

Outcomes

We studied 6 adverse pregnancy outcomes: PTB, spontaneous PTB, SGA, LGA, preeclampsia, and GDM. [10,24–26] PTB was defined as birth occurring before 37 completed weeks of gestation. Spontaneous PTB was defined as PTB with spontaneous onset of labour. SGA and LGA were defined as a birthweight in the lowest or highest 10th percentiles, based on the gestational week and sex-specific distributions of birthweight among all births in the birth registry. Preeclampsia was defined as any registration of preeclampsia, eclampsia, or HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count). GDM was defined based on the WHO-1999 criteria when fasting plasma glucose level ≥7.0 mmol/L or glucose tolerance test of ≥7.8 mmol/L and <11.0 mmol/l [27].

Statistical analysis

We evaluated the relationship between IPI and the pregnancy outcomes separately for births after miscarriages and births after induced abortions. We used log-binomial regression to estimate unadjusted and adjusted relative risk (aRR) and 95% CIs [17]. Robust cluster variance estimation was used to account for women who had more than one pregnancy during the study period. We adjusted for maternal age using restricted cubic splines with 5 knots (placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population; [28]), gravidity (categorical: 1, 2, 3, or more), and year of birth (continuous) at the time of index birth. We tested for the multiplicative interaction between IPI and maternal age, and the interaction between IPI and parity, using likelihood ratio test comparing models with and without interaction terms. We calculated e-values for the aRR as a measure of the minimum strength of association a confounder would have to have with the exposure and outcome to explain away the observed associations. Small e-values indicates that little unmeasured confounding is required to explain or nullify observed effects. The converse is true of high e-values. The e-value for the lower limit of the 95% CI represents the level of confounding required to render the interval estimate null [29].

We conducted sensitivity analyses additionally adjusting for prepregnancy body mass index (BMI) (using restricted cubic splines placed at 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population) and smoking during pregnancy (categorical: yes/no) for the index pregnancies with information available (n = 27,747 for births after a miscarriage; n = 13,932 for births after an induced abortion). We also explored adjustment for characteristics of the miscarriage or induced abortion prior to the index pregnancy (start of the IPI), such as maternal age, gravidity, and year of end of pregnancy [30]. Since IPI categorisation that consider <6 months in the short IPI category is widely considered in the literature and for our results to be compared with the WHO recommendation, we conducted additional analysis combining the first 2 IPI categories (<3 months and 3 to 5 months). We also conducted a sensitivity analysis restricting births from women with only 1 miscarriage (n = 47,411) or induced abortion (n = 23,185) in the cohort. All analyses were conducted using STATA version 16 (Statacorp, Texas).

Ethics statement

Ethics approval was obtained the Regional Committee for Medical and Health Research Ethics of South/East Norway (2014/404).

Results

Maternal characteristics at the time of birth after miscarriages and induced abortions

We included 49,058 index births after miscarriage and 23,707 index births after an induced abortion. The median maternal age at the index birth was 29 years (interquartile range (IQR) = 25 to 33 years) among women with births after a miscarriage and 28 years (IQR = 24 to 48) among women with births after an induced abortion (Tables 1 and 2).

Table 1. Characteristics for women with births after miscarriage and induced abortion at the time of birth after the IPI for births between 2008 and 2016 in Norway (n = 49,058).

Variable	Number (%)
Maternal age (in years)
14–19	377 (0.8)
20–24	5,148 (10.5)
25–29	13,157 (26.8)
30–34	16,174 (33.0)
35–39	10,867 (22.1)
≥40	3,335 (6.8)
Median (IQR)	29 (25–33)
Gravidity
1	19,602 (40.1)
2	14,305 (29.2)
3+	15,151 (30.8)
Prepregnancy BMI (kg/m ² )
<18.5	986 (2.0)
18.5–25	17,611 (35.9)
25–30	7,213 (14.7)
≥30	4,123 (8.4)
Missing	19,127 (39.0)
Smoking during pregnancy
No	39,302 (80.1)
Yes	3,780 (7.7)
Missing	5,976 (12.2)
Birth year
2008	238 (0.5)
2009	4,358 (8.9)
2010	5,955 (12.1)
2011	6,241 (12.7)
2012	6,330 (12.9)
2013	6,364 (12.9)
2014	6,364 (13.0)
2015	6,607 (13.5)
2016	6,585 (13.4)
IPI in months
<3	17,251 (35.2)
<6	30,076 (61.3)
6–11	9,975 (20.3)
12–17	3,653 (7.5)
18–23	1,973 (4.0)
≥24	3,381 (6.9)
Median (IQR)	4 (2–9)

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BMI, body mass index; IPI, interpregnancy interval; IQR, interquartile range.

Table 2. Characteristics for women with births after induced abortion at the time of birth after the IPI for births between 2008 and 2016 in Norway (n = 23,707).

Variable	Number (%)
Maternal age (in years)
14–19	734 (3.1)
20–24	5,531 (23.3)
25–29	8,041 (33.9)
30–34	5,944 (25.1)
35–39	2,782 (11.7)
≥40	675 (2.9)
Median (IQR)	28 (24–48)
Gravidity
1	15,082 (63.6)
2	5,233 (22.0)
3+	3,402 (14.4)
Prepregnancy BMI (kg/m ² )
18.5	765 (3.2)
18.5–25	9,523 (40.2)
25–30	3.277 (13.8)
≥30	1,583 (6.9)
Missing	8,559 (36.1)
Smoking during pregnancy
No	16,702 (70.5)
Yes	4,017 (16.9)
Missing	2,988 (12.6)
Birth year
2008	20 (0.1)
2009	933 (3.9)
2010	1,930 (8.1)
2011	2,576 (10.9)
2012	3,154 (13.3)
2013	3,455 (14.6)
2014	3,761 (15.9)
2015	3,879 (16.4)
2016	3,999 (16.9)
IPI in months
<3	1,633 (6.9)
<6	4,574 (19.3)
6–11	4,244 (17.9)
12–17	3,255 (13.7)
18–23	2,540 (10.7)
≥24	9,094 (38.4)
Median (IQR)	17 (7–34)

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BMI, body mass index; IPI, interpregnancy interval; IQR, interquartile range.

Previous miscarriage

The median IPI after a miscarriage was 4 months (IQR = 2 to 9 months); 61% (n = 30,076) conceived again within 6 months and 20% (n = 9,975) conceived between 6 and 11 months (Table 1 and Fig 2). In births following a previous miscarriage, there were 6.0% PTB, 3.5% spontaneous PTB, 9.5% SGA births, 10.3% LGA births, 3.2% preeclampsia, and 4.2% GDM (S1 Table).

In the adjusted analysis, women with an IPI <3 months (8.6%) (aRR 0.85, 95% CI: 0.79, 0.92, p < 0.01) and 3 to 5 months (9.0%) (aRR 0.89, 95% CI: 0.82, 0.96, p = 0.01) had a lower risk of SGA compared to women with an IPI of 6 to 11 months (10.1%). We also observed a lower risk of GDM (aRR 0.85, 95% CI: 0.75, 0.95, p = 0.01) among women with an IPI of <3 months (3.3%) compared to women with an IPI of 6 to 11 months (4.5%).

There was no evidence of increased risks of adverse pregnancy outcomes associated with an IPI >12 months (p > 0.05) except for GDM. For GDM, compared to IPI of 6 to 11 months (4.5%), there were increased risks for births after 12 to 17 months (5.8%) (aRR 1.20, 95% CI: 1.02, 1.40, p = 0.02), 18 to 23 months (aRR 1.24, 95% CI: 1.02, 1.50), but not for IPI ≥24 months (aRR 1.14, 95% CI: 0.97, 1.34, p = 0.10) (Table 3). The corresponding e-values were low, ranging between 1.11 and 1.83, for the associations between IPI and all adverse outcomes after previous miscarriage.

Table 3. IPI after previous miscarriage and risk of adverse pregnancy outcomes for births between 2008 and 2016 in Norway (n = 49,058).

Outcome	IPI	Number of cases (%)	RR (95% CI)	aRR (95% CI)^*	p-value for aRR	E-value aRR^** (lower 95% CI)
PTB (n = 49,058)	<3 m	1,002 (5.8)	0.94 (0.86, 1.04)	0.96 (0.87, 1.06)	0.40	1.25 (1)
	3–5 m	719 (5.6)	0.91 (0.82, 1.01)	0.92 (0.83, 1.02)	0.12	1.39 (1)
	6–11 m	615 (6.2)	Ref	Ref		Ref
	12–17 m	257 (7.0)	1.14 (0.99, 1.31)	1.14 (0.99, 1.31)	0.08	1.54 (1)
	18–23 m	150 (7.6)	1.23 (1.04, 1.45)	1.23 (1.04, 1.46)	0.02	1.76 (1.24)
	≥24 m	230 (6.8)	1.10 (0.95, 1.28)	1.14 (0.98, 1.32)	0.09	1.54 (1)
Spontaneous PTB (n = 47,780)	<3 m	592 (3.5)	0.98 (0.86, 1.11)	0.97 (0.85, 1.11)	0.64	1.21 (1)
	3–5 m	403 (3.2)	0.89 (0.78, 1.03)	0.89 (0.78, 1.03)	0.11	1.50 (1)
	6–11 m	350 (3.6)	Ref	Ref		Ref
	12–17 m	137 (3.9)	1.08 (0.89, 1.31)	1.08 (0.89, 1.31)	0.43	1.37 (1)
	18–23 m	86 (4.5)	1.25 (0.99, 1.57)	1.26 (1.00, 1.59)	0.05	1.83 (1)
	≥24 m	127 (3.9)	1.07 (0.88, 1.31)	1.12 (0.92, 1.37)	0.26	1.49 (1)
SGA (n = 49,058)	<3 m	1,483 (8.6)	0.85 (0.79, 0.92)	0.85 (0.79, 0.92)	0.00	1.63 (1.39)
	3–5 m	1,157 (9.0)	0.89 (0.82, 0.97)	0.89 (0.82, 0.96)	0.01	1.50 (1.25)
	6–11 m	1,008 (10.1)	Ref	Ref		Ref
	12–17 m	420 (11.5)	1.14 (1.02, 1.27)	1.13 (1.02, 1.26)	0.03	1.51 (1.16)
	18–23 m	197 (10.0)	0.99 (0.85, 1.14)	0.97 (0.84, 1.12)	0.70	1.21 (1)
	≥24 m	389 (11.5)	1.14 (1.02, 1.27)	1.09 (0.97, 1.21)	0.15	1.40 (1)
LGA (n = 49,058)	<3 m	1,809 (10.5)	1.02 (0.95, 1.10)	1.04 (0.97, 1.12)	0.30	1.24 (1)
	3–5 m	1,312 (10.2)	1.00 (0.93, 1.08)	1.01 (0.93, 1.09)	0.82	1.11 (1)
	6–11 m	1,021 (10.2)	Ref	Ref		Ref
	12–17 m	390 (10.7)	1.04 (0.93, 1.16)	1.05 (0.94, 1.17)	0.34	1.28 (1)
	18–23 m	197 (10.0)	0.98 (0.84, 1.13)	0.99 (0.86, 1.15)	0.92	1.11 (1)
	≥24 m	314 (9.3)	0.91 (0.80, 1.03)	0.95 (0.85, 1.08)	0.45	1.29 (1)
Preeclampsia (n = 49,058)	<3 m	512 (3.0)	0.91 (0.80, 1.05)	0.93 (0.81, 1.07)	0.29	1.36 (1)
	3–5 m	391 (3.1)	0.94 (0.81, 1.08)	0.95 (0.82, 1.09)	0.46	1.29 (1)
	6–11 m	324 (3.4)	Ref	Ref		Ref
	12–17 m	133 (3.7)	1.12 (0.92, 1.37)	1.11 (0.91, 1.35)	0.32	1.46 (1)
	18–23 m	72 (3.6)	1.12 (0.87, 1.44)	1.11 (0.86, 1.42)	0.43	1.46 (1)
	≥24 m	114 (3.4)	1.04 (0.84, 1.28)	1.01 (0.82, 1.25)	0.92	1.11 (1)
GDM (n = 49,058)	<3 m	571 (3.3)	0.74 (0.66, 0.84)	0.85 (0.75, 0.95)	0.01	1.67 (1.29)
	3–5 m	508 (4.0)	0.89 (0.79, 1.00)	0.95 (0.84, 1.08)	0.43	1.29 (1)
	6–11 m	446 (4.5)	Ref	Ref		Ref
	12–17 m	211 (5.8)	1.29 (1.10, 1.51)	1.20 (1.02, 1.40)	0.02	1.69 (1.16)
	18–23 m	122 (6.2)	1.38 (1.14, 1.68)	1.24 (1.02, 1.50)	0.03	1.79 (1.16)
	≥24 m	216 (6.4)	1.43 (1.22, 1.67)	1.14 (0.97, 1.34)	0.10	1.54 (1)

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aRR, adjusted relative risk; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age.

*Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years.

**E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

Previous induced abortion

The median IPI after a previous induced abortion was 17 months (IQR = 7 to 34 months), where 19% (n = 4,574) of births were conceived within 6 months, and 18% (n = 4,244) were conceived between 6 and 11 months (Table 2 and Fig 2). There were 5.5% PTB, 3.2% spontaneous PTB, 10.8% SGA births, 8.8% LGA births, 2.8% preeclampsia, and 3.2% GDM among births among births following induced abortions (S2 Table).

Compared with births following 6 to 11 months of IPI, there was a modest increased risk of SGA after an IPI of <3 months with a confidence interval spanning the null value (aRR 1.16, 95% CI: 0.99, 1.37, p = 0.07), and a modest decreased risk of LGA among those with an IPI of 3 to 5 months (aRR 0.84, 95% CI: 0.72, 0.98, p = 0.03). For IPI >12 months, there was no evidence of risk of adverse pregnancy outcomes (Table 4). Corresponding e-values were low, ranging between 1.21 and ≤2.55, for the associations between IPI and adverse outcomes after previous induced abortion.

Table 4. IPI after previous induced abortion and risk of adverse pregnancy outcomes for births between 2008 and 2016 in Norway (n = 23,707).

Outcome	IPI	Number of cases (%)	RR (95% CI)	aRR (95% CI)^*	p-value for aRR	E-value aRR^** (lower 95% CI)
PTB (n = 23,707)	<3 m	110 (6.7)	1.20 (0.97, 1.49)	1.17 (0.94, 1.46)	0.15	1.62 (1)
	3–5 m	157 (5.3)	0.95 (0.78, 1.16)	0.94 (0.77, 1.14)	0.53	1.32 (1)
	6–11 m	238 (5.6)	Ref	Ref		Ref
	12–17 m	150 (4.6)	0.82 (0.67, 1.00)	0.84 (0.69, 1.02)	0.08	1.67 (1)
	18–23 m	134 (5.3)	0.94 (0.77, 1.16)	0.97 (0.79, 1.20)	0.80	1.21 (1)
	≥24 m	506 (5.6)	1.00 (0.85, 1.15)	1.10 (0.94, 1.30)	0.22	1.43 (1)
Spontaneous PTB (n = 23,163)	<3 m	62 (3.9)	1.15 (0.86, 1.54)	1.13 (0.85, 1.52)	0.41	1.51 (1)
	3–5 m	102 (3.5)	1.04 (0.81, 1.34)	1.03 (0.80, 1.32)	0.83	1.21 (1)
	6–11 m	141 (3.4)	Ref	Ref		Ref
	12–17 m	67 (2.1)	0.62 (0.47, 0.83)	0.63 (0.47, 0.84)	0.00	2.55 (1.56)
	18–23 m	84 (3.4)	0.99 (0.76, 1.29)	1.02 (0.78, 1.33)	0.90	1.16 (1)
	≥24 m	295 (3.3)	0.98 (0.80, 1.19)	1.06 (0.86, 1.31)	0.56	1.31 (1)
SGA (n = 23,707)	<3 m	188 (11.5)	1.16 (0.98, 1.36)	1.16 (0.99, 1.37)	0.07	1.59 (1)
	3–5 m	318 (10.8)	1.08 (0.95, 1.24)	1.09 (0.95, 1.25)	0.23	1.40 (1)
	6–11 m	423 (10.0)	Ref	Ref		Ref
	12–17 m	363 (11.2)	1.12 (0.98, 1.28)	1.12 (0.98, 1.28)	0.09	1.49 (1)
	18–23 m	269 (10.6)	1.06 (0.92, 1.23)	1.07 (0.93, 1.24)	0.37	1.34 (1)
	≥24 m	997 (11.0)	1.10 (0.99, 1.23)	1.12 (1.00, 1.26)	0.05	1.49 (1)
LGA (n = 23,707)	<3 m	152 (9.3)	0.99 (0.83, 1.18)	0.98 (0.82, 1.17)	0.80	1.16 (1)
	3–5 m	234 (8.0)	0.84 (0.72, 0.99)	0.84 (0.72, 0.98)	0.03	1.67 (1.16)
	6–11 m	400 (9.4)	Ref	Ref		Ref
	12–17 m	307 (9.4)	1.00 (0.87, 1.15)	1.00 (0.87, 1.15)	0.99	1.00 (1)
	18–23 m	205 (8.1)	0.86 (0.73, 1.01)	0.85 (0.73, 1.01)	0.06	1.63 (1)
	≥24 m	811 (8.9)	0.95 (0.84, 1.06)	0.95 (0.84, 1.07)	0.41	1.29 (1)
Preeclampsia (n = 23,707)	<3 m	50 (3.1)	1.13 (0.81, 1.57)	1.15 (0.83, 1.60)	0.40	1.57 (1)
	3–5 m	80 (2.7)	1.00 (0.76, 1.33)	1.02 (0.77, 1.35)	0.90	1.16 (1)
	6–11 m	115 (2.7)	Ref	Ref		Ref
	12–17 m	80 (2.5)	0.91 (0.68, 1.20)	0.90 (0.68, 1.20)	0.49	1.46 (1)
	18–23 m	63 (2.5)	0.92 (0.69, 1.24)	0.91 (0.67, 1.23)	0.53	1.43 (1)
	≥24 m	277 (3.1)	1.12 (0.91, 1.39)	1.09 (0.87, 1.36)	0.46	1.40 (1)
GDM (n = 23,707)	<3 m	36 (2.2)	0.75 (0.52, 1.08)	0.75 (0.52, 1.08)	0.13	2.00 (1)
	3–5 m	76 (2.6)	0.88 (0.66, 1.16)	0.88 (0.67, 1.16)	0.37	1.53 (1)
	6–11 m	125 (3.0)	Ref	Ref		Ref
	12–17 m	98 (3.0)	1.02 (0.79, 1.33)	0.97 (0.75, 1.25)	0.81	1.21 (1)
	18–23 m	63 (2.5)	0.84 (0.62, 1.14)	0.79 (0.59, 1.06)	0.12	1.85 (1)
	≥24 m	354 (3.9)	1.32 (1.08, 1.62)	1.04 (0.85, 1.28)	0.72	1.24 (1)

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aRR, adjusted relative risk; CI, confidence interval; IPI, interpregnancy interval; GDM, gestational diabetes mellitus; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age.

**E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

Sensitivity analysis

Additional adjustment for smoking during pregnancy and prepregnancy BMI did not alter our conclusions (S3 and S4 Tables). Our results adjusting for covariates measured at the time of miscarriage or induced abortion (before interval) provided consistent findings (S5 and S6 Tables). Our analysis combining <3 months and 3 to 5 months of IPI into a <6 months category showed consistent results with estimates for IPI <3 months category (S7 and S8 Tables). Our results restring births from women with only 1 miscarriage or induced abortion in the cohort did not change our results (S9 and S10 Tables)

Discussion

We used a Norwegian national registry-linkage to investigate the association between IPI following a miscarriage or induced abortion with adverse pregnancy outcomes in the subsequent birth. Contrary to the current WHO recommendations advising women to wait a minimum of 6 months after miscarriages or induced abortions [9], we found no evidence of elevated risk of PTB, spontaneous PTB, LGA, or preeclampsia among women with a very short (<3) or short (<6 months) IPIs after a miscarriages or induced abortions. Rather, we found that the risk of SGA was lower among women with births following an IPI of <3 months and 3 to 5 months after miscarriage. We also found a lower risk of GDM among women with very short (<3 months) IPI after miscarriage. There was no evidence of higher risks of adverse pregnancy outcomes for IPIs >12 months after miscarriages or induced abortions except for a higher risk of GDM for births after miscarriages with IPIs between 12 and 23 months.

Our study is consistent with previous studies from Scotland [10] and the United States [15–17], which reported no difference or reduced risk of adverse pregnancy outcomes following short (<6 months) IPI after a previous miscarriage. Although not directly comparable to our study due to only including births after first trimester miscarriages and having a very small sample size (n = 107), our results were consistent with a study from Israel that indicated that conception shortly after a spontaneous miscarriage was not associated with adverse maternal or neonatal outcomes [31]. Our results differ from a large cohort study conducted in Latin America, which did not distinguish between miscarriages and induced abortions reporting an elevated risk of adverse pregnancy outcomes among women with an IPI of <6 months [8]. On the other hand, another study from the US considering births after miscarriages and induced abortions together showed a reduced risk of PTB [11]. Previous studies from Finland [12] and China [32] investigating the effect of IPI after induced abortions showed increased risks of PTB and SGA after short (<6 months) IPI. Unlike these studies, we observed no evidence of elevated risks of either PTB or SGA according to IPI following an induced abortion. Apart from one study from Finland [12], our study was not in agreement with previous studies that reported elevated risks of adverse pregnancy outcomes for those pregnancies with long (>24 months) IPI after miscarriages as compared to IPI 6 to 11 months [10,33,34]. As our study included women with at least 2 pregnancies occurring in less than a decade, we might not have observed adequate number of births with longer IPIs to observe any associations. There were also some differences between our study and previous studies where some studies used 18 to 23 months as reference [8,11,32], included smaller sample sizes [12,15,17,18,32], and relied on self-reported data [8,32].

Although the proportion of short (<6 months) IPI were generally high following both miscarriages and induced abortions, the proportion of short IPI that followed miscarriages (61%) were much higher than the proportion of short IPI that followed induced abortions (19%). A previous study reported over one-third of births (37%) following a stillbirth were conceived within the first 6 months [35]. However, for IPIs after live births, a study that involved 4 high-income countries including Norway showed that less than 5% of conceptions following live births occurred in the first 6 months [36]. Our findings, in combination with the previous findings of Regan and colleagues [35] indicate that women with early and late pregnancy losses (miscarriages or stillbirths) attempt pregnancy more quickly than those women whose pregnancies ended with live births. On the other hand, IPIs after induced abortions could be relatively longer if previous terminations resulted from unintended pregnancy, and, hence, these women could adopt contraceptive methods as part of routine postabortal care [37].

Our findings suggested that IPI <6 months following miscarriages may not increase the risks of adverse outcomes in the next pregnancy. One possible explanation would be that pregnancies conceived shortly after a miscarriage are more likely to be intended, and, hence, these women may seek health services with the aim of avoiding the previous unfavourable experience [10]. The reduced risk of SGA after very short (<3 months) and short (3 to 5 months) IPI in our study may support the previous hypothesis suggesting women who were able to conceive quickly after miscarriages might have better fecundity reflecting women’s high reproductive fitness in comparison to women with longer IPI [16]. Despite the assumption that women with previous pregnancies resulting in a live birth could have had nutritional depletions, which are mostly occurring in the second trimester and early postpartum period through breastfeeding [38], it is plausible that women with miscarriages would not reach at a point when nutritional depletion starts as most miscarriages usually occur in the first 12 weeks [39,40].

A large study conducted in Latin America indicated an elevated risk of adverse pregnancy outcomes despite not separating miscarriage from induced abortion [8]. The authors hypothesized that their results could be attributed to reproductive tract infections due to the possibility of unsafe abortions, which may lead to negative consequences to the growing fetus in the subsequent pregnancy. However, our results indicated no elevated risk of adverse pregnancy outcomes in those pregnancies that followed induced abortions. This could be due to the provision of safe abortion services free of cost in the public health system in Norway, and, hence, the risks of infections are minimal [37]. Studies also indicated that uterine infections are mostly associated with surgical abortions than medical terminations. In Norway, medical abortions comprising more than 80% of all abortions conducted in 2013, and 95% of these terminations were performed in the first trimester [41]. Since 2009, medical abortion services were further expanded for women to get access to self-administered misoprostol to use at home for pregnancies terminations up to 12 weeks of gestation [42].

Previous studies did not assess the association between previous miscarriage and risk of GDM in the subsequent pregnancy according to interpregnancy interval. Two Chinese studies [43,44] reported that women who had previous miscarriage had a higher risk for developing gestational diabetes during subsequent pregnancies, although their studies did not evaluate IPI specifically. In our study, while we observed an increased risk of risk of GDM for births between 12 and 23 months of IPI, we found a reduced risk of GDM for births after a very short (<3 months) IPI. The underlying mechanisms for the associations are unclear and warrant further investigations. Yang and colleagues [44] speculated that the association between previous miscarriages and GDM might have occurred due to common risk factors or shared pathological mechanisms.

The strengths of our study are its ability to provide comprehensive information of early miscarriages and induced abortions from the combination of national health registries in Norway, in addition to be able to distinguish the risks of adverse pregnancy outcomes according to IPI after a miscarriage and an induced abortion, which was not possible in most settings [8,11]. Unlike most previous studies [10,26,34] that investigated IPIs of <6 months after miscarriage or induced abortions, but not all [15,16], our study investigated the effect of IPI for very short (<3 months) and short (3 to 5 months) IPIs. To allow comparison with literature and WHO recommendation, we also estimated risk of adverse pregnancy outcomes for IPI <6 months, although the results broadly concurred with the estimates for IPI <3 months. Although the gestational age at previous miscarriage or induced abortion affects the IPI, we did not have information on exact gestational age for those miscarriages or induced abortions occurred before 12 weeks, which comprised 99% of miscarriages and 96% of induced abortions. However, we did have information on gestational age at miscarriages or induced abortions after 12 weeks, and, hence, the risk of misclassification of exposure is minimal for these pregnancies. With regard to the timing of confounder measurement, it has recently been recommended to adjust confounders for measures prior to IPI (i.e., at the time of the miscarriage or induced abortion), as these are the characteristics that may be associated both with IPI and adverse pregnancy outcomes [30,45]. Our sensitivity analysis adjusting for maternal age, gravidity, and year at the time of the miscarriage or induced abortion indicated no significant difference in the risk estimates from the main results. However, since smoking and prepregnancy BMI information were only available for pregnancies registered in the birth registry, we were not able to adjust for these variables at the time of miscarriage or induced abortion. These results were not unexpected because most of the pregnancies occurred within 1 year of miscarriage or induced abortion, and, hence, maternal characteristics including maternal age and socioeconomic status are unlikely to change significantly. Moreover, inherent to retrospective registry-based studies, we did not have information on potential confounders variables. For example, while pregnancy intention and health-seeking behaviour are likely to vary between women with longer pregnancies [46–48] but were unfortunately not available. Furthermore, we only had information on miscarriages that resulted in contact with the healthcare system. Since our study employed data from a single high-income country with better healthcare services, our results could not be generalisable to other settings with different population.

In conclusion, our study found that that conceiving within 6 months after a miscarriage or an induced abortion was not associated with increased risks of adverse pregnancy outcomes. In combination with previous research, these results suggest that women could attempt pregnancy soon after a previous miscarriage or induced abortion without increasing perinatal health risks. Our results do not support current international recommendations to wait at least 6 months after miscarriages or induced abortions.

Supporting information

S1 STROBE Checklist. STROBE checklist.

(DOCX)

Click here for additional data file.^{(33.7KB, docx)}

S1 Table. Adverse pregnancy outcomes after miscarriages between 2008 and 2016 in Norway (n = 49,058).

GDM, gestational diabetes mellitus; LGA, large for gestational age; PTB, preterm birth; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB.

(DOCX)

Click here for additional data file.^{(14.7KB, docx)}

S2 Table. Adverse pregnancy outcomes after induced abortion between 2008 and 2016 in Norway (n = 23,707).

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S3 Table. Sensitivity analysis—IPI after previous miscarriage and risk of adverse pregnancy outcomes with complete information on maternal smoking during pregnancy and prepregnancy BMI for births between 2008 and 2016 in Norway (n = 27,747).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, year of birth, maternal smoking during pregnancy, and prepregnancy BMI at the time of birth after interval. For maternal age and prepregnancy BMI variables, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years for maternal age, and 19, 21, 24, 27, and 34 kg/m² for prepregnancy BMI.

(DOCX)

Click here for additional data file.^{(30.1KB, docx)}

S4 Table. Sensitivity analysis—IPI after previous induced abortion and risk of adverse pregnancy outcomes with complete information on maternal smoking during pregnancy and prepregnancy BMI for births between 2008 and 2016 in Norway (n = 13,932).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, parity, year of birth, maternal smoking during pregnancy, and prepregnancy BMI at the time of birth after interval. For maternal age and prepregnancy BMI variables, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years for maternal age, and 18, 21, 23, 26, and 33 kg/m² for prepregnancy BMI.

(DOCX)

Click here for additional data file.^{(21.3KB, docx)}

S5 Table. Sensitivity analysis—aRR for the association between IPI after a miscarriage and adverse pregnancy outcomes adjusted for covariates prior to IPI (n = 49,058).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of miscarriage (before interval). For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years for births after a miscarriage.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

S6 Table. Sensitivity analysis—aRR for the association between IPI after an induced abortion and adverse pregnancy outcomes adjusted for covariates prior to IPI (n = 23,707).

aRR, adjusted relative risk. BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of miscarriage (before interval). For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 18, 22, 25, 29, and 36 for births after an induced abortion.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

S7 Table. Sensitivity analysis—IPI after previous miscarriage and risk of adverse pregnancy outcomes accounting <6 months of IPI category (n = 49,058). aRR, adjusted relative risk.

BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years.

(DOCX)

Click here for additional data file.^{(19.9KB, docx)}

S8 Table. Sensitivity analysis—IPI after previous induced abortion and risk of adverse pregnancy outcomes accounting <6 months of IPI category (n = 23,707).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years.

(DOCX)

Click here for additional data file.^{(19KB, docx)}

S9 Table. Sensitivity analysis—IPI after previous miscarriages and risk of adverse pregnancy outcomes among births from women with only 1 miscarriage in the cohort (n = 47,411).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. *Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years. **E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

(DOCX)

Click here for additional data file.^{(21.9KB, docx)}

S10 Table. Sensitivity analysis—IPI after previous induced abortion and risk of adverse pregnancy outcomes among births from women with only 1 induced abortion in the cohort (n = 23,185).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years. **E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

(DOCX)

Click here for additional data file.^{(24.2KB, docx)}

Abbreviations

aRR: adjusted relative risk
BMI: body mass index
CI: confidence interval
GDM: gestational diabetes mellitus
HELLP: haemolysis, elevated liver enzymes, and low platelet count
ICD: International Classification of Diseases
IPI: interpregnancy interval
IQR: interquartile range
LBW: low birth weight
LGA: large for gestational age
OR: odds ratio
PTB: preterm birth
SGA: small for gestational age
WHO: World Health Organization

Data Availability

Study data are available on application. Information on how to apply and access data can be found from https://helsedata.no/. Data access is subject to compulsory ethics and governance approvals.

Funding Statement

This work was supported with funding from the Research Council of Norway through its Centres of Excellence funding scheme (#262700 to GAT, SEH, GP, and MCM, and #320656 to SEH and MCM). GAT is funded by the National Health and Medical Research Council Investigator Grant (#1195716) and the Charter Hall Collaborative Grant from the Raine Medical Research Foundation (#RCA02-20). GP is funded by the National Health and Medical Research Council Project (#1099655) and Investigator Grants (#1173991). MCM is funded by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (#947684). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Med. doi: 10.1371/journal.pmed.1004129.r001

Decision Letter 0

Louise Gaynor-Brook

6 May 2022

Dear Dr Tessema,

Thank you for submitting your manuscript entitled "Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by May 10 2022 11:59PM.

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

PLoS Med. doi: 10.1371/journal.pmed.1004129.r002

Decision Letter 1

Philippa Claire Dodd

17 Aug 2022

Dear Dr. Tessema,

Thank you very much for submitting your manuscript "Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions" (PMEDICINE-D-22-01509R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Sep 07 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

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Your article can be found in the "Submissions Needing Revision" folder.

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Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

pdodd@plos.org

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

GENERAL

Please revise your title to include the study design in the subtitle such as: “Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages and induced abortions: a cohort study”

As the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (this cannot be a study author).

Thank you for including an author summary we would suggest emphasizing as a final point in “what do these findings mean” that the results may prompt a review of guidelines, as we understand it

There are a number of typographical and grammatical errors throughout as detailed below and highlighted by the reviewers. Please check through the manuscript carefully for these errors

ABSTRACT METHODS and FINDINGS

Please include the main outcome measures and define any abbreviations used

Please quantify the main results with p values as well as 95% CIs

Please include the absolute risk(s) of relevant outcomes, not just relative risks (an example for absolute risk inclusion in the abstract can be found here: PMID: 28399126).

Please include the important dependent variables that are adjusted for in the analyses.

In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

MAIN MANUSCRIPT METHODS AND RESULTS

Participants and exclusions – line 3 please check grammar … “we left with” suggest adding “were”

Please provide p values as well as 95% CIs, where a p value is given please also specify the statistical test used to determine it

TABLES

Please define the numbers in brackets in table 1 [i.e. 384 (0.8)] ?median

Please define the numbers in brackets in table 2 [i.e 47,308 (94.0) ? percentage

Please provide the unadjusted comparisons as well as the adjusted comparisons in Table S3

FIGURES

Please provide titles and legends for each individual table and figures in the Supporting Information.

DISCUSSION

Some sentences throughout might benefit from shortening and re-wording to improve clarity and readability for example, in the Strengths and limitations of the study – the sentence on page 19 “…information were only available for pregnancies ending in the birth registry…” is a little confusing

Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. The general approach is fine, and I found some aspects commendable, but I do have some issues to resolve before I can recommend publication

NOTE: Line numbers would have made the review process easier

p. 2 "Log binomial" isn't the usual term. I would use "logistic", but this is not a big deal.

Not a stat issue, but SGA and other acronyms should be spelled out at first use.

p. 5 Where possible, please give the effect size estimates from the various studies you report on. The fact that some studies found a significant effect and others did not is not enough. See Andrew Gelman's paper "The difference between significant and nonsignificant is not, itself, significant". Also, where you say "no increased risk" please insert "significant" (or, if they found a decrease, say that).

p. 7 Do not categorize IPI. Doing so increases type I and type II error and introduces a kind of magical thinking. that something amazing happens at the cutpoints. See my article https://medium.com/@peterflom/what-happens-when-we-categorize-an-independent-variable-in-regression-77d4c5862b6c (the article is about linear regression, but applies to logistic as well). If you wish to report results by category, for comparison purposes, that's OK, but the analysis should use IPI as a number, and maybe use splines to look at nonlinearity. Splines could even find that the categories are bad ones.

p. 8 Same issue for age and BMI as for IPI. BMI could easily have nonlinear effects.

Congratulations for doing some sensitivity analyses. Not enough studies include them

I also commend the authors for not using stepwise or other automatic variable selection methods. They are deeply flawed.

How were the reference categories for the categorized continuous variables selected? I don't like categorization (see above) but, if you do categorize, there should be some stated reasons for choosing a reference category. The most usual choices are either the most common category or an extreme category. For IPI, both of those would suggest using < 3 month. Also, table 3 shows another problem with categorization - some of the cells are small sized, and the sizes vary a lot, so, the same OR can be significant in one category and not another.

Finally, figure 2 seems to be based on using IPI as a continuous measure. Both of these show very nonlinear relationships. This makes use of splines for IPI more important.

Reviewer #3: Delighted to review this manuscript that adds to the literature supporting early conception after miscarriage or induced abortion and calls into question WHO's guidance published in 2007.

Abstract: Please mention that only births following previous miscarriage/ induced abortion were looked at and not early pregnancy outcomes.

Author summary: "Available small studies exploring pregnancy outcomes after miscarriage (n<1,100) focused on the limited pregnancy outcomes such as recurrent miscarriage and preterm birth"- is this true? Some of the references cited have used larger datasets and the systematic review included many more pregnancies! This needs to be amended in the introduction section also. I feel the biggest strength of this study is in being able to look at IPI of <3 months and study outcomes following both miscarriage and induced abortion in the same population. "Our study suggests that conceiving within 6 months after a miscarriage or an induced abortion is not associated with increased risks of adverse pregnancy outcomes" - this should be reported in "what did the researchers find?" Perhaps highlight that this was true for IPI less than 3 months too?

Methods: The ICD codes used to identify miscarriage include Hydatidiform mole - these have completely different management and reproductive trajectory and should not be included in miscarriage. In the big scheme of things the numbers are probably too few to make any difference but if possible, the analyses should be repeated excluding these cases. Similarly, threatened abortion does not necessarily end in a miscarriage - in fact the vast majority of them don't. Not clear how more than one birth could have contributed to the index birth? Statistical analysis is appropriate and described well but could perhaps benefit from justifying why log binomial regression was used and relative risks calculated as effect measure particularly since the covariates adjusted for were at the time of the index pregnancy.

Results: I would prefer to see tables 1 and 2 separately for miscarriage and induced abortion with the characteristics and outcomes presented by IPI. As such the reader gets no idea as to what number (%) of outcomes occurred in each IPI category. Although, these are presented in table 3 and so table 2 is perhaps redundant? Table 3 should mention which covariates were adjusted for to calculate ARR. were the same covariates adjusted for in all the models? What was the rationale behind including these?

Discussion: A main strength of this study is the ability to study separately the effects of increasing IPI after miscarriage and induced abortion in the same population. This inevitably begs the question as to how confident researchers were that there was no or minimal misclassification. Looking at the codes used to identify the cases i am not convinced that there was not some mixing. However, given that similar findings were observed in both groups, this probably does not matter. Another strength is the ability to study outcomes in IPI <3 months. This again begs the question as to how confident the researchers were that the two pregnancies were not the same, particularly as i note that threatened miscarriage and bleeding in pregnancy were included as miscarriage. A recent publication had suggested that even the current guidance of waiting for at least one normal period after a miscarriage was not justified. Would the authors like to comment on that vis a vis guidance in Norway? Lee Reicher, Ronni Gamzu, Yuval Fouks, Ofer Isakov, Yariv Yogev, Sharon Maslovitz,The effects of a postmiscarriage menstrual period prior to reconceiving, American Journal of Obstetrics and Gynecology, Volume 223, Issue 3,2020, Pages 444.e1-444.e5,ISSN 0002-9378,

https://doi.org/10.1016/j.ajog.2020.06.051.

I would urge the authors to proof read the manuscript carefully as there are several missed words and typographical errors throughout. Some references are also not formatted correctly (Se ref 11)

Reviewer #4: Thank you for this well-written paper. I see this is a revision but cannot seem to access previous reviewer comments or responses. I have no further comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachment

Submitted filename: review_PlosMed.docx

Click here for additional data file.^{(12.9KB, docx)}

PLoS Med. 2022 Nov 22;19(11):e1004129. doi: 10.1371/journal.pmed.1004129.r003

Author response to Decision Letter 1

19 Sep 2022

Attachment

Submitted filename: Point by point response_R2.docx

Click here for additional data file.^{(86.7KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004129.r004

Decision Letter 2

Philippa Claire Dodd

14 Oct 2022

Dear Dr. Tessema,

Thank you very much for re-submitting your manuscript "Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008-2016): a cohort study" (PMEDICINE-D-22-01509R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by 2 reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Oct 21 2022 11:59PM.

Sincerely,

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Thank you for the opportunity to handle your manuscript and for your careful and considerate attention in addressing the previous reviewer and editor comments. There are some further minor revisions detailed below that require your attention prior to publication.

GENERAL

Thank you for reporting according to STROBE. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

ABSTRACT

Thank you for revising the abstract.

Thank you for including p-values. When reporting p-values please replace “p-value =…” with p = 0.07”. Please report p as <0.01 as opposed to p=0.00. Please check and amend throughout the abstract and main manuscript text

Thank you for including limitations of your data set. Please also include limitations of the study methodology (i.e. retrospective, observational etc), any problems with the use of registry data (reliability)?

AUTHOR SUMMARY

Thank you for revising the author summary

I suggest “review of current international….” instead of “revision”

METHODS and RESULTS

Table 1: Thank you making revisions. I suggest a few further thing. There seems to be a redundant third unfilled column on the right please remove this. Suggest relabeling the heading to column 2: “Number of participants” or something similar. Perhaps also include the total number of ppts in the table in an appropriate place.

DISCUSSION

Please remove sub headings and include the strengths and limitations section within the discussion which should be structured as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

Please remove the funding statement and COI from the end of the manuscript and include only in the submission form

REFERENCES

Please see our website for reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Please ensure journal name abbreviations are those found in the National Center for Biotechnology Information (NCBI) databases.

To help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.

Comments from the academic editor:

I have one remaining thing that I think they need to clarify. Their response to comment 4.2 in relation to gestational age (page 11) is, for me, inadequate. They refer to the gestational age of the miscarriage or induced abortion as a "confounder". But it is not. The gestational age at the time of the miscarriage or induced abortion is a determinant of the exposure. These events are broadly classified into first trimester and second trimester. The vast majority of both are first trimester. It seems plausible to me that later miscarriage or induced abortion (e.g. ~20 weeks) might be more like a previous birth where a very short IPI is thought to be associated with greater risks. I think that they need to spell out in the discussion that they were unable to sub-classify miscarriages or induced abortions by gestational age, that the vast majority will be first trimester and their results should be extrapolated cautiously to second trimester miscarriages or induced abortions.

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication

Reviewer #3: Many thanks for taking on board my comments and suggestions and revising the manuscript accordingly. I have no further comments and feel that this paper will add to the body of evidence supporting early conception following miscarriage and induced abortion.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2022 Nov 22;19(11):e1004129. doi: 10.1371/journal.pmed.1004129.r005

Author response to Decision Letter 2

18 Oct 2022

Attachment

Submitted filename: Point by point responses_R3.docx

Click here for additional data file.^{(32.9KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004129.r006

Decision Letter 3

Philippa Claire Dodd

19 Oct 2022

Dear Dr Tessema,

On behalf of my colleagues and the Academic Editor, Professor Gordon Smith, I am pleased to inform you that we have agreed to publish your manuscript "Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008-2016): a cohort study" (PMEDICINE-D-22-01509R3) in PLOS Medicine.

I noted two very minor further revisions to be made prior to publication. Please see below:

* Where you report statistics in the abstract, please insert a space between the text and the parentheses - see lines

28, 31, 32, 33, 35, 38

* Line 374 – suggest replacing “occurred” with “occurring” such that the sentence reads as follows: “Although the

gestational age at previous miscarriage or induced abortion affects the IPI, we did not have information on exact

gestational age for those miscarriages or induced abortions occurring before 12 weeks, which comprised 99% of

miscarriages and 96% of induced abortions.”

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 STROBE Checklist. STROBE checklist.

(DOCX)

Click here for additional data file.^{(33.7KB, docx)}

S1 Table. Adverse pregnancy outcomes after miscarriages between 2008 and 2016 in Norway (n = 49,058).

(DOCX)

Click here for additional data file.^{(14.7KB, docx)}

S2 Table. Adverse pregnancy outcomes after induced abortion between 2008 and 2016 in Norway (n = 23,707).

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

(DOCX)

Click here for additional data file.^{(30.1KB, docx)}

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, parity, year of birth, maternal smoking during pregnancy, and prepregnancy BMI at the time of birth after interval. For maternal age and prepregnancy BMI variables, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years for maternal age, and 18, 21, 23, 26, and 33 kg/m² for prepregnancy BMI.

(DOCX)

Click here for additional data file.^{(21.3KB, docx)}

S5 Table. Sensitivity analysis—aRR for the association between IPI after a miscarriage and adverse pregnancy outcomes adjusted for covariates prior to IPI (n = 49,058).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of miscarriage (before interval). For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years for births after a miscarriage.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

S6 Table. Sensitivity analysis—aRR for the association between IPI after an induced abortion and adverse pregnancy outcomes adjusted for covariates prior to IPI (n = 23,707).

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

S7 Table. Sensitivity analysis—IPI after previous miscarriage and risk of adverse pregnancy outcomes accounting <6 months of IPI category (n = 49,058). aRR, adjusted relative risk.

(DOCX)

Click here for additional data file.^{(19.9KB, docx)}

S8 Table. Sensitivity analysis—IPI after previous induced abortion and risk of adverse pregnancy outcomes accounting <6 months of IPI category (n = 23,707).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years.

(DOCX)

Click here for additional data file.^{(19KB, docx)}

S9 Table. Sensitivity analysis—IPI after previous miscarriages and risk of adverse pregnancy outcomes among births from women with only 1 miscarriage in the cohort (n = 47,411).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. *Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 21, 26, 30, 33, and 40 years. **E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

(DOCX)

Click here for additional data file.^{(21.9KB, docx)}

S10 Table. Sensitivity analysis—IPI after previous induced abortion and risk of adverse pregnancy outcomes among births from women with only 1 induced abortion in the cohort (n = 23,185).

aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; IPI, interpregnancy interval; LGA, large for gestational age; PTB, preterm birth; RR, relative risk; SGA, small for gestational age. *Births with nonspontaneous preterm outcomes were excluded when defining spontaneous PTB. **Adjusted for maternal age, gravidity, and year of birth at the time of birth after interval. For maternal age, we used restricted cubic splines with 5 knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles in the study population, which corresponds to 20, 25, 28, 32, and 38 years. **E-values for unmeasured confounding for the association between IPI after miscarriage and induced abortion and adverse pregnancy outcomes.

(DOCX)

Click here for additional data file.^{(24.2KB, docx)}

Attachment

Submitted filename: review_PlosMed.docx

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Attachment

Submitted filename: Point by point response_R2.docx

Click here for additional data file.^{(86.7KB, docx)}

Attachment

Submitted filename: Point by point responses_R3.docx

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Data Availability Statement

Study data are available on application. Information on how to apply and access data can be found from https://helsedata.no/. Data access is subject to compulsory ethics and governance approvals.

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PERMALINK

Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008–2016): A cohort study

Gizachew A Tessema

Siri E Håberg

Gavin Pereira

Annette K Regan

Jennifer Dunne

Maria C Magnus

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Study design and data sources

Participants and exclusions

Fig 1. Flow chart for selection of births following miscarriages and induced abortions between 2008 and 2016 in Norway.

Exposure

Outcomes

Statistical analysis

Ethics statement

Results

Maternal characteristics at the time of birth after miscarriages and induced abortions

Table 1. Characteristics for women with births after miscarriage and induced abortion at the time of birth after the IPI for births between 2008 and 2016 in Norway (n = 49,058).

Table 2. Characteristics for women with births after induced abortion at the time of birth after the IPI for births between 2008 and 2016 in Norway (n = 23,707).

Previous miscarriage

Fig 2. Kernel density distributions of interpregnancy interval after miscarriages and induced abortions for births between 2008 and 2016 in Norway.

Table 3. IPI after previous miscarriage and risk of adverse pregnancy outcomes for births between 2008 and 2016 in Norway (n = 49,058).

Previous induced abortion

Table 4. IPI after previous induced abortion and risk of adverse pregnancy outcomes for births between 2008 and 2016 in Norway (n = 23,707).

Sensitivity analysis

Discussion

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Louise Gaynor-Brook

Roles

Decision Letter 1

Philippa Claire Dodd

Roles

Author response to Decision Letter 1

Decision Letter 2

Philippa Claire Dodd

Roles

Author response to Decision Letter 2

Decision Letter 3

Philippa Claire Dodd

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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